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| Open AccessFine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
Here, the authors perform large trans-ancestry fine-mapping analyses identifying large numbers of association signals and putative target genes for colorectal cancer risk, advancing our understanding of the genetic and biological basis of this cancer.
- Zhishan Chen
- , Xingyi Guo
- & Wei Zheng
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Article
| Open AccessIntegration of pathologic characteristics, genetic risk and lifestyle exposure for colorectal cancer survival assessment
Risk prediction for prognosis in colorectal cancer is an important tool. Here, the authors utilise GWAS from 5 cohorts of colorectal cancer patients, and show a healthy lifestyle is associated with a 7.6% improvement in overall survival among patients with high pathologic and genetic risk.
- Junyi Xin
- , Dongying Gu
- & Meilin Wang
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Article
| Open AccessA population-based cohort study of longitudinal change of high-density lipoprotein cholesterol impact on gastrointestinal cancer risk
High-density Lipoprotein Cholesterol (HDL-C) levels have been associated with cancer. Here, the authors show the association between longitudinal changes of HDL-C and risk of gastrointestinal cancer in a patients.
- Su Youn Nam
- , Junwoo Jo
- & Chang-Min Cho
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Article
| Open AccessPolygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis
Colitis is one of the most common immune-related adverse events in patients with cancer treated with immune checkpoint inhibitors. Here the authors show that a polygenic risk score for ulcerative colitis can predict immune checkpoint inhibitor-mediated colitis in patients with cancer.
- Pooja Middha
- , Rohit Thummalapalli
- & Elad Ziv
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Article
| Open AccessPhenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers
Mendelian randomisation can identify potential risk factors from large populations. Here, the authors analyse 3000 traits across multiple cancer types to search for potential risk factors and molecular biomarkers.
- Molly Went
- , Amit Sud
- & Richard Houlston
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Article
| Open AccessCauses of death among people living with metastatic cancer
Studying survivorship and causes of death in patients with metastatic cancer remains an important task. Here, the authors characterise the causes of death in over a million patients with metastatic cancer, and predict the risk of death after diagnosis due to cancer-related or other causes.
- Kyle Mani
- , Daxuan Deng
- & Nicholas G. Zaorsky
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Article
| Open AccessHealthy dietary patterns and the risk of individual chronic diseases in community-dwelling adults
Dietary patterns have been linked to a limited number of major chronic diseases. Here, the authors show greater adherence to healthy dietary patterns, especially Alternate Mediterranean Diet, is associated with a lower risk of most of the 48 tested chronic diseases.
- Xianwen Shang
- , Jiahao Liu
- & Mingguang He
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Article
| Open AccessGenome-wide enhancer-gene regulatory maps link causal variants to target genes underlying human cancer risk
Here, the authors apply the Activity-by-Contact (ABC) model to infer enhancer-gene regulation and the effect of associated variants across multiple cancer types, integrating genetic and multi-omics data. Then, they explore the mechanisms associated with ABC regulatory variants in colorectal cancer.
- Pingting Ying
- , Can Chen
- & Xiaoping Miao
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Article
| Open AccessDisentangling age, gender, and racial/ethnic disparities in multiple myeloma burden: a modeling study
Multiple myeloma (MM) is a haematological malignancy that is preceded by monoclonal gammopathy of undetermined significance (MGUS). Here, the authors use a mechanistic model fitted to surveillance data from the United States to investigate whether variation in MM is best explained by incidence of MGUS or rate of progression to MM.
- John H. Huber
- , Mengmeng Ji
- & Su-Hsin Chang
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Article
| Open AccessLongitudinal body mass index and cancer risk: a cohort study of 2.6 million Catalan adults
Here, the authors show that longer duration and greater degree of overweight and obesity during early adulthood as well as younger age of onset of a high body mass index are associated with a higher risk of 18 cancer types.
