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

Whitworth J1, Smith PS1, Martin JE1, West H1, Luchetti A1, Rodger F1, Clark G1, Carss K2, Stephens J2, Stirrups K2, Penkett C2, Mapeta R2, Ashford S3, Megy K2, Shakeel H1, Ahmed M4, Adlard J5, Barwell J6, Brewer C7, Casey RT1, Armstrong R8, Cole T9, Evans DG10, Fostira F11, Greenhalgh L12, Hanson H13, Henderson A14, Hoffman J9, Izatt L15, Kumar A16, Kwong A17, Lalloo F10, Ong KR9, Paterson J18, Park SM8, Chen-Shtoyerman R19, Searle C20, Side L4, Skytte AB21, Snape K13, Woodward ER10; NIHR BioResource Rare Diseases Consortium3, Tischkowitz MD22, Maher ER23.

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 (χ2 = 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.