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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.

Ian Tomlinson and colleagues report the identification of germline variants in POLE and POLD1 that are susceptibility alleles for colorectal cancer. POLE and POLD1 encode DNA polymerases that function in DNA replication.

DNA repair defects underlie many cancer syndromes. This study investigates whether parents with inherited problems of DNA repair pass on an increased number of de novo mutations to their children. The authors find that this does occur, but that clinical consequences are unlikely.

Healthy tissues from individuals with germline mutations in POLE or POLD1 show increased mutational burden, suggesting that normal cells are capable of tolerating high mutation rates.

A multi-ancestry genome-wide association study meta-analysis, combined with transcriptome- and methylome-wide association analyses, identifies risk loci associated with colorectal cancer. Credible effector genes and their target tissues are also highlighted, showing that over a third probably act outside the colonic mucosa.

Whole-genome sequencing and phenotype data sharing are introduced in a national health system to streamline diagnosis and to discover coding and non-coding variants that cause rare diseases.

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.

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.

Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. They report three loci newly associated with colorectal cancer, bringing the total number of common susceptibility loci to 20.

Gastroesophageal reflux disease (GERD) is a major risk factor for Barret’s esophagus (BE) and esophageal adenocarcinoma (EA). Here, An et al. report 25 genetic loci for GERD, many of which associate with BE and EA or with other traits such as BMI.

The genetic factors that predispose individuals to familial colorectal cancer are poorly understood. In this study, the authors use whole exome sequencing of 1,006 patients and 1,609 healthy controls and show it is unlikely that further major high-penetrance susceptibility genes exist.

Defective ribonucleotide excision repair causes ID4, an indel cancer signature characterized by deletions of 2–5 base pairs.

Genome sequence data from colorectal tumours show how adenomas progress to carcinomas on the fitness landscape.

In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.

Oesophageal adenocarcinoma is often treated with chemotherapy before surgery. Here, the authors sequence cancer samples before and after chemotherapy and examine how the genome changes, focusing on changes in driver gene mutations and differential clonal evolution between good and poor responders.

Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.

Peter Donnelly and colleagues report a genome-wide association study for Barrett's esophagus, a common premalignant condition associated with stomach acid reflux and predisposing to esophageal adenocarcinoma. They identify two loci associated with susceptibility to Barrett's esophagus.

The burden of chemotherapy-associated toxicity is well recognized, but we have relatively few tools that increase the precision of anticancer drug prescribing. This article proposes that broader agnostic analyses to systematically correlate germline genetic variants with adverse events in large, well-defined cancer populations might improve the current situation.

Whole-genome sequencing of chronic lymphocytic leukemia from 485 patients identifies putative coding and noncoding drivers of disease. Genomically defined subgroups show distinct clinical and biological characteristics.

Recent studies have shown that germline and somatic mutations in the proofreading exonuclease domains of the replicative DNA polymerases Pol δ and Pol ε are associated with several cancers. This Review summarizes what these mutations are and how they might drive tumorigenesis, and highlights their potential as novel biomarkers and therapeutic targets.

Amanda Spurdle, Ian Tomlinson, Douglas Easton and colleagues conduct a GWAS meta-analysis and identify five new risk loci for endometrial cancer. Functional studies show that one risk-associated SNP is located in an active chromatin region that interacts with the KLF5 promoter.