- Martina Recalde
- , Andrea Pistillo
- & Talita Duarte-Salles
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Article
| Open AccessGenome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population
Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of lung adenocarcinoma but known susceptibility variants explain only a small fraction of the familial risk. Here, the authors perform a two-stage GWAS and report 12 novel genetic loci associated with lung adenocarcinoma in East Asians.
- Jianxin Shi
- , Kouya Shiraishi
- & Qing Lan
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Article
| Open AccessPancreatic cancer is associated with medication changes prior to clinical diagnosis
Pancreatic cancer patients have previously been noted to have a change in medication history prior to diagnosis. Here, the authors utilise two large population cohorts to show associations between recent medication changes and risk of a subsequent pancreatic cancer diagnosis.
- Yin Zhang
- , Qiao-Li Wang
- & Brian M. Wolpin
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Article
| Open AccessAntimicrobial exposure is associated with decreased survival in triple-negative breast cancer
Here, in a cohort of 772 women undergoing triple-negative breast cancer (TNBC) therapy, the authors show that antimicrobial prescription during TNBC treatment associates with inferior overall and breast cancer-specific survival, in turn related to peripheral lymphocyte count and gut microbiome dysbiosis.
- Julia D. Ransohoff
- , Victor Ritter
- & Allison W. Kurian
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Article
| Open AccessFood abundance in men before puberty predicts a range of cancers in grandsons
Nutritional conditions experienced early in life may influence the disease risk of future children and grandchildren. Here the authors report that food abundance among boys before puberty associates with the relative risk of a range of cancers in grandsons, but not in granddaughters.
- Denny Vågerö
- , Agneta Cederström
- & Gerard J. van den Berg
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Article
| Open AccessEvaluating cancer etiology and risk with a mathematical model of tumor evolution
Modelling how endogenous mutations accumulate in tissues is valuable to understand how cancers develop and evolve. Here, the authors establish a mathematical model that can predict the number of endogenous somatic mutations in the lifetime of tissues and approximate the time to cancer development.
- Sophie Pénisson
- , Amaury Lambert
- & Cristian Tomasetti
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Article
| Open AccessDNA methylation at birth in monozygotic twins discordant for pediatric acute lymphoblastic leukemia
The role of DNA methylation in predisposing to pediatric acute lymphoblastic leukemia remains unknown. Here, the authors utilize a discordant twin model to investigate how DNA methylation variation contributes to disease risk in genetically identical subjects.
- Eric M. Nickels
- , Shaobo Li
- & Joseph L. Wiemels
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Article
| Open AccessIntegrated analysis of cervical squamous cell carcinoma cohorts from three continents reveals conserved subtypes of prognostic significance
Human papillomavirus (HPV) is a known cause of cervical cancer. Here, the authors perform a multi-omic analysis using published cervical squamous cell carcinoma cohorts from the USA, Europe, and SubSaharan Africa and identify two cervical squamous cell carcinoma subtypes that display prognostic differences.
- Ankur Chakravarthy
- , Ian Reddin
- & Tim R. Fenton
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Article
| Open AccessThe comparison of cancer gene mutation frequencies in Chinese and U.S. patient populations
Frequency of cancer-related gene mutations can vary between populations. Here, the authors show differences in TP53 and other gene mutations between the U.S. and Chinese patients, and analyse differences in environmental risk factors to demonstrate that population-specific factors should be considered when discussing cancer risk.
- Fayang Ma
- , Kyle Laster
- & Zigang Dong
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Article
| Open AccessDNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival
Glucocorticoids, such as dexamethasone, are used as anti-inflammatory and immunosuppressive drugs, however patients may exhibit resistance or side effects. Here the authors propose that a dexamethasone related neutrophil-specific DNA methylation index can be used as a marker of glucocorticoid exposure and response and as a prognostic factor in brain tumor survival.
- J. K. Wiencke
- , Annette M. Molinaro
- & Karl T. Kelsey
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Article
| Open AccessmolBV reveals immune landscape of bacterial vaginosis and predicts human papillomavirus infection natural history
Here, Burk et al. develop an algorithm to diagnose bacterial vaginosis (BV) using the 16S rRNA gene, called molBV, which they use to profile the inflammatory landscape of BV and predict progression of human papillomavirus infection to cervical pre-cancer.
