Publications by authors named "Annika Lindblom"

262 Publications

Gene-Environment Interactions Relevant to Estrogen and Risk of Breast Cancer: Can Gene-Environment Interactions Be Detected Only among Candidate SNPs from Genome-Wide Association Studies?

Cancers (Basel) 2021 May 14;13(10). Epub 2021 May 14.

Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, 2730 Herlev, Denmark.

In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (-2df = 1.2 × 10). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (-2df = 1.1 × 10). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.
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http://dx.doi.org/10.3390/cancers13102370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156547PMC
May 2021

Massive parallel sequencing in a family with rectal cancer.

Hered Cancer Clin Pract 2021 Apr 7;19(1):23. Epub 2021 Apr 7.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Solna, Stockholm, Sweden.

Background: We have previously reported a family with a suspected autosomal dominant rectal and gastric cancer syndrome without any obvious causative genetic variant. Here, we focused the study on a potentially isolated rectal cancer syndrome in this family.

Methods: We included seven family members (six obligate carriers). Whole-exome sequencing and whole-genome sequencing data were analyzed and filtered for shared coding and splicing sequence and structural variants among the affected individuals.

Results: When considering family members with rectal cancer or advanced adenomas as affected, we found six new potentially cancer-associated variants in the genes CENPB, ZBTB20, CLINK, LRRC26, TRPM1, and NPEPL1. All variants were missense variants and none of the genes have previously been linked to inherited rectal cancer. No structural variant was found.

Conclusion: By massive parallel sequencing in a family suspected of carrying a highly penetrant rectal cancer predisposing genetic variant, we found six genetic missense variants with a potential connection to the rectal cancer in this family. One of them could be a high-risk genetic variant, or one or more of them could be low risk variants. The p.(Glu438Lys) variant in the CENPB gene was found to be of particular interest. The CENPB protein binds DNA and helps form centromeres during mitosis. It is involved in the WNT signaling pathway, which is critical for colorectal cancer development and its role in inherited rectal cancer needs to be further examined.
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http://dx.doi.org/10.1186/s13053-021-00181-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028209PMC
April 2021

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Am J Clin Nutr 2021 06;113(6):1490-1502

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.

Objectives: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.

Conclusions: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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http://dx.doi.org/10.1093/ajcn/nqab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168352PMC
June 2021

Identification of known and novel familial cancer genes in Swedish colorectal cancer families.

Int J Cancer 2021 Aug 25;149(3):627-634. Epub 2021 Mar 25.

Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.

Identifying new candidate colorectal cancer (CRC) genes and mutations are important for clinical cancer prevention as well as in cancer care. Genetic counseling is already implemented for known high-risk variants; however, the majority of CRC are of unknown causes. In our study, 110 CRC patients in 55 Swedish families with a strong history of CRC but unknown genetic causes were analyzed with the aim of identifying novel candidate CRC predisposing genes. Exome sequencing was used to identify rare and high-impact variants enriched in the families. No clear pathogenic variants were found in known CRC predisposing genes; however, potential pathogenic variants in novel CRC predisposing genes were identified. Over 3000 variants with minor allele frequency (MAF) <0.01 and Combined Annotation Dependent Depletion (CADD) > 20 were seen aggregating in the CRC families. Of those, 27 variants with MAF < 0.001 and CADD>25 were considered high-risk mutations. Interestingly, more than half of the high-risk variants were detected in three families, suggesting cumulating contribution of several variants to CRC. In summary, our study shows that despite a strong history of CRC within families, identifying pathogenic variants is challenging. In a small number of families, few rare mutations were shared by affected family members. This could indicate that in the absence of known CRC predisposing genes, a cumulating contribution of mutations leads to CRC observed in these families.
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http://dx.doi.org/10.1002/ijc.33567DOI Listing
August 2021

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

Gut 2021 Jul 25;70(7):1325-1334. Epub 2021 Feb 25.

Cancer Prevention and Control Program, Catalan Institute of Oncology - IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.

Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.

Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.

Results: We identified 13 loci that reached genome-wide significance (p<5×10) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.

Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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http://dx.doi.org/10.1136/gutjnl-2020-321534DOI Listing
July 2021

Breast Cancer Risk Factors and Survival by Tumor Subtype: Pooled Analyses from the Breast Cancer Association Consortium.

Cancer Epidemiol Biomarkers Prev 2021 Apr 26;30(4):623-642. Epub 2021 Jan 26.

Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype.

Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype.

Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype ( > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5-25 kg/m [HR (95% confidence interval (CI), 1.19 (1.06-1.34)]; current versus never smoking [1.37 (1.27-1.47)], high versus low physical activity [0.43 (0.21-0.86)], age ≥30 years versus <20 years at first pregnancy [0.79 (0.72-0.86)]; >0-<5 years versus ≥10 years since last full-term birth [1.31 (1.11-1.55)]; ever versus never use of oral contraceptives [0.91 (0.87-0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen-progestin therapy [0.61 (0.54-0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02-1.21) for current versus never smoking.

Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype.

Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026532PMC
April 2021

Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women.

N Engl J Med 2021 02 20;384(5):428-439. Epub 2021 Jan 20.

The authors' affiliations are as follows: the Centre for Cancer Genetic Epidemiology, Departments of Public Health and Primary Care (L.D., S. Carvalho, J.A., K.A.P., Q.W., M.K.B., J.D., B.D., N. Mavaddat, K. Michailidou, A.C.A., P.D.P.P., D.F.E.) and Oncology (C.L., P.A.H., C. Baynes, D.M.C., L.F., V.R., M. Shah, P.D.P.P., A.M.D., D.F.E.), University of Cambridge, Cambridge, the Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine (A. Campbell, D.J.P.), and the Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology (D.J.P.), University of Edinburgh, the Cancer Research UK Edinburgh Centre (D.A.C., J.F.), and the Usher Institute of Population Health Sciences and Informatics, University of Edinburgh Medical School (A. Campbell, J.F.), Edinburgh, the Divisions of Informatics, Imaging, and Data Sciences (E.F.H.), Cancer Sciences (A. Howell), Population Health, Health Services Research, and Primary Care (A. Lophatananon, K. Muir), and Evolution and Genomic Sciences, School of Biological Sciences (W.G.N., E.M.V., D.G.E.), University of Manchester, the NIHR Manchester Biomedical Research Unit (E.F.H.) and the Nightingale Breast Screening Centre, Wythenshawe Hospital (E.F.H., H.I.), Academic Health Science Centre and North West Genomics Laboratory Hub, and the Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust (W.G.N., E.M.V., D.G.E.), Manchester, the School of Cancer and Pharmaceutical Sciences, Comprehensive Cancer Centre, Guy's Campus, King's College London, London (E.J.S.), the Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham (I.T.), and the Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford (I.T.) - all in the United Kingdom; the Human Genotyping-CEGEN Unit, Human Cancer Genetic Program (A.G.-N., M.R.A., N.Á., B.H., R.N.-T.), and the Human Genetics Group (V.F., A.O., J.B.), Spanish National Cancer Research Center, Centro de Investigación en Red de Enfermedades Raras (A.O., J.B.), Servicio de Oncología Médica, Hospital Universitario La Paz (M.P.Z.), and Molecular Oncology Laboratory, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (M. de la Hoya), Madrid, the Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario Universitario de Santiago (A. Carracedo, M.G.-D.), and Centro de Investigación en Red de Enfermedades Raras y Centro Nacional de Genotipado, Universidad de Santiago de Compostela (A. Carracedo), Santiago de Compostela, the Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur, Xerencia de Xestion Integrada de Vigo-Servizo Galeo de Saúde, Vigo (J.E.C.), and Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo (J.I.A.P.) - all in Spain; the Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund (C. Wahlström, J.V., M.L., T. Törngren, Å.B., A.K.), the Department of Oncology, Örebro University Hospital, Örebro (C. Blomqvist), and the Departments of Medical Epidemiology and Biostatistics (K.C., M.E., M.G., P. Hall, W.H., K.H.), Oncology, Södersjukhuset (P. Hall, S. Margolin), Molecular Medicine and Surgery (A. Lindblom), and Clinical Science and Education, Södersjukhuset (S. Margolin, C. Wendt), Karolinska Institutet, and the Department of Clinical Genetics, Karolinska University Hospital (A. Lindblom), Stockholm - all in Sweden; the Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD (M.T.P., C.F., G.C.