Publications by authors named "Angela Cox"

200 Publications

Patterns and rates of confirmed transfer of care of patients with Juvenile Idiopathic Arthritis at a tertiary paediatric rheumatology centre.

Intern Med J 2021 Sep 8. Epub 2021 Sep 8.

Rheumatology Service, Department of General Medicine, Royal Children's Hospital, 50 Flemington Rd, Parkville, Melbourne, VIC, 3052, Australia.

Background: Disease activity in Juvenile Idiopathic Arthritis (JIA) commonly persists into adulthood. Transfer of JIA patients to adult healthcare services can be challenging, with prior studies showing poor rates of success.

Aims: This audit sought to examine characteristics of patients undergoing transfer of care within the rheumatology unit at the Royal Children's Hospital (RCH) in Melbourne, with the aim of identifying areas for improvement. Specifically, we sought to determine the rate at which confirmation of established care with an adult service (confirmed transfer of care) was documented in the patient chart.

Methods: Patients with a diagnosis of JIA who turned 18 years of age between 2012-2019 were identified. A chart review was undertaken to collect relevant data.

Results: 177 patients were identified. 64% (114/177) were referred for adult care. The commonest JIA subtypes referred were seronegative polyarticular (35/114 or 30.7%) and oligoarticular JIA (22/114 or 19.3%). Documentation of confirmed transfer of care occurred in 62.3% (71/114), with correspondence received from adult services in 49.1% (56/114). There was no difference in rate of return correspondence from public versus private providers (45% vs. 53.8%, p=0.38). The use of 'backstop appointments' was more likely in those with confirmed transfer of care (66% vs. 30%, p=0.0002).

Conclusions: Lack of confirmed transfer of care for JIA patients is common and carries a risk of suboptimal outcomes. Strategies to improve communication with adult services, the routine use of 'backstop' appointments and vigilance regarding potential loss to follow-up at the time of transfer would minimise this risk. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/imj.15509DOI Listing
September 2021

Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment.

Breast Cancer Res 2021 Aug 18;23(1):86. Epub 2021 Aug 18.

Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.

Background: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.

Methods: We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).

Results: Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.

Conclusions: We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
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http://dx.doi.org/10.1186/s13058-021-01450-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371820PMC
August 2021

Genetic insights into biological mechanisms governing human ovarian ageing.

Nature 2021 08 4;596(7872):393-397. Epub 2021 Aug 4.

Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.

Reproductive longevity is essential for fertility and influences healthy ageing in women, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
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http://dx.doi.org/10.1038/s41586-021-03779-7DOI Listing
August 2021

Mendelian randomisation study of smoking exposure in relation to breast cancer risk.

Br J Cancer 2021 Aug 2. Epub 2021 Aug 2.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.

Background: Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk.

Methods: We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy.

Results: Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07-1.30, P = 0.11 × 10), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78-1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect.

Conclusion: Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.
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http://dx.doi.org/10.1038/s41416-021-01432-8DOI Listing
August 2021

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

Am J Hum Genet 2021 07 18;108(7):1190-1203. Epub 2021 Jun 18.

Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10).
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http://dx.doi.org/10.1016/j.ajhg.2021.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322933PMC
July 2021

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

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

Cancer Epidemiol Biomarkers Prev 2021 04 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

CYP3A7*1C allele: linking premenopausal oestrone and progesterone levels with risk of hormone receptor-positive breast cancers.

Br J Cancer 2021 02 26;124(4):842-854. Epub 2021 Jan 26.

Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Epidemiological studies provide strong evidence for a role of endogenous sex hormones in the aetiology of breast cancer. The aim of this analysis was to identify genetic variants that are associated with urinary sex-hormone levels and breast cancer risk.

Methods: We carried out a genome-wide association study of urinary oestrone-3-glucuronide and pregnanediol-3-glucuronide levels in 560 premenopausal women, with additional analysis of progesterone levels in 298 premenopausal women. To test for the association with breast cancer risk, we carried out follow-up genotyping in 90,916 cases and 89,893 controls from the Breast Cancer Association Consortium. All women were of European ancestry.

