Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes



Whitworth, James, Smith, Philip S, Martin, Jose-Ezequiel, West, Hannah, Luchetti, Andrea, Rodger, Faye, Clark, Graeme, Carss, Keren, Stephens, Jonathan, Stirrups, Kathleen
et al (show 33 more authors) (2018) Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. AMERICAN JOURNAL OF HUMAN GENETICS, 103 (1). pp. 3-18.

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Abstract

Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition. Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type. We ascertained pre-assessed MPT individuals (with at least two primary tumors by age 60 years or at least three by 70 years) from genetics centers and performed whole-genome sequencing (WGS) on 460 individuals from 440 families. Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands. WGS detected variants that would not be (or were not) detected by targeted resequencing strategies, including low-frequency structural variants (6/440 [1.4%] probands). In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG. However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant. The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (χ<sup>2</sup> = 43.642; p ≤ 0.0001). 2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs. Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.

Item Type: Article
Uncontrolled Keywords: NIHR BioResource Rare Diseases Consortium, Humans, Neoplasms, Multiple Primary, Genetic Predisposition to Disease, Phenotype, Germ-Line Mutation, Adult, Aged, Middle Aged, Female, Male, Genetic Variation, Genetic Testing, Biomarkers, Tumor
Depositing User: Symplectic Admin
Date Deposited: 14 May 2019 07:37
Last Modified: 19 Jan 2023 00:46
DOI: 10.1016/j.ajhg.2018.04.013
Open Access URL: https://doi.org/10.1371/journal.pone.0205737
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3041172