-T., A.B.S.), the Cancer Epidemiology Division, Cancer Council Victoria (G.G.G., R.J.M., R.L.M.), the Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health (G.G.G., R.J.M., R.L.M.), and the Department of Clinical Pathology (M.C.S.), University of Melbourne, Anatomical Pathology, Alfred Hospital (C.M.), and the Cancer Epidemiology Division, Cancer Council Victoria (M.C.S.), Melbourne, VIC, and Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC (G.G.G., M.C.S., R.L.M.) - all in Australia; the Division of Molecular Pathology (R.K., S. Cornelissen, M.K.S.), Family Cancer Clinic (F.B.L.H., L.E.K.), Department of Epidemiology (M.A.R.), and Division of Psychosocial Research and Epidemiology (M.K.S.), the Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Division Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Center, Utrecht (M.G.E.M.A.), the Department of Clinical Genetics, Erasmus University Medical Center (J.M.C., A.M.W.O.), and the Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute (B.A.M.H.-G., A. Hollestelle, M.J.H.), Rotterdam, the Department of Clinical Genetics, Maastricht University Medical Center, Maastricht (E.B.G.G.), the Departments of Human Genetics (I.M.M.L., M.P.G.V., P.D.), Clinical Genetics (C.J.A.), and Pathology (P.D.), Leiden University Medical Center, Leiden, the Department of Human Genetics, Radboud University Medical Center, Nijmegen (A.R.M.), and the Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen (J.C.O.) - all in the Netherlands; the Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute (B.D.), and the Division of Cancer Epidemiology and Genetics, National Cancer Institute (T.A., S.J.C., X.R.Y., M.G.-C.), National Institutes of Health, Bethesda, MD; the Department of Pathology, Brigham and Women's Hospital, Harvard Medical School (B.D.), and the Department of Nutrition, Harvard T.H. Chan School of Public Health (R.M.V.D.), Boston; the Departments of Clinical Genetics (K.A.), Oncology (C. Blomqvist), and Obstetrics and Gynecology (H.N., M. Suvanto), Helsinki University Hospital, University of Helsinki, Helsinki, and the Unit of Clinical Oncology, Kuopio University Hospital (P. Auvinen), the Institute of Clinical Medicine, Oncology (P. Auvinen), the Translational Cancer Research Area (J.M.H., V.-M.K., A. Mannermaa), and the Institute of Clinical Medicine, Pathology, and Forensic Medicine (J.M.H., V.-M.K., A. Mannermaa), University of Eastern Finland, and the Biobank of Eastern Finland, Kuopio University Hospital (V.-M.K., A. Mannermaa), Kuopio - both in Finland; the N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus (N.N.A., N.V.B.); the Department of Gynecology and Obstetrics and Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel (N.A.), the Institute of Medical Biometry and Epidemiology (H. Becher) and Cancer Epidemiology Group (T.M., J.C.-C.), University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, the Department of Gynecology and Obstetrics (M.W.B., P.A.F., L.H.) and Institute of Human Genetics (A.B.E.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-European Metropolitan Region of Nuremberg, Erlangen, the Division of Cancer Epidemiology (S.B., A. Jung, P.M.K., J.C.-C.), Molecular Epidemiology Group, C080 (B. Burwinkel, H.S.), Division of Pediatric Neurooncology (A.F.), and Molecular Genetics of Breast Cancer (U.H., M.M., M.U.R., D.T.), German Cancer Research Center, Molecular Biology of Breast Cancer, University Women's Clinic Heidelberg, University of Heidelberg (B. Burwinkel, A.S., H.S.), Hopp Children's Cancer Center (A.F.), Faculty of Medicine, University of Heidelberg (P.M.K.), and National Center for Tumor Diseases, University Hospital and German Cancer Research Center (A.S., C.S.), Heidelberg, the Department of Radiation Oncology (N.V.B., M. Bremer, H.C.) and the Gynecology Research Unit (N.V.B., T.D., P. Hillemanns, T.-W.P.-S., P.S.), Hannover Medical School, Hannover, the Institute of Human Genetics, University of Münster, Münster (N.B.-M.), Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart (H. Brauch, W.-Y.L.), iFIT-Cluster of Excellence, University of Tübingen, and the German Cancer Consortium, German Cancer Research Center, Partner Site Tübingen (H. Brauch), and the University of Tübingen (W.-Y.L.), Tübingen, Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum, Bochum (T.B.), Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig (C.E.), Center for Hereditary Breast and Ovarian Cancer (E.H., R.K.S.) and Center for Integrated Oncology (E.H., R.K.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, the Department of Internal Medicine, Evangelische Kliniken Bonn, Johanniter Krankenhaus, Bonn (Y.