Results: For pregnanediol-3-glucuronide, there were no genome-wide significant associations; for oestrone-3-glucuronide, we identified a single peak mapping to the CYP3A locus, annotated by rs45446698. The minor rs45446698-C allele was associated with lower oestrone-3-glucuronide (-49.2%, 95% CI -56.1% to -41.1%, P = 3.1 × 10); in follow-up analyses, rs45446698-C was also associated with lower progesterone (-26.7%, 95% CI -39.4% to -11.6%, P = 0.001) and reduced risk of oestrogen and progesterone receptor-positive breast cancer (OR = 0.86, 95% CI 0.82-0.91, P = 6.9 × 10).

Conclusions: The CYP3A7*1C allele is associated with reduced risk of hormone receptor-positive breast cancer possibly mediated via an effect on the metabolism of endogenous sex hormones in premenopausal women.
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http://dx.doi.org/10.1038/s41416-020-01185-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884683PMC
February 2021

The utility of the Laplace effect size prior distribution in Bayesian fine-mapping studies.

Genet Epidemiol 2021 Jun 6;45(4):386-401. Epub 2021 Jan 6.

School of Mathematics and Statistics, University of Sheffield, Sheffield, UK.

The Gaussian distribution is usually the default causal single-nucleotide polymorphism (SNP) effect size prior in Bayesian population-based fine-mapping association studies, but a recent study showed that the heavier-tailed Laplace prior distribution provided a better fit to breast cancer top hits identified in genome-wide association studies. We investigate the utility of the Laplace prior as an effect size prior in univariate fine-mapping studies. We consider ranking SNPs using Bayes factors and other summaries of the effect size posterior distribution, the effect of prior choice on credible set size based on the posterior probability of causality, and on the noteworthiness of SNPs in univariate analyses. Across a wide range of fine-mapping scenarios the Laplace prior generally leads to larger 90% credible sets than the Gaussian prior. These larger credible sets for the Laplace prior are due to relatively high prior mass around zero which can yield many noncausal SNPs with relatively large Bayes factors. If using conventional credible sets, the Gaussian prior generally yields a better trade off between including the causal SNP with high probability and keeping the set size reasonable. Interestingly when using the less well utilised measure of noteworthiness, the Laplace prior performs well, leading to causal SNPs being declared noteworthy with high probability, whilst generally declaring fewer than 5% of noncausal SNPs as being noteworthy. In contrast, the Gaussian prior leads to the causal SNP being declared noteworthy with very low probability.
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http://dx.doi.org/10.1002/gepi.22375DOI Listing
June 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

Causal relationships between body mass index, smoking and lung cancer: Univariable and multivariable Mendelian randomization.

Int J Cancer 2021 03 23;148(5):1077-1086. Epub 2020 Sep 23.

The National Institute of Occupational Health (STAMI), Oslo, Norway.

At the time of cancer diagnosis, body mass index (BMI) is inversely correlated with lung cancer risk, which may reflect reverse causality and confounding due to smoking behavior. We used two-sample univariable and multivariable Mendelian randomization (MR) to estimate causal relationships of BMI and smoking behaviors on lung cancer and histological subtypes based on an aggregated genome-wide association studies (GWASs) analysis of lung cancer in 29 266 cases and 56 450 controls. We observed a positive causal effect for high BMI on occurrence of small-cell lung cancer (odds ratio (OR) = 1.60, 95% confidence interval (CI) = 1.24-2.06, P = 2.70 × 10 ). After adjustment of smoking behaviors using multivariable Mendelian randomization (MVMR), a direct causal effect on small cell lung cancer (OR = 1.28, 95% CI = 1.06-1.55, P = .011), and an inverse effect on lung adenocarcinoma (OR = 0.86, 95% CI = 0.77-0.96, P = .008) were observed. A weak increased risk of lung squamous cell carcinoma was observed for higher BMI in univariable Mendelian randomization (UVMR) analysis (OR = 1.19, 95% CI = 1.01-1.40, P = .036), but this effect disappeared after adjustment of smoking (OR = 1.02, 95% CI = 0.90-1.16, P = .746). These results highlight the histology-specific impact of BMI on lung carcinogenesis and imply mediator role of smoking behaviors in the association between BMI and lung cancer.
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http://dx.doi.org/10.1002/ijc.33292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845289PMC
March 2021

