Patterns and functional implications of rare germline variants across 12 cancer types
Open Access
- 22 December 2015
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 6 (1), 10086
- https://doi.org/10.1038/ncomms10086
Abstract
Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine.This publication has 54 references indexed in Scilit:
- Comprehensive molecular portraits of human breast tumoursNature, 2012
- Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencingProceedings of the National Academy of Sciences of the United States of America, 2011
- Comparison of statistical tests for disease association with rare variantsGenetic Epidemiology, 2011
- GWAS Integrator: a bioinformatics tool to explore human genetic associations reported in published genome-wide association studiesEuropean Journal of Human Genetics, 2011
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- ATM activates p53 by regulating MDM2 oligomerization and E3 processivityThe EMBO Journal, 2009
- Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short readsBioinformatics, 2009
- PALB2 is an integral component of the BRCA complex required for homologous recombination repairProceedings of the National Academy of Sciences of the United States of America, 2009
- Repeated observation of breast tumor subtypes in independent gene expression data setsProceedings of the National Academy of Sciences of the United States of America, 2003
- Mutation and Cancer: Statistical Study of RetinoblastomaProceedings of the National Academy of Sciences of the United States of America, 1971