-D.K.), the Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich (A. Meindl), and the Institute of Pathology, Städtisches Klinikum Karlsruhe, Karlsruhe (T.R.) - all in Germany; the Gynecological Cancer Registry, Centre Georges-François Leclerc, Dijon (P. Arveux), and the Center for Research in Epidemiology and Population Health, Team Exposome and Heredity, INSERM, University Paris-Saclay, Villejuif (E.C.-D., P.G., T. Truong) - both in France; the Institute of Biochemistry and Genetics, Ufa Federal Research Center of the Russian Academy of Sciences (M. Bermisheva, E.K.), the Department of Genetics and Fundamental Medicine, Bashkir State University (E.K., D.P., Y.V.), and the Ufa Research Institute of Occupational Health and Human Ecology (Y.V.), Ufa, Russia; the Department of Genetics and Pathology (K.B., A. Jakubowska, J. Lubiński, K.P.) and the Independent Laboratory of Molecular Biology and Genetic Diagnostics (A. Jakubowska), Pomeranian Medical University, Szczecin, Poland; the Copenhagen General Population Study, the Department of Clinical Biochemistry (S.E.B., B.G.N.), and the Department of Breast Surgery (H.F.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, and the Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (S.E.B., B.G.N.) - both in Denmark; the Division of Cancer Prevention and Genetics, European Institute of Oncology Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) (B. Bonanni), the Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (S. Manoukian), the Genome Diagnostics Program, FIRC Institute of Molecular Oncology (P.P.), and the Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (P.R.), Milan; the Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet (A.-L.B.-D., G.I.G.A., V.N.K.), and the Institute of Clinical Medicine, Faculty of Medicine, University of Oslo (A.-L.B.-D., V.N.K.), Oslo; Medical Faculty, Universidad de La Sabana (I.B.), and the Clinical Epidemiology and Biostatistics Department (F.G.) and Institute of Human Genetics (D.T.), Pontificia Universidad Javeriana, Bogota, Colombia; the Department of Internal Medicine and Huntsman Cancer Institute, University of Utah (N.J.C., M.J.M., J.A.W.), and the Intermountain Healthcare Biorepository and Department of Pathology, Intermountain Healthcare (M.H.C.), Salt Lake City; the David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California, Los Angeles (P.A.F.), and Moores Cancer Center (M.G.-D., M.E.M.) and the Department of Family Medicine and Public Health (M.E.M.), University of California San Diego, La Jolla; the Departments of Medical Oncology (V.G., D.M.) and Pathology (M.T.), University Hospital of Heraklion, Heraklion, and the Department of Oncology, University Hospital of Larissa, Larissa (E.S.) - both in Greece; the Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital (G.G., I.L.A.), the Departments of Laboratory Medicine and Pathobiology (A.M.M.) and Molecular Genetics (I.L.A.), University of Toronto, and the Laboratory Medicine Program, University Health Network (A.M.M.), Toronto, and the Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, QC (J.S.) - both in Canada; the Department of Electron Microscopy and Molecular Pathology (A. Hadjisavvas, K.K., M.A.L.), the Cyprus School of Molecular Medicine (A. Hadjisavvas, K.K., M.A.L., K. Michailidou), and the Biostatistics Unit (K. Michailidou), Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; the Saw Swee Hock School of Public Health (M. Hartman, R.M.V.D.) and the Department of Medicine, Yong Loo Lin School of Medicine (R.M.V.D.), National University of Singapore, the Department of Surgery, National University Health System (M. Hartman, J. Li), and the Human Genetics Division, Genome Institute of Singapore (J. Li), Singapore; the Department of Mathematical Sciences, Faculty of Science and Engineering, University of Nottingham Malaysia (W.K.H.), and the Breast Cancer Research Programme, Cancer Research Malaysia (W.K.H., P.S.N., S.-Y.Y., S.H.T.), Selangor, and the Breast Cancer Research Unit, Cancer Research Institute (N.A.M.T.), and the Department of Surgery, Faculty of Medicine (N.A.M.T., P.S.N., S.H.T.), University Malaya, Kuala Lumpur - both in Malaysia; Surgery, School of Medicine, National University of Ireland, Galway (M.J.K., N. Miller); the Department of Surgery, Daerim Saint Mary's Hospital (S.-W.K.), the Department of Surgery, Ulsan University College of Medicine and Asan Medical Center (J.W.L.), the Department of Surgery, Soonchunhyang University College of Medicine and Soonchunhyang University Hospital (M.H.L.), Integrated Major in Innovative Medical Science, Seoul National University College of Medicine (S.K.P.), and the Cancer Research Institute, Seoul National University (S.K.P.), Seoul, South Korea; the Department of Basic Sciences, Shaukat Khanum Memorial Cancer Hospital and Research Center, Lahore, Pakistan (M.U.R.); and the National Cancer Institute, Ministry of Public Health, Nonthaburi, Thailand (S.T.).