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

Protein-altering germline mutations implicate novel genes related to lung cancer development.

Nat Commun 2020 05 11;11(1):2220. Epub 2020 May 11.

Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10) and replication (adjusted OR = 2.93, P = 2.22 × 10) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.
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http://dx.doi.org/10.1038/s41467-020-15905-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214407PMC
May 2020

Combined Associations of a Polygenic Risk Score and Classical Risk Factors With Breast Cancer Risk.

J Natl Cancer Inst 2021 03;113(3):329-337

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

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
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http://dx.doi.org/10.1093/jnci/djaa056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936056PMC
March 2021

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Genet Epidemiol 2020 07 1;44(5):442-468. Epub 2020 Mar 1.

Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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http://dx.doi.org/10.1002/gepi.22288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987299PMC
July 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

Bayesian variable selection using partially observed categorical prior information in fine-mapping association studies.

Genet Epidemiol 2019 09 12;43(6):690-703. Epub 2019 Jul 12.

School of Mathematics and Statistics, University of Sheffield, Sheffield, UK.

Several methods have been proposed to allow functional genomic information to inform prior distributions in Bayesian fine-mapping case-control association studies. None of these methods allow the inclusion of partially observed functional genomic information. We use functional significance (FS) scores that combine information across multiple bioinformatics sources to inform our effect size prior distributions. These scores are not available for all single-nucleotide polymorphisms (SNPs) but by partitioning SNPs into naturally occurring FS score groups, we show how missing FS scores can easily be accommodated via finite mixtures of elicited priors. Most current approaches adopt a formal Bayesian variable selection approach and either limit the number of causal SNPs allowed or use approximations to avoid the need to explore the vast parameter space. We focus instead on achieving differential shrinkage of the effect sizes through prior scale mixtures of normals and use marginal posterior probability intervals to select candidate causal SNPs. We show via a simulation study how this approach can improve localisation of the causal SNPs compared to existing mutli-SNP fine-mapping methods. We also apply our approach to fine-mapping a region around the CASP8 gene using the iCOGS consortium breast cancer SNP data.
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http://dx.doi.org/10.1002/gepi.22213DOI Listing
September 2019

Using GWAS top hits to inform priors in Bayesian fine-mapping association studies.

Genet Epidemiol 2019 09 9;43(6):675-689. Epub 2019 Jul 9.

School of Mathematics and Statistics, University of Sheffield, Sheffield, UK.

The default causal single-nucleotide polymorphism (SNP) effect size prior in Bayesian fine-mapping studies is usually the Normal distribution. This choice is often based on computational convenience, rather than evidence that it is the most suitable prior distribution. The choice of prior is important because previous studies have shown considerable sensitivity of causal SNP Bayes factors to the form of the prior. In some well-studied diseases there are now considerable numbers of genome-wide association study (GWAS) top hits along with estimates of the number of yet-to-be-discovered causal SNPs. We show how the effect sizes of the top hits and estimates of the number of yet-to-be-discovered causal SNPs can be used to choose between the Laplace and Normal priors, to estimate the prior parameters and to quantify the uncertainty in this estimation. The methodology can readily be applied to other priors. We show that the top hits available from breast cancer GWAS provide overwhelming support for the Laplace over the Normal prior, which has important consequences for variant prioritisation. This work in this paper enables practitioners to derive more objective priors than are currently being used and could lead to prioritisation of different variants.
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http://dx.doi.org/10.1002/gepi.22212DOI Listing
September 2019

Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer.

