Publications by authors named "Kari Hemminki"

753 Publications

A Novel Low-Risk Germline Variant in the SH2 Domain of the SRC Gene Affects Multiple Pathways in Familial Colorectal Cancer.

J Pers Med 2021 Apr 1;11(4). Epub 2021 Apr 1.

Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Colorectal cancer (CRC) shows one of the largest proportions of familial cases among different malignancies, but only 5-10% of all CRC cases are linked to mutations in established predisposition genes. Thus, familial CRC constitutes a promising target for the identification of novel, high- to moderate-penetrance germline variants underlying cancer susceptibility by next generation sequencing. In this study, we performed whole genome sequencing on three members of a family with CRC aggregation. Subsequent integrative in silico analysis using our in-house developed variant prioritization pipeline resulted in the identification of a novel germline missense variant in the gene (V177M), a proto-oncogene highly upregulated in CRC. Functional validation experiments in HT-29 cells showed that introduction of resulted in increased cell proliferation and enhanced protein expression of phospho-SRC (Y419), a potential marker for SRC activity. Upregulation of , and mRNA levels, increased levels of phospho-ERK, CREB, and CCND1 proteins and downregulation of the tumor suppressor p53 further proposed the activation of several pathways due to the variant. The findings of our pedigree-based study contribute to the exploration of the genetic background of familial CRC and bring insights into the molecular basis of upregulated SRC activity and downstream pathways in colorectal carcinogenesis.
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http://dx.doi.org/10.3390/jpm11040262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066297PMC
April 2021

Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, ( = 2.19 × 10) and ( = 6.28 × 10) were associated with the risk of CRC. Mechanistically, the allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with ( = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood ( = 0.0038) and serum levels of en-RAGE ( = 0.0068). allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS ( = 0.0088 and = 0.0076, respectively), CD14+CD16- cell levels in blood ( = 0.0068) and serum levels of CCL19 and cortisol ( = 0.0052 and = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the and loci in the pathogenesis of CRC, likely through the modulation of host immune responses.
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http://dx.doi.org/10.3390/cancers13061258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998818PMC
March 2021

Whole Genome Sequencing Prioritizes , and as Possible Predisposition Genes for Familial Non-Medullary Thyroid Cancer.

Front Endocrinol (Lausanne) 2021 22;12:600682. Epub 2021 Feb 22.

Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.

Familial inheritance in non-medullary thyroid cancer (NMTC) is an area that has yet to be adequately explored. Despite evidence suggesting strong familial clustering of non-syndromic NMTC, known variants still account for a very small percentage of the genetic burden. In a recent whole genome sequencing (WGS) study of five families with several NMTCs, we shortlisted promising variants with the help of our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2). Here, we report potentially disease-causing variants in checkpoint kinase 2 (), Ewing sarcoma breakpoint region 1 () and T-lymphoma invasion and metastasis-inducing protein 1 () in one family. Performing WGS on three cases, one probable case and one healthy individual in a family with familial NMTC left us with 112254 variants with a minor allele frequency of less than 0.1%, which was reduced by pedigree-based filtering to 6368. Application of the pipeline led to the prioritization of seven coding and nine non-coding variants from this family. The variant identified in , a known tumor suppressor gene involved in DNA damage-induced DNA repair, cell cycle arrest, and apoptosis, has been previously identified as a germline variant in breast and prostate cancer and has been functionally validated by Roeb et al. in a yeast-based assay to have an intermediate effect on protein function. We thus hypothesized that this family may harbor additional disease-causing variants in other functionally related genes. We evaluated two further variants in and with promising in silico results and reported interaction in the DNA-damage repair pathway. Hence, we propose a polygenic mode of inheritance in this family. As familial NMTC is considered to be more aggressive than its sporadic counterpart, it is important to identify such susceptibility genes and their associated pathways. In this way, the advancement of personalized medicine in NMTC patients can be fostered. We also wish to reopen the discussion on monogenic vs polygenic inheritance in NMTC and instigate further development in this area of research.
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http://dx.doi.org/10.3389/fendo.2021.600682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937922PMC
February 2021

DNA repair gene polymorphisms and chromosomal aberrations in healthy, nonsmoking population.

DNA Repair (Amst) 2021 May 27;101:103079. Epub 2021 Feb 27.

Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany; Faculty of Medicine and Biomedical Center in Pilsen, Charles University in Prague, 30605 Pilsen, Czech Republic; Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), 69120 Heidelberg, Germany.

Nonspecific structural chromosomal aberrations (CAs) can be found at around 1% of circulating lymphocytes from healthy individuals but the frequency may be higher after exposure to carcinogenic chemicals or radiation. The frequency of CAs has been measured in occupational monitoring and an increased frequency of CAs has also been associated with cancer risk. Alterations in DNA damage repair and telomere maintenance are thought to contribute to the formation of CAs, which include chromosome type of aberrations and chromatid type of aberrations. In the present study, we used the result of our published genome-wide association studies to extract data on 153 DNA repair genes from 866 nonsmoking persons who had no known occupational exposure to genotoxic substances. Considering an arbitrary cut-off level of P< 5 × 10, single nucleotide polymorphisms (SNPs) tagging 22 DNA repair genes were significantly associated with CAs and they remained significant at P < 0.05 when adjustment for multiple comparisons was done by the Binomial Sequential Goodness of Fit test. Nucleotide excision repair pathway genes showed most associations with 6 genes. Among the associated genes were several in which mutations manifest CA phenotype, including Fanconi anemia, WRN, BLM and genes that are important in maintaining genome stability, as well as PARP2 and mismatch repair genes. RPA2 and RPA3 may participate in telomere maintenance through the synthesis of the C strand of telomeres. Errors in NHEJ1 function may lead to translocations. The present results show associations with some genes with known CA phenotype and suggest other pathways with mechanistic rationale for the formation of CAs in healthy nonsmoking population.
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http://dx.doi.org/10.1016/j.dnarep.2021.103079DOI Listing
May 2021

Whole Exome Sequencing Identifies and Genes as Potentially Cancer Predisposing in Familial Colorectal Cancer.

