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Patterns and functional implications of rare germline variants across 12 cancer types.

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.

SUBMITTER: Lu C

PROVIDER: S-EPMC4703835 | biostudies-other | 2015 Dec

REPOSITORIES: biostudies-other

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Patterns and functional implications of rare germline variants across 12 cancer types.

Lu Charles C Xie Mingchao M Wendl Michael C MC Wang Jiayin J McLellan Michael D MD Leiserson Mark D M MD Huang Kuan-Lin KL Wyczalkowski Matthew A MA Jayasinghe Reyka R Banerjee Tapahsama T Ning Jie J Tripathi Piyush P Zhang Qunyuan Q Niu Beifang B Ye Kai K Schmidt Heather K HK Fulton Robert S RS McMichael Joshua F JF Batra Prag P Kandoth Cyriac C Bharadwaj Maheetha M Koboldt Daniel C DC Miller Christopher A CA Kanchi Krishna L KL Eldred James M JM Larson David E DE Welch John S JS You Ming M Ozenberger Bradley A BA Govindan Ramaswamy R Walter Matthew J MJ Ellis Matthew J MJ Mardis Elaine R ER Graubert Timothy A TA Dipersio John F JF Ley Timothy J TJ Wilson Richard K RK Goodfellow Paul J PJ Raphael Benjamin J BJ Chen Feng F Johnson Kimberly J KJ Parvin Jeffrey D JD Ding Li L

Nature communications 20151222

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 ...[more]

PMID: 26689913

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Project description:We investigated a Spanish and Catalan family in which multiple cancer types tracked across three generations, but for which no genetic etiology had been identified. Whole-exome sequencing of germline DNA from multiple affected family members was performed to identify candidate variants to explain this occurrence of familial cancer. We discovered in all cancer-affected family members a single rare heterozygous germline variant (I654V, rs1801201) in ERBB2/HER2, which is located in a transmembrane glycine zipper motif critical for ERBB2-mediated signaling and in complete linkage disequilibrium (D' = 1) with a common polymorphism (I655V, rs1136201) previously reported in some populations as associated with cancer risk. Because multiple cancer types occurred in this family, we tested both the I654V and the I655V variants for association with cancer across multiple tumor types in 6,371 cases of Northern European ancestry drawn from The Cancer Genome Atlas and 6,647 controls, and found that the rare variant (I654V) was significantly associated with an increased risk for cancer (OR = 1.40; P = 0.021; 95% confidence interval (CI), 1.05-1.89). Functional assays performed in HEK 293T cells revealed that both the I655V single mutant (SM) and the I654V;I655V double mutant (DM) stabilized ERBB2 protein and activated ERBB2 signaling, with the DM activating ERBB2 significantly more than the SM alone. Thus, our results suggest a model whereby heritable genetic variation in the transmembrane domain activating ERBB2 signaling is associated with both sporadic and familial cancer risk, with increased ERBB2 stabilization and activation associated with increased cancer risk. PREVENTION RELEVANCE: By performing whole-exome sequencing on germline DNA from multiple cancer-affected individuals belonging to a family in which multiple cancer types track across three generations, we identified and then characterized functional common and rare variation in ERBB2 associated with both sporadic and familial cancer. Our results suggest that heritable variation activating ERBB2 signaling is associated with risk for multiple cancer types, with increases in signaling correlated with increases in risk, and modified by ancestry or family history.

Dataset Information

Patterns and functional implications of rare germline variants across 12 cancer types.

Publications

Patterns and functional implications of rare germline variants across 12 cancer types.

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