Nat Commun 2019 04 15;10(1):1741. Epub 2019 Apr 15.

Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), 28040, Madrid, Spain.

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
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http://dx.doi.org/10.1038/s41467-018-08053-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465407PMC
April 2019

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development.

Oncotarget 2019 Mar 5;10(19):1760-1774. Epub 2019 Mar 5.

Department of Epidemiology and Prevention, N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation.

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in (OR=0.44, value=3.27x10 in overall lung cancer and OR=0.41, value=9.71x10 in non-small cell lung cancer), (OR=0.73, value=1.01x10 in adenocarcinoma) and (OR=1.82, value=7.62x10 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.
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http://dx.doi.org/10.18632/oncotarget.26678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442994PMC
March 2019

Challenges in the diagnosis and treatment of disabling pansclerotic morphea of childhood: case-based review.

Rheumatol Int 2019 05 5;39(5):933-941. Epub 2019 Mar 5.

Paediatric Rheumatology Unit, The Royal Children's Hospital, Parkville, VIC, Australia.

Disabling pansclerotic morphea of childhood (DPMC) is a rare subtype of juvenile localized scleroderma (JLS) characterized by pansclerosis mainly affecting children under the age of 14. This aggressive disease has a poor prognosis due to the rapid progression of deep musculoskeletal atrophy resulting in cutaneous ulceration and severe joint contractures. We describe the challenges in treating a previously well 5-year-old male who has refractory symptoms of DPMC. Over the 29 months, since his initial presentation, we trialed over ten therapies. There was subjective improvement with prednisolone and mycophenolate mofetil (MMF). However, other therapies including biologics and tyrosine kinase inhibitors (TKI) were ineffective. The patient has been referred for hematopoietic stem cell transplant given ongoing disease progression. We conducted a literature search focusing on English articles with keywords including DPMC. Publications with limited information or describing cases aged 20 and above were excluded. Thirty-seven case reports were identified and the reported treatments were evaluated. Methotrexate and corticosteroids have been the most commonly utilized. MMF has been anecdotally effective. Biologics, TKI, and Janus kinase inhibitors lack evidence in DPMC, but have had demonstrated efficacy in similar pathologies including systemic sclerosis, and, thus, have been used for DPMC. Phototherapy has been documented to be reducing skin thickness and stiffness of plaques. Eventually, most children require multi-modal and high-dose immunosuppressive therapies to reduce the inflammation inflicted by the disease. Long-term antibiotics and nutritional support are important in the ongoing care of these patients.
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http://dx.doi.org/10.1007/s00296-019-04269-wDOI Listing
May 2019

Genome-wide association study of germline variants and breast cancer-specific mortality.

Br J Cancer 2019 03 21;120(6):647-657. Epub 2019 Feb 21.

Lund University, Department of Cancer Epidemiology, Clinical Sciences, Lund, Sweden.

Background: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.

Methods: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).

Results: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.

Conclusions: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
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http://dx.doi.org/10.1038/s41416-019-0393-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461853PMC
March 2019

Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis.

Cancer Epidemiol Biomarkers Prev 2019 05 30;28(5):935-942. Epub 2019 Jan 30.

Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.

Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear.

Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk.

Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall non-small cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings.

Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention.

Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075698PMC
May 2019

Shared heritability and functional enrichment across six solid cancers.

Nat Commun 2019 01 25;10(1):431. Epub 2019 Jan 25.

Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Calle de Melchor Fernández Almagro, 3, 28029, Madrid, Spain.

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r = 0.57, p = 4.6 × 10), breast and ovarian cancer (r = 0.24, p = 7 × 10), breast and lung cancer (r = 0.18, p =1.5 × 10) and breast and colorectal cancer (r = 0.15, p = 1.1 × 10). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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http://dx.doi.org/10.1038/s41467-018-08054-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347624PMC
January 2019

Genetic susceptibility to radiation-induced breast cancer after Hodgkin lymphoma.