Background: Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.

Methods: We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.

Results: Protein-truncating variants in 5 genes (, , , , and ) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (, , , and ) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in and , odds ratios were higher for estrogen receptor (ER)-positive disease than for ER-negative disease; for protein-truncating variants in , , , , , and , odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in , , and were associated with a risk of breast cancer overall with a P value of less than 0.001. For , , and , missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.

Conclusions: The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.).
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http://dx.doi.org/10.1056/NEJMoa1913948DOI Listing
February 2021

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study.

BMC Med 2020 12 17;18(1):396. Epub 2020 Dec 17.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.

Methods: We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.

Results: In sex-specific MR analyses, higher BMI (per 4.2 kg/m) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.

Conclusions: Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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http://dx.doi.org/10.1186/s12916-020-01855-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745469PMC
December 2020

A Combined Proteomics and Mendelian Randomization Approach to Investigate the Effects of Aspirin-Targeted Proteins on Colorectal Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Mar 14;30(3):564-575. Epub 2020 Dec 14.

Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.

Background: Evidence for aspirin's chemopreventative properties on colorectal cancer (CRC) is substantial, but its mechanism of action is not well-understood. We combined a proteomic approach with Mendelian randomization (MR) to identify possible new aspirin targets that decrease CRC risk.

Methods: Human colorectal adenoma cells (RG/C2) were treated with aspirin (24 hours) and a stable isotope labeling with amino acids in cell culture (SILAC) based proteomics approach identified altered protein expression. Protein quantitative trait loci (pQTLs) from INTERVAL ( = 3,301) and expression QTLs (eQTLs) from the eQTLGen Consortium ( = 31,684) were used as genetic proxies for protein and mRNA expression levels. Two-sample MR of mRNA/protein expression on CRC risk was performed using eQTL/pQTL data combined with CRC genetic summary data from the Colon Cancer Family Registry (CCFR), Colorectal Transdisciplinary (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls).

