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.

Investigation of clinically relevant germline variants detected by next-generation sequencing in patients with childhood cancer: a review of the literature

“…Of the cancer types in the cases selected for these studies, pathogenic or likely pathogenic variants were detected most frequently (15.5%) in patients with non-CNS solid tumours and least frequently (4.5%) in patients with haematological malignancies. The frequency of cancer predisposing germline variants is known to vary between cancer types 25. This review comprised a broad spectrum of cancer types including rare cancer diagnoses and/or those with poor clinical outcomes,13 15–18 and this may influence the frequency of carriers identified with cancer predisposing germline variants.…”

Seltene Tumordispositionssyndrome

“…Damit treten in Deutschland jährlich mindestens 15-20.000 Malignome im Kontext eines TDS auf (www.rki.de; [1,3,4] Die seit langem bekannte unzureichende Identifizierung und medizinische Betreuung der von TDS betroffenen Familien liegt insbesondere an der mangelnden Sensitivität etablierter klinischer Kriterien, komplexer diagnostischer Pfade (HNPCC/Lynch-Syndrom), der unzureichenden Erhebung aussagekräftiger Familienanamnesen im klinischen Alltag, der eingeschränkten Qualität familienanamnestischer Angaben und kleiner Familien sowie der vergleichsweise noch geringen ärztlichen Aufmerksamkeit der Problematik gegenüber. Die Steigerung der diagnostischen Sensitivität durch eine umfangreiche Keimbahn-Analyse hinsichtlich TDS unabhängig von klinischen Verdachtsmomenten beginnt deshalb schon jetzt Realität zu werden, insbesondere im pädiatrischen Bereich, wo bis zu 9 % der Tumorpatienten Anlageträger eines TDS sind und es sich häufig um sporadisch auftretende Fälle handelt [7].…”

Targeted Gene Sequencing of Gallbladder Carcinoma Identifies High-impact Somatic and Rare Germline Mutations

“…Knudson's two-hit hypothesis and recent cancer genomics studies, the importance of inherited germline mutations in carcinogenesis has become clearer (27)(28)(29). Instead of entire profile of germline variants, we restricted our study only to rare and deleterious germline mutations.…”

“…Several cancer drivers and progression markers were established in this way. More recently, the cancer research field has begun to understand the importance of rare deleterious germline variants in carcinogenesis and progression (28,29,37). GBC is not among the most heritable types of human cancer, although variability in its ethnic and geographical incidence rates has been partly associated with cancer predisposition (38)(39)(40).…”