Blood 2019 03 20;133(10):1130-1139. Epub 2018 Dec 20.

Department of Epidemiology and Biostatistics.

Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy (RT) have a very high risk of breast cancer. The contribution of genetic factors to this risk is unclear. We therefore examined 211 155 germline single-nucleotide polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a case-only analysis including 327 breast cancer patients after chest RT for HL and 4671 first primary breast cancer patients. Nine SNPs showed statistically significant interaction with RT on breast cancer risk (false discovery rate, <20%), of which 1 SNP in the oncogene attained the Bonferroni threshold for statistical significance. A polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and a previously published breast cancer PRS (BC-PRS) derived in the general population were evaluated in a case-control analysis comprising the 327 chest-irradiated HL patients with breast cancer and 491 chest-irradiated HL patients without breast cancer. Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast cancer risk than those in the lowest tertile. Remarkably, we observed a fourfold increased RT-induced breast cancer risk in the highest compared with the lowest decile of the BC-PRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviation of the BC-PRS, similar to the effect size found in the general population. This study demonstrates that genetic factors influence breast cancer risk after chest RT for HL. Given the high absolute breast cancer risk in radiation-exposed women, these results can have important implications for the management of current HL survivors and future patients.
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http://dx.doi.org/10.1182/blood-2018-07-862607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405334PMC
March 2019

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

Am J Hum Genet 2019 01 13;104(1):21-34. Epub 2018 Dec 13.

Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki 00290, Finland; Department of Oncology, Örebro University Hospital, Örebro 70185, Sweden.

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
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http://dx.doi.org/10.1016/j.ajhg.2018.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323553PMC
January 2019

Juvenile idiopathic arthritis managed in the new millennium: one year outcomes of an inception cohort of Australian children.

Pediatr Rheumatol Online J 2018 Nov 9;16(1):69. Epub 2018 Nov 9.

Department of Rheumatology, The Royal Children's Hospital, 50 Flemington Rd, Parkville, Melbourne, VIC, 3052, Australia.

Background: The advent of new treatments for Juvenile Idiopathic Arthritis (JIA) has prompted interest in systematically studying the outcomes of patients treated in the 'modern era'. Such data provide both benchmarks for assessing local outcomes and important information for use in counselling families of newly diagnosed patients. While data are available for cohorts in Europe and North America, no such data exist for Australian patients. The aim was to examine the demographics, treatment and outcomes at 12 months of an inception cohort of newly diagnosed patients with JIA at a single tertiary referral paediatric rheumatology centre in Australia.

Methods: Retrospective review of prospectively collected data from patients newly diagnosed with JIA between 2010 and 2014 at the Royal Children's Hospital in Melbourne.

Results: One hundred thirty four patients were included (62% female). Oligoarthritis was the single largest category of JIA (36%) and rheumatoid factor positive polyarthritis the least common (2%). Undifferentiated JIA accounted for 13% of patients and was the third largest category. Across the cohort 94% received NSAIDs, 53% oral steroids, 62% methotrexate and 15% a biologic DMARD. Intra-articular steroids were used in 62%, most commonly in the oligoarticular subtype (94%). 95% of patients achieved a joint count of zero at a median of 4.1 months, however flares occurred in 42%. At 12 months 65% had no active joint disease, though more than half remained on medication.

Conclusion: Australian children with JIA managed in the modern era have similar characteristics and achieve short term outcomes comparable to cohorts in Europe and North America, with high rates of joint remission in the first 12 months of follow-up but with a significant relapse rate and requirement for ongoing medication.
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http://dx.doi.org/10.1186/s12969-018-0288-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230231PMC
November 2018

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Nat Commun 2018 08 13;9(1):3221. Epub 2018 Aug 13.

Clalit National Cancer Control Center, Carmel Medical Center, Haifa, 34361, Israel.

Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
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http://dx.doi.org/10.1038/s41467-018-05074-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6089967PMC
August 2018
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