Results: Altered expression was detected for 125/5886 proteins. Of these, aspirin decreased MCM6, RRM2, and ARFIP2 expression, and MR analysis showed that a standard deviation increase in mRNA/protein expression was associated with increased CRC risk (OR: 1.08, 95% CI, 1.03-1.13; OR: 3.33, 95% CI, 2.46-4.50; and OR: 1.15, 95% CI, 1.02-1.29, respectively).

Conclusions: MCM6 and RRM2 are involved in DNA repair whereby reduced expression may lead to increased DNA aberrations and ultimately cancer cell death, whereas ARFIP2 is involved in actin cytoskeletal regulation, indicating a possible role in aspirin's reduction of metastasis.

Impact: Our approach has shown how laboratory experiments and population-based approaches can combine to identify aspirin-targeted proteins possibly affecting CRC risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086774PMC
March 2021

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

Gastroenterology 2021 Mar 12;160(4):1164-1178.e6. Epub 2020 Oct 12.

Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Background And Aims: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes.

Methods: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted.

Results: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis.

Conclusions: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.
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http://dx.doi.org/10.1053/j.gastro.2020.08.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956223PMC
March 2021

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk.

Am J Hum Genet 2020 11 5;107(5):837-848. Epub 2020 Oct 5.

Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong; Hong Kong Sanatorium and Hospital, Department of Pathology, Happy Valley, Hong Kong.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS was quantified using Cox regression analyses. We assessed PRS interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10 percentile and 20.5% at the 90 percentile of PRS. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675034PMC
November 2020

Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses.

BMC Med 2020 09 3;18(1):229. Epub 2020 Sep 3.

Public Health Directorate, Asturias, Spain.

Background: Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex.

Methods: In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P < 5 × 10) with circulating total bilirubin were instrumented in a 2-sample MR to test for a potential causal effect of bilirubin on CRC risk in 52,775 CRC cases and 45,940 matched controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colon Cancer Family Registry (CCFR), and the Colorectal Transdisciplinary (CORECT) study.

Results: The associations between circulating UCB levels and CRC risk differed by sex (P = 0.008). Among men, higher levels of UCB were positively associated with CRC risk (odds ratio [OR] = 1.19, 95% confidence interval [CI] = 1.04-1.36; per 1-SD increment of log-UCB). In women, an inverse association was observed (OR = 0.86 (0.76-0.97)). In the MR analysis of the main UGT1A1 SNP (rs6431625), genetically predicted higher levels of total bilirubin were associated with a 7% increase in CRC risk in men (OR = 1.07 (1.02-1.12); P = 0.006; per 1-SD increment of total bilirubin), while there was no association in women (OR = 1.01 (0.96-1.06); P = 0.73). Raised bilirubin levels, predicted by instrumental variables excluding rs6431625, were suggestive of an inverse association with CRC in men, but not in women. These differences by sex did not reach formal statistical significance (P ≥ 0.2).

Conclusions: Additional insight into the relationship between circulating bilirubin and CRC is needed in order to conclude on a potential causal role of bilirubin in CRC development.
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http://dx.doi.org/10.1186/s12916-020-01703-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469292PMC
September 2020

Mendelian randomization analyses suggest a role for cholesterol in the development of endometrial cancer.

Int J Cancer 2021 01 7;148(2):307-319. Epub 2020 Aug 7.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia, USA.

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.
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http://dx.doi.org/10.1002/ijc.33206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757859PMC
January 2021

Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Am J Hum Genet 2020 09 5;107(3):432-444. Epub 2020 Aug 5.

School of Public Health, Imperial College London, London SW7 2AZ, UK.