Int J Mol Sci 2021 Feb 12;22(4). Epub 2021 Feb 12.

Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Germline mutations in predisposition genes account for only 20% of all familial colorectal cancers (CRC) and the remaining genetic burden may be due to rare high- to moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer-predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants: a coding variant in APC downregulated 1 gene (, p.R299H) and a non-coding variant in the 5' untranslated region (UTR) of histone deacetylase 5 gene (). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additional variants in a cohort of 1705 familial CRC patients and no further variants. Proliferation assays indicated an insignificant proliferative impact for the variant. Luciferase reporter assays using the variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by the variant showed a significant impact of TCF4 on promoter activity of mutated . Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5'UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders.
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http://dx.doi.org/10.3390/ijms22041837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917948PMC
February 2021

Familial Risks between Pernicious Anemia and Other Autoimmune Diseases in the Population of Sweden.

Autoimmune Dis 2021 12;2021:8815297. Epub 2021 Jan 12.

Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Background: Pernicious anemia (PA) is an autoimmune disease (AID) which is caused by lack of vitamin B12 (cobalamin) due to its impaired uptake. PA is a multifactorial disease which is associated with a number of other AID comorbidities and which is manifested as part of autoimmune polyglandular syndrome. Due to the shortage of family studies on PA, we planned to address the problem by assessing familial risks for concordant PA between family members and for discordant PA in families of other AID patients.

Methods: We collected data on patients diagnosed with AIDs from the Swedish hospitals and family data from a population register. We calculated standardized incidence ratios (SIRs) in families for concordant and discordant risks.

Results: The number of PA patients in the offspring generation (for which the familial risk was calculated) was 7701; 278 (3.6%) patients had a family history of PA. The population prevalence of PA was 0.9/1000. The familial risk for PA was 3.88 when any first-degree relative was the proband, equal for men and women. The familial risk was two times higher between siblings than between offspring and parents which may be due to complex genetic background. Associations of PA with 14 discordant AIDs were significant; these included some AIDs that have previously been described as comorbidities in PA patients and several yet unreported associations, including rheumatoid arthritis and other AIDs.

Conclusions: The familial risks for PA were high suggesting multifactorial genetic etiology. The results call for further population-level studies to unravel mechanisms of familial PA which may help to understand the etiology of this disease.
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http://dx.doi.org/10.1155/2021/8815297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815416PMC
January 2021

A rare large duplication of MLH1 identified in Lynch syndrome.

Hered Cancer Clin Pract 2021 Jan 19;19(1):10. Epub 2021 Jan 19.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120, Heidelberg, Germany.

Background: The most frequently identified strong cancer predisposition mutations for colorectal cancer (CRC) are those in the mismatch repair (MMR) genes in Lynch syndrome. Laboratory diagnostics include testing tumors for immunohistochemical staining (IHC) of the Lynch syndrome-associated DNA MMR proteins and/or for microsatellite instability (MSI) followed by sequencing or other techniques, such as denaturing high performance liquid chromatography (DHPLC), to identify the mutation.

Methods: In an ongoing project focusing on finding Mendelian cancer syndromes we applied whole-exome/whole-genome sequencing (WES/WGS) to 19 CRC families.

Results: Three families were identified with a pathogenic/likely pathogenic germline variant in a MMR gene that had previously tested negative in DHPLC gene variant screening. All families had a history of CRC in several family members across multiple generations. Tumor analysis showed loss of the MMR protein IHC staining corresponding to the mutated genes, as well as MSI. In family A, a structural variant, a duplication of exons 4 to 13, was identified in MLH1. The duplication was predicted to lead to a frameshift at amino acid 520 and a premature stop codon at amino acid 539. In family B, a 1 base pair deletion was found in MLH1, resulting in a frameshift and a stop codon at amino acid 491. In family C, we identified a splice site variant in MSH2, which was predicted to lead loss of a splice donor site.

Conclusions: We identified altogether three pathogenic/likely pathogenic variants in the MMR genes in three of the 19 sequenced families. The MLH1 variants, a duplication of exons 4 to 13 and a frameshift variant, were novel, based on the InSiGHT and ClinVar databases; the MSH2 splice site variant was reported by a single submitter in ClinVar. As a variant class, duplications have rarely been reported in the MMR gene literature, particularly those covering several exons.
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http://dx.doi.org/10.1186/s13053-021-00167-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814444PMC
January 2021

Telomere length in peripheral blood lymphocytes related to genetic variation in telomerase, prognosis and clinicopathological features in breast cancer patients.

Mutagenesis 2020 12;35(6):491-497

Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska, Prague, Czech Republic.