- Mykhaylo Usyk
- , Nicolas F. Schlecht
- & Robert D. Burk
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Article
| Open AccessCancer gene mutation frequencies for the U.S. population
Understanding the frequency of gene mutations in cancer could be important for generating targeted therapeutics. Here, the authors use SEER data and cancer genomics data from TCGA to estimate the gene mutation frequencies in the US cancer population.
- Gaurav Mendiratta
- , Eugene Ke
- & Edward C. Stites
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Article
| Open AccessA microRNA panel compared to environmental and polygenic scores for colorectal cancer risk prediction
Appropriate risk models could facilitate risk stratification for colorectal cancer (CRC) screening. Here, the authors propose a blood-based microRNA signature observed to have altered expression in pre-diagnostic samples, which might be useful to identify high-risk populations for colorectal cancer screening.
- Janhavi R. Raut
- , Ben Schöttker
- & Hermann Brenner
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Article
| Open AccessAn umbrella review of the evidence associating diet and cancer risk at 11 anatomical sites
Diet and food intake have been associated with a risk of developing different types of cancer but individual nutritional epidemiology studies are prone to inherent bias. Here, the authors perform an umbrella review of meta-analyses of observational studies and show the level of evidence for associating food and nutrients to cancer risk.
- Nikos Papadimitriou
- , Georgios Markozannes
- & Konstantinos K. Tsilidis
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Article
| Open AccessCross-ancestry GWAS meta-analysis identifies six breast cancer loci in African and European ancestry women
GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.
- Babatunde Adedokun
- , Zhaohui Du
- & Dezheng Huo
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Article
| Open AccessA case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers
Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.
- Juliette Coignard
- , Michael Lush
- & Antonis C. Antoniou
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Article
| Open AccessCross-cancer evaluation of polygenic risk scores for 16 cancer types in two large cohorts
While genetic loci shared between cancer types have been identified, cross-cancer relationships for polygenic risk scores have not been well studied. Here, the authors have developed polygenic risk scores for 16 cancers in two large cohorts and identified positive and inverse cross-cancer associations.
- Rebecca E. Graff
- , Taylor B. Cavazos
- & Lori C. Sakoda
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Article
| Open AccessA comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization
Studies of the genetic association between vitamin D and cancer risk have typically been underpowered. Here the authors analyse this using Mendelian Randomisation with more than 70 vitamin D variants obtained from the UK Biobank and large-scale data from various consortia, confirming null associations between vitamin D and most cancers.
- Jue-Sheng Ong
- , Suzanne C. Dixon-Suen
- & Stuart MacGregor
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| Open AccessPan-cancer analysis demonstrates that integrating polygenic risk scores with modifiable risk factors improves risk prediction
Predicting cancer risk requires large datasets and sophisticated models. Here the authors integrate polygenic risk scores and modifiable risk factors for multiple cancers in the UK Biobank, improving general risk prediction and distinguishing cases where genetic or lifestyle factors have stronger associations.
- Linda Kachuri
- , Rebecca E. Graff
- & Mattias Johansson
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Article
| Open AccessIdentification of 31 loci for mammographic density phenotypes and their associations with breast cancer risk
Mammographic density represents one the strongest predictors of breast cancer risk. Here the authors perform genome-wide association study meta-analysis of women screened with full-field digital mammography and identify 31 previously unreported loci associated with mammographic density phenotypes.
- Weiva Sieh
- , Joseph H. Rothstein
- & Laurel A. Habel
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Article
| Open AccessPan-cancer study detects genetic risk variants and shared genetic basis in two large cohorts
Pleiotropic loci and genome-wide genetic correlations have identified shared heritability across some types of cancers. Here, the authors perform genome-wide association studies and characterize pan-cancer heritability and pleiotropy in individuals of European ancestry across 18 cancer types from two large cohorts.