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.
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http://dx.doi.org/10.1016/j.ajhg.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477007PMC
September 2020

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

Sci Rep 2020 06 16;10(1):9688. Epub 2020 Jun 16.

Department of Gynecology and Obstetrics, University of Tübingen, Tübingen, Germany.

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR = 1.035, 95% CI = 0.859-1.246, P = 0.718 and OR = 0.798, 95% CI = 0.482-1.322, P = 0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.
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http://dx.doi.org/10.1038/s41598-020-65665-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297796PMC
June 2020

Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.

Lancet 2020 06;395(10240):1855-1863

Division of Haematology and Immunology, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.

Background: Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population.

Methods: In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990.

Findings: Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43-0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39-0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34-0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31-0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43-0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously.

Interpretation: The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results.

Funding: Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.
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http://dx.doi.org/10.1016/S0140-6736(20)30366-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294238PMC
June 2020

Increased risk for uterine cancer among first-degree relatives to Swedish gastric cancer patients.

Hered Cancer Clin Pract 2020 5;18:12. Epub 2020 Jun 5.

Division of Surgery, Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institutet and Department of Surgery, Norrtälje Hospital, Norrtälje, Sweden.

Purpose: In order to further understand genetically predisposing factors of gastric cancer, a retrospective study on 107 patients with gastric cancer was conducted. The family history of cancer cases was registered, in search of associations between gastric cancer and other cancer types.

Materials And Methods: Within Stockholm County in Sweden, all patients previously diagnosed with gastric cancer and still alive were invited to participate in the study. Patients were asked to complete a questionnaire about their gastric cancer diagnosis and if any cancers had occurred in their family. A blood sample for DNA extraction was collected. The proportions of different cancer types in the relatives of the patients were compared to the general Swedish population in 1970 and 2010.

Results: Among first- and second-degree relatives to the index patients with gastric cancer, the frequency of uterine cancer as well as gastric cancer was significantly overrepresented compared to the general population in Sweden. The frequency of breast cancer was significantly lower.

Conclusions: There seems to be an increased risk of both gastric cancer and uterine cancer in the families of gastric cancer survivors, indicating a possible hereditary connection between these two cancer types.
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http://dx.doi.org/10.1186/s13053-020-00145-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275318PMC
June 2020

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Nat Genet 2020 06 18;52(6):572-581. Epub 2020 May 18.

Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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http://dx.doi.org/10.1038/s41588-020-0609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808397PMC
June 2020

Prediction of contralateral breast cancer: external validation of risk calculators in 20 international cohorts.

Breast Cancer Res Treat 2020 Jun 11;181(2):423-434. Epub 2020 Apr 11.

Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Background: Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC).

Methods: We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope.

Results: The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula.

Conclusions: Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low- and high-CBC risk patients for clinical decision-making.
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http://dx.doi.org/10.1007/s10549-020-05611-8DOI Listing
June 2020

Mendelian Randomization of Circulating Polyunsaturated Fatty Acids and Colorectal Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 04 12;29(4):860-870. Epub 2020 Feb 12.

Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.

Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk.

Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined.

Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [OR = 0.96; 95% confidence interval (CI) = 0.93-0.98; = 5.2 × 10] and α-linolenic acid (OR = 0.95; 95% CI = 0.92-0.97; = 5.4 × 10), whereas modest increased risks were observed for arachidonic (OR = 1.06; 95% CI = 1.03-1.08; = 3.3 × 10), eicosapentaenoic (OR = 1.04; 95% CI = 1.01-1.07; = 2.5 × 10), and docosapentaenoic acids (OR = 1.03; 95% CI = 1.01-1.06; = 1.2 × 10). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses.

Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk.

Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125012PMC
April 2020

Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis.

Nat Commun 2020 01 30;11(1):597. Epub 2020 Jan 30.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.
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http://dx.doi.org/10.1038/s41467-020-14389-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992637PMC
January 2020

A network analysis to identify mediators of germline-driven differences in breast cancer prognosis.