Disruption of telomere length (TL) homeostasis in peripheral blood lymphocytes has been previously assessed as a potential biomarker of breast cancer (BC) risk. The present study addressed the relationship between lymphocyte TL (LTL), prognosis and clinicopathological features in the BC patients since these associations are insufficiently explored at present. LTL was measured in 611 BC patients and 154 healthy controls using the monochrome multiplex quantitative Polymerase Chain Reaction assay. In addition, we genotyped nine TL-associated single-nucleotide polymorphisms that had been identified through genome-wide association studies. Our results showed that the patients had significantly (P = 0.001, Mann-Whitney U-test) longer LTL [median (interquartile range); 1.48 (1.22-1.78)] than the healthy controls [1.27 (0.97-1.82)]. Patients homozygous (CC) for the common allele of hTERT rs2736108 or the variant allele (CC) of hTERC rs16847897 had longer LTL. The latter association remained statistically significant in the recessive genetic model after the Bonferroni correction (P = 0.004, Wilcoxon two-sample test). We observed no association between LTL and overall survival or relapse-free survival of the patients. LTL did not correlate with cancer staging based on Union for International Cancer Control (UICC), The tumor node metastasis (TNM) staging system classification, tumour grade or molecular BC subtypes. Overall, we observed an association between long LTL and BC disease and an association of the hTERC rs16847897 CC genotype with increased LTL. However, no association between LTL, clinicopathological features and survival of the patients was found.
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http://dx.doi.org/10.1093/mutage/geaa030DOI Listing
December 2020

Familial risks between giant cell arteritis and Takayasu arteritis and other autoimmune diseases in the population of Sweden.

Sci Rep 2020 11 30;10(1):20887. Epub 2020 Nov 30.

Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), 69120, Heidelberg, Germany.

Giant cell arteritis (GCA, also called temporal arteritis) is a rare and Takayasu arteritis (TA) is an even rarer autoimmune disease (AID), both of which present with inflammatory vasculitis of large and medium size arteries. The risk factors are largely undefined but disease susceptibility has been associated with human leukocyte antigen locus. Population-level familial risk is not known. In the present nation-wide study we describe familial risk for GCA and for GCA and TA with any other AID based on the Swedish hospital diagnoses up to years 2012. Family relationships were obtained from the Multigeneration Register. Familial standardized incidence ratios (SIRs) were calculated for offspring whose parents or siblings were diagnosed with GCA, TA or any other AID. The number of GCA patients in the offspring generation was 4695, compared to 209 TA patients; for both, familial patients accounted for 1% of all patients. The familial risk for GCA was 2.14, 2.40 for women and non-significant for men. GCA was associated with 10 other AIDs and TA was associated with 6 other AIDs; both shared associations with polymyalgia rheumatica and rheumatoid arthritis. The results showed that family history is a risk factor for GCA. Significant familial associations of both GCA and TA with such a number of other AIDs provide evidence for polyautoimmunity among these diseases.
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http://dx.doi.org/10.1038/s41598-020-77857-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7705754PMC
November 2020

Familial associations for rheumatoid autoimmune diseases.

Rheumatol Adv Pract 2020 22;4(2):rkaa048. Epub 2020 Sep 22.

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

Objective: Previous studies have shown a familial component in RA and in some other rheumatic autoimmune diseases (RAIDs), but because of the different study designs the risk estimates for familial risks differ extensively. The objective of this study is to identify familial components for RAIDs.

Methods: We collected data on patients diagnosed in Swedish hospitals with RA, AS, PM/DM, SS, SLE and SSc (and scleroderma) and calculated familial standardized incidence ratios (SIRs) for each of these (concordant) and between them (discordant).

Results: The combined number of RAID patients in the offspring population (for whom SIRs were calculated) was 71 544, and in the whole population the number was 152 714, accounting for 19.8% of all autoimmune diseases in Sweden. AS showed the highest concordant familial risk of 18.42, followed by SLE (14.04), SS (8.63), SSc (4.50), PM/DM (4.03) and RA (3.03). There was no sex difference in SIRs. Risks for AS and SLE were 80.28 and 19.53 for persons whose parents and siblings were affected. Discordant risks were far lower than concordant risks, but they were significant for RA with all the other five RAIDs, for SLE and SSc with four RAIDs, for AS and SS with three RAIDs and for PM/DM with two RAIDs, attesting to extensive polyautoimmunity between RAIDs.

Conclusion: The derived familial risks in this nationwide family study on medically diagnosed RAID are compatible with emerging evidence on the polygenic background of these complex diseases. Novel genetic pathways offer new therapeutic targets that alleviate disease onset optimally in high-risk familial patients and others.
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http://dx.doi.org/10.1093/rap/rkaa048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673201PMC
September 2020

Impact of genetic polymorphisms in kinetochore and spindle assembly genes on chromosomal aberration frequency in healthy humans.

Mutat Res 2020 Oct - Dec;858-860:503253. Epub 2020 Sep 15.

Department of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.

Genomic instability is a characteristic of a majority of human malignancies. Chromosomal instability is a common form of genomic instability that can be caused by defects in mitotic checkpoint genes. Chromosomal aberrations in peripheral blood are also indicative of genotoxic exposure and potential cancer risk. We evaluated associations between inherited genetic variants in 33 mitotic checkpoint genes and the frequency of chromosomal aberrations (CAs) in the presence and absence of environmental genotoxic exposure. Associations with both chromosome and chromatid type of aberrations were evaluated in two cohorts of healthy individuals, namely an exposed and a reference group consisting of 607 and 866 individuals, respectively. Binary logistic and linear regression analyses were performed for the association studies. Bonferroni-corrected significant p-value was 5 × 10 for 99 tests based on the number of analyzed genes and phenotypes. In the reference group the most prominent associations were found with variants in CCNB1, a master regulator of mitosis, and in genes involved in kinetochore function, including CENPH and TEX14, whereas in the exposed group the main association was found with variants in TTK, also an important gene in kinetochore function. How the identified variants may affect the fidelity of mitotic checkpoint remains to be investigated, however, the present study suggests that genetic variation may partly explain interindividual variation in the formation of CAs.
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http://dx.doi.org/10.1016/j.mrgentox.2020.503253DOI Listing
March 2021

Familial associations for Addison's disease and between Addison's disease and other autoimmune diseases.