- Sara R. Rashkin
- , Rebecca E. Graff
- & John S. Witte
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Article
| Open AccessAn integrative multi-omics analysis to identify candidate DNA methylation biomarkers related to prostate cancer risk
Genome wide association studies have identified multiple loci associated with risk of developing prostate cancer but the functional significance of many of these are unknown. Here, after generating models to predict methylation, the authors identify CpG methylation sites associated with prostate cancer.
- Lang Wu
- , Yaohua Yang
- & Stella Koutros
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Article
| Open AccessPhosphodiesterase-5 inhibitors use and risk for mortality and metastases among male patients with colorectal cancer
Phosphodiesterase-5 (PDE5) inhibitors have been suggested to have an anti-tumor effect and block surgery-induced immunosuppression. Here, the authors show that postdiagnostic use of PDE5 inhibitors is associated with a decreased risk of colorectal cancerspecific mortality as well as a decreased risk of metastasis.
- Wuqing Huang
- , Jan Sundquist
- & Jianguang Ji
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Article
| Open Accessm5C modification of mRNA serves a DNA damage code to promote homologous recombination
Post-translational modifications of proteins at DNA damage sites can facilitate the recruitment of DNA repair factors. Here, the authors show that mRNA is locally modified with m5C at sites of DNA damage by the RNA methyltransferase TRDMT1 to promote homologous recombination repair.
- Hao Chen
- , Haibo Yang
- & Li Lan
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Article
| Open AccessFatal heart disease among cancer patients
As the overlap between heart disease and cancer patients increases as cancer-specific mortality is decreasing, identifying cancer patients who are at an increased risk of death from heart disease is important. Here the authors report on risk of death from heart diseases among more than 7.5 million cancer patients.
- Kelsey C. Stoltzfus
- , Ying Zhang
- & Nicholas G. Zaorsky
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Article
| Open AccessPhysical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis
Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.
- Nikos Papadimitriou
- , Niki Dimou
- & Neil Murphy
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Article
| Open AccessImmune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility
The role of impaired lung function in lung cancer etiology is complex due to the relation of cigarette smoking to both conditions. Here, supported by Mendelian randomization analysis the authors find a link between pulmonary function impairment and lung cancer risk beyond smoking, implicating immune-related pathways
- Linda Kachuri
- , Mattias Johansson
- & Rayjean J. Hung
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Article
| Open AccessInterval breast cancer is associated with other types of tumors
Interval cancer patients are more likely to carry rare gene mutations than screen-detected breast cancer patients. Here, the authors report that interval cancer patients are more likely cancer survivors and are at a greater risk of developing other non-breast tumors.
- Felix Grassmann
- , Wei He
- & Kamila Czene
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Article
| Open AccessHigh-fat diet fuels prostate cancer progression by rewiring the metabolome and amplifying the MYC program
Prostate cancer progression may be enhanced by a high-fat diet. Here the authors show that a diet high in saturated fats enhance the MYC-driven transcriptional program, a feature that independently predicts prostate cancer progression and death.
- David P. Labbé
- , Giorgia Zadra
- & Myles Brown
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Article
| Open AccessCentral body fatness is a stronger predictor of cancer risk than overall body size
Obesity is linked to increased cancer risk but the impact of body size versus weight distribution in determining the increased risk is unclear. Here the authors examined body mass index, waist circumference, and waist to hip ratio in relation to all-cancer incidence and incidence of seven individual cancers in a population of approximately 26,000 individual and conclude that central adiposity appears to be a stronger predictor of all-cancer risk than body size.
- Amanda M. Barberio
- , Asalah Alareeki
- & Darren R. Brenner
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Article
| Open AccessSuicide among cancer patients
Cancer patients are at an increased risk of suicide: elderly, white, unmarried males with localized disease are at highest risk vs other cancer patients. Among those diagnosed at < 50 years of age, the plurality of suicides is from hematologic and testicular tumors; if > 50, from prostate, lung, and colorectal cancer patients.