Nat Commun 2020 01 16;11(1):312. Epub 2020 Jan 16.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
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http://dx.doi.org/10.1038/s41467-019-14100-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965101PMC
January 2020

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Nat Genet 2020 01 7;52(1):56-73. Epub 2020 Jan 7.

Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
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http://dx.doi.org/10.1038/s41588-019-0537-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974400PMC
January 2020

Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses.

Gastroenterology 2020 04 27;158(5):1300-1312.e20. Epub 2019 Dec 27.

Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.

Background & Aims: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development.

Methods: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2.

Conclusions: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.
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http://dx.doi.org/10.1053/j.gastro.2019.12.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152801PMC
April 2020

Cumulative Burden of Colorectal Cancer-Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer.

Gastroenterology 2020 04 19;158(5):1274-1286.e12. Epub 2019 Dec 19.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington.

Background & Aims: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.

Methods: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.

Results: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 × 10). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.

Conclusions: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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http://dx.doi.org/10.1053/j.gastro.2019.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103489PMC
April 2020

Prediction and clinical utility of a contralateral breast cancer risk model.

Breast Cancer Res 2019 12 17;21(1):144. Epub 2019 Dec 17.

VIB Center for Cancer Biology, VIB, Leuven, Belgium.

Background: Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making.

Methods: We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility.

Results: In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52-0.74; at 10 years, 0.53-0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62-1.37), and the calibration slope was 0.90 (95% PI: 0.73-1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52-0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4-10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers.

Conclusions: We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.
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http://dx.doi.org/10.1186/s13058-019-1221-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918633PMC
December 2019

Identification of Novel Loci and New Risk Variant in Known Loci for Colorectal Cancer Risk in East Asians.

Cancer Epidemiol Biomarkers Prev 2020 02 11;29(2):477-486. Epub 2019 Dec 11.

Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.

Background: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians.

Methods: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians.

Results: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at × 10 in Asians ( per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 ( = 7.7 × 10). Of the remaining 59 variants, 12 showed an association at < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at < 5 × 10 and two variants with an association near the genome-wide significance level (rs60911071, = 5.8 × 10; rs62558833, = 7.5 × 10) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS.

Conclusions: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously.

Impact: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571256PMC
February 2020

Systematic meta-analyses, field synopsis and global assessment of the evidence of genetic association studies in colorectal cancer.

Gut 2020 08 9;69(8):1460-1471. Epub 2019 Dec 9.

School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Objective: To provide an understanding of the role of common genetic variations in colorectal cancer (CRC) risk, we report an updated field synopsis and comprehensive assessment of evidence to catalogue all genetic markers for CRC (CRCgene2).

Design: We included 869 publications after parallel literature review and extracted data for 1063 polymorphisms in 303 different genes. Meta-analyses were performed for 308 single nucleotide polymorphisms (SNPs) in 158 different genes with at least three independent studies available for analysis. Scottish, Canadian and Spanish data from genome-wide association studies (GWASs) were incorporated for the meta-analyses of 132 SNPs. To assess and classify the credibility of the associations, we applied the Venice criteria and Bayesian False-Discovery Probability (BFDP). Genetic associations classified as 'positive' and 'less-credible positive' were further validated in three large GWAS consortia conducted in populations of European origin.

Results: We initially identified 18 independent variants at 16 loci that were classified as 'positive' polymorphisms for their highly credible associations with CRC risk and 59 variants at 49 loci that were classified as 'less-credible positive' SNPs; 72.2% of the 'positive' SNPs were successfully replicated in three large GWASs and the ones that were not replicated were downgraded to 'less-credible' positive (reducing the 'positive' variants to 14 at 11 loci). For the remaining 231 variants, which were previously reported, our meta-analyses found no evidence to support their associations with CRC risk.

Conclusion: The CRCgene2 database provides an updated list of genetic variants related to CRC risk by using harmonised methods to assess their credibility.
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http://dx.doi.org/10.1136/gutjnl-2019-319313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398467PMC
August 2020