Endocr Connect 2020 Nov;9(11):1114-1120

Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.

Design: Addison's disease (AD) is a rare autoimmune disease (AID) of the adrenal cortex, present as an isolated AD or part of autoimmune polyendocrine syndromes (APSs) 1 and 2. Although AD patients present with a number of AID co-morbidities, population-based family studies are scarce, and we aimed to carry out an unbiased study on AD and related AIDs.

Methods: We collected data on patients diagnosed with AIDs in Swedish hospitals and calculated standardized incidence ratios (SIRs) in families for concordant AD and for other AIDs, the latter as discordant relative risks.

Results: The number of AD patients was 2852, which accounted for 0.4% of all hospitalized AIDs. A total of 62 persons (3.6%) were diagnosed with familial AD. The SIR for siblings was remarkably high, reaching 909 for singleton siblings diagnosed before age 10 years. It was 32 in those diagnosed past age 29 years and the risk for twins was 323. SIR was 9.44 for offspring of affected parents. AD was associated with 11 other AIDs, including thyroid AIDs and type 1 diabetes and some rarer AIDs such as Guillain-Barre syndrome, myasthenia gravis, polymyalgia rheumatica and Sjögren's syndrome.

Conclusions: The familial risk for AD was very high implicating genetic etiology, which for juvenile siblings may be ascribed to APS-1. The adult part of sibling risk was probably contributed by recessive polygenic inheritance. AD was associated with many common AIDs; some of these were known co-morbidities in AD patients while some other appeared to more specific for a familial setting.
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http://dx.doi.org/10.1530/EC-20-0328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774767PMC
November 2020

Familial associations between autoimmune hepatitis and primary biliary cholangitis and other autoimmune diseases.

PLoS One 2020 20;15(10):e0240794. Epub 2020 Oct 20.

Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.

Autoimmune hepatitis (AH) and primary biliary cirrhosis (PBC) are autoimmune diseases (AIDs) targeting cellular components of the liver. Being rare diseases, limited data are available about familial risks among these AIDs (concordant) or between them and other AIDs (discordant). We aimed to carry out an unbiased study on these AIDs based on medically diagnosed patients. We collected data on patients diagnosed in Swedish hospitals with AH, PBC and other AIDs and calculated familial standardized incidence ratios (SIRs) for concordant and discordant familial relative risks. The number of AH patients was 6,269, of whom 43.0% were male; patient numbers for PBC were 4,269, with 17.8% males. AH accounted for 0.8% and 0.6% of all hospitalized AIDs in Sweden. For AH only the familial risk between siblings was significant (3.83). For PBC the risks for offspring of parents (9.05) and siblings (10.88) were high, but only risk for females was significant. Spousal risks were very high, 5.91 and 6.07 for AH. Risk for AH was 2.21 in families of PBC, and it was 2.47 for PBC in families of AH patients. Among other AIDs, 14 showed a significant association with AH, compared to 16 AIDs with PBC. The surprising finding in this nation-wide family study on medically diagnosed patients was the high risk for AH (6.0) between spouses, which exceed the risk between siblings, suggesting the existence of strong environmental risk factors. AH and PBC were associated with multiple other AIDs. The results call attention to environmental factors in AID etiology which should also be in focus in taking anamnestic data from patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240794PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575086PMC
December 2020

Chromosomal damage and telomere length in peripheral blood lymphocytes of cancer patients.

Oncol Rep 2020 Nov 21;44(5):2219-2230. Epub 2020 Sep 21.

Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague 142 00, Czech Republic.

Accumulation of non‑specific structural chromosomal aberrations (CAs) and telomere shortening contribute to genome instability, which constitutes as one of the hallmarks of cancer. CAs arise due to direct DNA damage or telomere shortening. CAs in peripheral blood lymphocytes (PBL), which are considered to be markers of exposure, have been previously reported to serve a role in the pathophysiology and progression of cancer through mechanisms that are poorly understood. In addition, the prognostic relevance of telomere length (TL) in patients with cancer remains to be elucidated. In the present study, CAs and TL in PBL isolated from patients with newly diagnosed cancer (151 breast, 96 colorectal, 90 lung) and 335 cancer‑free control individuals were investigated. These results were then correlated with clinicopathological factors and follow‑up data. The accumulation of CAs in PBL was observed with increased susceptibility to breast and lung cancer (P<0.0001), while individuals with longer TL were found to be at a higher risk of breast cancer (P<0.0001). Increased chromatid‑type aberrations were also revealed to be associated with lower overall survival of patients with breast and colorectal cancers using a multivariate model. Compared with control individuals, no association was observed between TL and CAs or age in patients with cancer. In conclusion, the present study demonstrates the association between CAs/TL in PBL and the susceptibility, prognosis and survival of patients with breast, colorectal and lung cancer.
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http://dx.doi.org/10.3892/or.2020.7774DOI Listing
November 2020

Cancer Predisposition Genes in Cancer-Free Families.

Cancers (Basel) 2020 Sep 27;12(10). Epub 2020 Sep 27.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.