- Nicholas G. Zaorsky
- , Ying Zhang
- & Vernon M. Chinchilli
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Article
| Open AccessTwo high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia
Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a non-Hodgkin-type B cell lymphoma. Here, the authors identify two risk loci for WM/LPL in a two-stage GWAS involving a family-oversampling approach and provide evidence for a functional role of the non-coding SNP rs116446171.
- Mary L. McMaster
- , Sonja I. Berndt
- & Neil E. Caporaso
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Article
| Open AccessA Mendelian randomization study of the effects of blood lipids on breast cancer risk
The link between circulating lipids and breast cancer risk is complex. Here, the authors utilise data from more than 400,000 participants in two-sample Mendelian randomization to assess the link between blood lipids and breast cancer risk, and they find risk-promoting effects of raised LDL-cholesterol and CETP-mediated raised HDL-cholesterol.
- Christoph Nowak
- & Johan Ärnlöv
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Perspective
| Open AccessEvaluating intrinsic and non-intrinsic cancer risk factors
Understanding the contributions of extrinsic and intrinsic factors on cancer risk is fundamental in determining the intervention and prevention strategies to tackle cancer. Here the authors provide a review of the different factors impacting cancer risk and discuss the limitations of different approaches in evaluating the relative contributions of these factors.
- Song Wu
- , Wei Zhu
- & Yusuf A Hannun
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Article
| Open AccessAssociation between post-diagnostic use of cholera vaccine and risk of death in prostate cancer patients
Post-diagnostic use of cholera vaccine can improve the prognosis in patients with colorectal cancer suggesting cholera toxin might have an antineoplastic effect. Here the authors perform a nationwide population-based study and report an association between cholera vaccine administration and reduction in prostate cancer mortality.
- Jianguang Ji
- , Jan Sundquist
- & Kristina Sundquist
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Article
| Open AccessGenome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
Genetic variants associated with susceptibility to pancreatic cancer have been identified using genome wide association studies (GWAS). Here, the authors combine data from over 9000 patients and perform a meta-analysis to identify five novel loci linked to pancreatic cancer.
- Alison P. Klein
- , Brian M. Wolpin
- & Laufey T. Amundadottir
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Article
| Open AccessInequality in genetic cancer risk suggests bad genes rather than bad luck
Cancer heritability estimates can be obtained via decomposing trait variance into genetic and other factors. Here, the authors obtain the distribution of absolute genetic risk for 15 common cancers, and they use a number of metrics to show that the genetic risk varies considerably across individuals.
- Mats Julius Stensrud
- & Morten Valberg
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Article
| Open AccessAndrogen receptor increases hematogenous metastasis yet decreases lymphatic metastasis of renal cell carcinoma
The incidence of renal cell carcinoma is higher in males than in females due to the different androgen receptor signaling but the molecular mechanisms behind this gender bias are unclear. Here the authors show how androgen receptor expression influences the metastatic route through the regulation of miR-185 and VEGF isoforms.
- Qingbo Huang
- , Yin Sun
- & Chawnshang Chang
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Article
| Open AccessGenome-wide association study identifies multiple risk loci for renal cell carcinoma
Risk for renal cell carcinoma (RCC) is higher when there are first-degree family members with the disease. Here, Scelo and colleagues perform a genome-wide association meta-analysis and new genome-wide scan to identify seven new loci with significant RCC association.
- Ghislaine Scelo
- , Mark P. Purdue
- & Stephen J. Chanock
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Article
| Open AccessComprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2
Lynch syndrome is characterized by predisposition to colorectal cancer and mutations in genes involved in mismatch repair. Here, the authors use whole genome sequencing and immunohistochemistry of mismatch repair proteins to show a high prevalence of Lynch syndrome in the Icelandic population.
- Sigurdis Haraldsdottir
- , Thorunn Rafnar
- & Kari Stefansson