Familial clustering, twin concordance, and identification of high- and low-penetrance cancer predisposition variants support the idea that there are families that are at a high to moderate excess risk of cancer. To what extent there may be families that are protected from cancer is unknown. We wanted to test genetically whether cancer-free families share fewer breast, colorectal, and prostate cancer risk alleles than the population at large. We addressed this question by whole-genome sequencing (WGS) of 51 elderly cancer-free individuals whose numerous (ca. 1000) family members were found to be cancer-free ('cancer-free families', CFFs) based on face-to-face interviews. The average coverage of the 51 samples in the WGS was 42x. We compared cancer risk allele frequencies in cancer-free individuals with those in the general population available in public databases. The CFF members had fewer loss-of-function variants in suggested cancer predisposition genes compared to the ExAC data, and for high-risk cancer predisposition genes, no pathogenic variants were found in CFFs. For common low-penetrance breast, colorectal, and prostate cancer risk alleles, the results were not conclusive. The results suggest that, in line with twin and family studies, random environmental causes are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible.
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http://dx.doi.org/10.3390/cancers12102770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600438PMC
September 2020

Rate differences between first and second primary cancers may outline immune dysfunction as a key risk factor.

Cancer Med 2020 11 22;9(21):8258-8265. Epub 2020 Sep 22.

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

Background: Many cancers are increased in immunosuppressed patients and evidence is accumulating that immune dysfunction may be a contributing risk factor for second primary cancers (SPCs). The aim of this study was to explore the potential influence of immune mechanisms in SPC.

Methods: We used the Swedish Cancer Registry (1990-2015) to select 13 male and 14 female first primary cancers (FPCs) that are known to be related to immune suppression. We assessed relative risks (RRs) for any of these as concordant (same first and second cancer) and discordant FPC-SPC pairs. Hierarchical clustering of significant RRs was performed for cancers as FPC and SPC.

Results: Concordant risks for SPCs were excessive in men and women for nasal (RRs 59.3 for men and 150.6 for women), tongue/mouth (51.7 and 100.8), and lip (32.4 and 61.2) cancers. Heatmaps showed that some cancers, such as skin cancer, tongue/mouth cancers, and non-Hodgkin lymphoma had multiple bidirectional associations as FPC and SPC. Nasal cancer and chronic lymphocytic leukemia had associations mainly as FPC while liver and kidney cancers showed most associations as SPC.

Conclusions: Immune dysfunction may be a plausible contributing factor for most of the associations, which calls for experimental verification.
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http://dx.doi.org/10.1002/cam4.3454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643639PMC
November 2020

Incidence Differences Between First Primary Cancers and Second Primary Cancers Following Skin Squamous Cell Carcinoma as Etiological Clues.

Clin Epidemiol 2020 6;12:857-864. Epub 2020 Aug 6.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany.

Background: Most literature on second primary cancers (SPCs) focuses on possible factors, which may increase the risk of these cancers, and little attention has been paid for the overall incidence differences between first primary cancers (FPCs) and same SPCs. We wanted to compare the incidence rates for all common cancers when these were diagnosed as FPCs and SPCs after invasive and in situ squamous cell carcinoma (SCC) of the skin, which are usually treated by surgery only.

Methods: Cancers were identified from the Swedish Cancer Registry from the years 1990 through to 2015, and they included, in addition to skin cancers, 20 male cancers totaling 484,850 patients and 22 female cancers totaling 452,909 patients. Standardized incidence rates and relative risks (RRs) were calculated for sex-specific common cancers as FPC and as SPC after skin SCC. Spearman rank correlations were used in the analysis of incidence ranking of FPC and SPC.

Results: Of total, 29,061 men and 23,533 women developed invasive SCC and 27,842 men and 36,383 women in situ SCC. The total number of 20 other male cancers was 484,850 and of 22 female cancers it was 452,909. Rank correlations ranged from 0.90 to 0.96 (P~5×10), indicating that overall skin SCC did not interfere with SPC formation. The exceptions were increased SPC risks for melanoma, sharing risk factors with skin SCC, and non-Hodgkin and Hodgkin lymphoma, and cancers of the upper aerodigestive tract, connective tissue, and male and female genitals suggesting contribution by skin cancer initiated immune dysfunction.

Conclusion: The incidence ranking of SPCs after skin cancers largely follows the incidence ranking of FPCs indicating that overall skin SCC does not greatly interfere with the intrinsic carcinogenic process. The main deviations in incidence between FPC and SPC appeared to be due to shared risk factors or immunological processes promoting immune responsive cancer types.
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http://dx.doi.org/10.2147/CLEP.S256662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417931PMC
August 2020

Informing patients about their mutation tests: CDKN2A c.256G>A in melanoma as an example.

Hered Cancer Clin Pract 2020 31;18:15. Epub 2020 Jul 31.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.

Background: When germline mutations are suspected as causal in cancer, patient DNA may be sequenced to detect variants in relevant genes. If a particular mutation has not been reported in reliable family studies, genetic counselors are facing a dilemma of appropriately informing patients. Many sequencing facilities provide an interpretation of the findings based on the available sequence databases or on prediction tools that are curated from bioinformatics and mechanistic datasets. The counseling dilemma is exacerbated if the pedigree data are not informative but the in silico predictions suggest pathogenicity.

Methods: We present here a real world example of the c.256G > A variant, which was detected in one melanoma patient where two siblings were diagnosed with melanoma in situ. We investigated a detailed family history of the affected siblings in order to survey probability of the cancer risks within the context to this mutation.

Results: This c.256G > A variant was detected in one of the brothers and in the melanoma-free mother while the other brother in the family tested negative. The variant had been previously described in one patient from a melanoma family. In the family under investigation, the mother's 16 first-and second-degree relatives had survived past the median onset age for melanoma and none presented melanoma. We tested the variant using multiple bioinformatic tools that all predicted deleteriousness of the variant. The genetic counseling report to the melanoma patient stated that the variant was 'likely pathogenic' and the disease was defined as 'likely hereditary melanoma'.

Conclusions: The pedigree data showed at the most a low penetrance variant, which, if taken into consideration, might have altered the provided diagnosis. When dealing with 'practically' unknown variants the counselors would be advised to incorporate a detailed family history rather than basing predictions on functionality provided by sequencing facilities.
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http://dx.doi.org/10.1186/s13053-020-00146-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393828PMC
July 2020

Familial risks between Graves disease and Hashimoto thyroiditis and other autoimmune diseases in the population of Sweden.

J Transl Autoimmun 2020 1;3:100058. Epub 2020 Jun 1.

Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), 69120, Heidelberg, Germany.

Genetic and family studies have indicated that Graves disease and Hashimoto thyroiditis have a heritable component which appears to be shared to some extend also with some other autoimmune diseases (AIDs). In the present nation-wide study we describe familial risk for Graves disease and Hashimoto thyroiditis identified from the Swedish Hospital Discharge Register (years 1964 through 2012) and the Outpatient Register (2001 through 2012). Family relationships were obtained from the Multigeneration Register and cancers from the Cancer Registry. Familial standardized incidence ratios (SIRs) were calculated for 29,005 offspring with Graves disease and for 25,607 offspring with Hashimoto thyroiditis depending on any of 43 AIDs in parents or siblings. The concordant familial risks for Graves disease and Hashimoto thyroiditis were 3.85 and 4.75, higher for men than for women. The familial risks were very high (11.35, Graves and 22.06, Hashimoto) when both a parent and a sibling were affected. Spousal familial risks were higher for Hashimoto thyroiditis (1.98/1.93) than for Graves disease (1.48/1.50). For Graves disease, 24 discordant AIDs showed a significant association; for Hashimoto thyroiditis, 20 discordant associations were significant. All significant discordant associations were positive for the two thyroid AIDs, with the exception of Hashimoto thyroiditis with Reiter disease. Overall 8 associations were significant only for Graves disease and 6 Hashimoto thyroiditis. The overall high concordant familial risks for Graves disease and Hashimoto thyroiditis suggest a strong genetic contribution to the familial risk. Significant familial associations among more than half of the 43 AIDs attest to the extensive polyautoimmunity among thyroid AIDs.
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http://dx.doi.org/10.1016/j.jtauto.2020.100058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388361PMC
June 2020

Genomic imprinting analyses identify maternal effects as a cause of phenotypic variability in type 1 diabetes and rheumatoid arthritis.

Sci Rep 2020 07 14;10(1):11562. Epub 2020 Jul 14.

Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany.

Imprinted genes, giving rise to parent-of-origin effects (POEs), have been hypothesised to affect type 1 diabetes (T1D) and rheumatoid arthritis (RA). However, maternal effects may also play a role. By using a mixed model that is able to simultaneously consider all kinds of POEs, the importance of POEs for the development of T1D and RA was investigated in a variance components analysis. The analysis was based on Swedish population-scale pedigree data. With P = 0.18 (T1D) and P = 0.26 (RA) imprinting variances were not significant. Explaining up to 19.00% (± 2.00%) and 15.00% (± 6.00%) of the phenotypic variance, the maternal environmental variance was significant for T1D (P = 1.60 × 10) and for RA (P = 0.02). For the first time, the existence of maternal genetic effects on RA was indicated, contributing up to 16.00% (± 3.00%) of the total variance. Environmental factors such as the social economic index, the number of offspring, birth year as well as their interactions with sex showed large effects.
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http://dx.doi.org/10.1038/s41598-020-68212-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360775PMC
July 2020

A Germline Mutation in the Gene Is a Candidate for Familial Non-Medullary Thyroid Cancer.

Cancers (Basel) 2020 Jun 1;12(6). Epub 2020 Jun 1.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

Non-medullary thyroid cancer (NMTC) is a common endocrine malignancy with a genetic basis that has yet to be unequivocally established. In a recent whole-genome sequencing study of five families with occurrence of NMTCs, we shortlisted promising variants with the help of bioinformatics tools. Here, we report in silico analyses and in vitro experiments on a novel germline variant (p.V29L) in the highly conserved oligonucleotide/oligosaccharide binding domain of the () gene in one of the families. The results showed a reduction in telomere-bound POT1 levels in the mutant protein as compared to its wild-type counterpart. HEK293T cells carrying showed increased telomere length in comparison to wild-type cells, suggesting that the mutation causes telomere dysfunction and may play a role in predisposition to NMTC in this family. While one germline mutation in has already been reported in a melanoma-prone family with prevalence of thyroid cancers, we report the first of such mutations in a family affected solely by NMTCs, thus expanding current knowledge on shelterin complex-associated cancers.
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http://dx.doi.org/10.3390/cancers12061441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352431PMC
June 2020

Search for multiple myeloma risk factors using Mendelian randomization.

Blood Adv 2020 05;4(10):2172-2179

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.

The etiology of multiple myeloma (MM) is poorly understood. Summary data from genome-wide association studies (GWASs) of multiple phenotypes can be exploited in a Mendelian randomization (MR) phenome-wide association study (PheWAS) to search for factors influencing MM risk. We performed an MR-PheWAS analyzing 249 phenotypes, proxied by 10 225 genetic variants, and summary genetic data from a GWAS of 7717 MM cases and 29 304 controls. Odds ratios (ORs) per 1 standard deviation increase in each phenotype were estimated under an inverse variance weighted random effects model. A Bonferroni-corrected threshold of P = 2 × 10-4 was considered significant, whereas P < .05 was considered suggestive of an association. Although no significant associations with MM risk were observed among the 249 phenotypes, 28 phenotypes showed evidence suggestive of association, including increased levels of serum vitamin B6 and blood carnitine (P = 1.1 × 10-3) with greater MM risk and ω-3 fatty acids (P = 5.4 × 10-4) with reduced MM risk. A suggestive association between increased telomere length and reduced MM risk was also noted; however, this association was primarily driven by the previously identified risk variant rs10936599 at 3q26 (TERC). Although not statistically significant, increased body mass index was associated with increased risk (OR, 1.10; 95% confidence interval, 0.99-1.22), supporting findings from a previous meta-analysis of prospective observational studies. Our study did not provide evidence supporting any modifiable factors examined as having a major influence on MM risk; however, it provides insight into factors for which the evidence has previously been mixed.
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http://dx.doi.org/10.1182/bloodadvances.2020001502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252541PMC
May 2020

Determining the Appropriate Risk-Adapted Screening Age for Familial Breast Cancer.

Authors:
Kari Hemminki

JAMA Oncol 2020 06;6(6):933-934

Biomedical Center in Pilsen, Faculty of Medicine, Charles University in Prague, Pilsen, Czech Republic.

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http://dx.doi.org/10.1001/jamaoncol.2020.0286DOI Listing
June 2020

Loci associated with genomic damage levels in chronic kidney disease patients and controls.

Mutat Res 2020 04 10;852:503167. Epub 2020 Mar 10.

Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Edifici C, Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Carlos III Institute of Health, Madrid, Spain. Electronic address:

Chronic kidney disease (CKD) is a multifactorial disorder with an important genetic component, and several studies have demonstrated potential associations with allelic variants. In addition, CKD patients are also characterized by high levels of genomic damage. Nevertheless, no studies have established relationships between DNA damage, or genomic instability present in CKD patients, and gene polymorphisms. To fill in this gap, the potential role of polymorphisms in genes involved in base excision repair (OGG1, rs1052133; MUTYH, rs3219489; XRCC1, rs25487), nucleotide excision repair (ERCC2/XPD, rs1799793, rs171140, rs13181; ERCC4, rs3136166); phase II metabolism (GSTP1, rs749174; GSTO1, rs2164624; GSTO2, rs156697), and antioxidant enzymes (SOD1, rs17880135, rs1041740, rs202446; SOD2, rs4880; CAT, rs1001179; GPX1, rs17080528; GPX3, rs870406: GPX4, rs713041) were inquired. In addition, some genes involved in CKD (AGT, rs5050; GLO1, rs386572987; SHROOM3, rs17319721) were also evaluated. The genomic damage, the genomic instability, and oxidative damage were evaluated by using the micronucleus and the comet assay in 589 donors (415 CKD patients and 174 controls). Our results showed significant associations between genomic damage and genes directly involved in DNA repair pathways (XRCC1, and ERCC2), and with genes encoding for antioxidant enzymes (SOD1 and GPX1). GSTO2, as a gene involved in phase II metabolism, and MUTYH showed also an association with genomic instability. Interestingly, the three genes associated with CKD (AGT, GLO1, and SHROOM3) showed associations with both the high levels of oxidatively damaged DNA and genomic instability. These results support our view that genomic instability can be considered a biomarker of the CKD status.
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http://dx.doi.org/10.1016/j.mrgentox.2020.503167DOI Listing
April 2020

Identification of Familial Hodgkin Lymphoma Predisposing Genes Using Whole Genome Sequencing.

Front Bioeng Biotechnol 2020 6;8:179. Epub 2020 Mar 6.

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

Hodgkin lymphoma (HL) is a lymphoproliferative malignancy of B-cell origin that accounts for 10% of all lymphomas. Despite evidence suggesting strong familial clustering of HL, there is no clear understanding of the contribution of genes predisposing to HL. In this study, whole genome sequencing (WGS) was performed on 7 affected and 9 unaffected family members from three HL-prone families and variants were prioritized using our Familial Cancer Variant Prioritization Pipeline (FCVPPv2). WGS identified a total of 98,564, 170,550, and 113,654 variants which were reduced by pedigree-based filtering to 18,158, 465, and 26,465 in families I, II, and III, respectively. In addition to variants affecting amino acid sequences, variants in promoters, enhancers, transcription factors binding sites, and microRNA seed sequences were identified from upstream, downstream, 5' and 3' untranslated regions. A panel of 565 cancer predisposing and other cancer-related genes and of 2,383 potential candidate HL genes were also screened in these families to aid further prioritization. Pathway analysis of segregating genes with Combined Annotation Dependent Depletion Tool (CADD) scores >20 was performed using Ingenuity Pathway Analysis software which implicated several candidate genes in pathways involved in B-cell activation and proliferation and in the network of "Cancer, Hematological disease and Immunological Disease." We used the FCVPPv2 for further analyses and prioritized 45 coding and 79 non-coding variants from the three families. Further literature-based analysis allowed us to constrict this list to one rare germline variant each in families I and II and two in family III. Functional studies were conducted on the candidate from family I in a previous study, resulting in the identification and functional validation of a novel heterozygous missense variant in the tumor suppressor gene as potential HL predisposition factor. We aim to identify the individual genes responsible for predisposition in the remaining two families and will functionally validate these in further studies.
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http://dx.doi.org/10.3389/fbioe.2020.00179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067901PMC
March 2020

Second Primary Cancers in Melanoma Patients Critically Shorten Survival.

Clin Epidemiol 2020 23;12:105-112. Epub 2020 Jan 23.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg D-69120, Germany.

Background: Survival in malignant cutaneous melanoma has improved but increasing survival will result in an increased likelihood of the occurrence of second primary cancers (SPCs). SPCs may adversely interfere with survival. We quantified survival in patients with different types of SPCs, in comparison to known poor prognostic indicators of metastatic disease.

Methods: Data for melanoma and any SPCs were obtained from the Swedish Cancer Registry for years 2003 through 2015, including clinical TNM classification. SPCs were grouped into three 'prognostic groups' based on 5-year relative survival of these cancers as first primary cancer. Kaplan-Meier survival curves were generated and hazard ratios were estimated using Cox regression, adjusted for a number of variables and treating diagnosis of SPC as a time-dependent variable.

Results: The total number of first melanoma patients was 28,716 followed by 3,202 (11.1%) SPCs, 1/3 of which had a second melanoma while 2/3 had other SPCs. Among men diagnosed at age over 70 years, who survived at least 10 years, 31.4% had SPC. HRs (95% CI) for survival increased systematically from the reference rate of 1.00 (no SPC) to 1.59 (1.35-1.87) with SPC of good prognosis (78.6% of SPCs) to 3.49 (2.58-4.72) of moderate prognosis (12.0%) and to 7.93 (5.50-11.44) of poor prognosis (9.4%). In patients without SPC, the HRs increased to 2.62 (2.02-3.39) with any nodal metastases and to 5.88 (4.57-7.57) with any distant metastases compared to patients without local or distant metastases.

Conclusion: The data showed that SPCs are an increasingly common negative prognostic factor for melanoma. Future attempts to improve melanoma survival need to target SPCs.
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http://dx.doi.org/10.2147/CLEP.S230149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986257PMC
January 2020

Association between tumor characteristics and second primary cancers with cutaneous melanoma survival: A nationwide cohort study.

Pigment Cell Melanoma Res 2020 07 19;33(4):625-632. Epub 2020 Feb 19.

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

The increased survival in malignant cutaneous melanoma (melanoma) is probably due to early diagnosis combined with improved treatment most recently. National health campaigns and screening programs for melanoma detection were started in Sweden several decades ago. We want to assess the influence of tumor characteristics, based on the TNM classification, and of second primary cancers on overall survival in melanoma. We used the Swedish Cancer Registry to assess all-cause survival in melanoma from 2003 to 2015. Hazard ratios (HRs) were estimated using multivariable Cox regression models. A total of 19,773 melanoma patients were diagnosed with TNM data. Survival showed a strong improving trend over time (p-trend <.001). T1a was the most common classification (48.0% of all), while higher T class was associated systematically with worse survival (p-trend <.001). For distant metastases, the HR was 3.17, accounting for 0.9% of the patients. Any types of second primary cancers, other than melanoma, were associated with an HR of 2.00, accounted for 6.7% of all cases. Even if melanoma survival in Sweden ranks among the best national rates, the large percentage of patients with advanced tumors (T3b, T4a, and T4b, 17%) and 21% of deaths with T1a call for improved preventive and follow-up strategies.
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http://dx.doi.org/10.1111/pcmr.12868DOI Listing
July 2020

TERT promoter mutations in actinic keratosis before and after treatment.

Int J Cancer 2020 05 30;146(10):2932-2934. Epub 2020 Jan 30.

Division of Functional Genome Analysis, German Cancer Research Center, Heidelberg, Germany.

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http://dx.doi.org/10.1002/ijc.32878DOI Listing
May 2020

Genetic Variants Associated with Chronic Kidney Disease in a Spanish Population.

Sci Rep 2020 01 10;10(1):144. Epub 2020 Jan 10.

Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Edifici C, Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Vallès, Spain.

Chronic kidney disease (CKD) patients have many affected physiological pathways. Variations in the genes regulating these pathways might affect the incidence and predisposition to this disease. A total of 722 Spanish adults, including 548 patients and 174 controls, were genotyped to better understand the effects of genetic risk loci on the susceptibility to CKD. We analyzed 38 single nucleotide polymorphisms (SNPs) in candidate genes associated with the inflammatory response (interleukins IL-1A, IL-4, IL-6, IL-10, TNF-α, ICAM-1), fibrogenesis (TGFB1), homocysteine synthesis (MTHFR), DNA repair (OGG1, MUTYH, XRCC1, ERCC2, ERCC4), renin-angiotensin-aldosterone system (CYP11B2, AGT), phase-II metabolism (GSTP1, GSTO1, GSTO2), antioxidant capacity (SOD1, SOD2, CAT, GPX1, GPX3, GPX4), and some other genes previously reported to be associated with CKD (GLO1, SLC7A9, SHROOM3, UMOD, VEGFA, MGP, KL). The results showed associations of GPX1, GSTO1, GSTO2, UMOD, and MGP with CKD. Additionally, associations with CKD related pathologies, such as hypertension (GPX4, CYP11B2, ERCC4), cardiovascular disease, diabetes and cancer predisposition (ERCC2) were also observed. Different genes showed association with biochemical parameters characteristic for CKD, such as creatinine (GPX1, GSTO1, GSTO2, KL, MGP), glomerular filtration rate (GPX1, GSTO1, KL, ICAM-1, MGP), hemoglobin (ERCC2, SHROOM3), resistance index erythropoietin (SOD2, VEGFA, MTHFR, KL), albumin (SOD1, GSTO2, ERCC2, SOD2), phosphorus (IL-4, ERCC4 SOD1, GPX4, GPX1), parathyroid hormone (IL-1A, IL-6, SHROOM3, UMOD, ICAM-1), C-reactive protein (SOD2, TGFB1,GSTP1, XRCC1), and ferritin (SOD2, GSTP1, SLC7A9, GPX4). To our knowledge, this is the second comprehensive study carried out in Spanish patients linking genetic polymorphisms and CKD.
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http://dx.doi.org/10.1038/s41598-019-56695-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954113PMC
January 2020