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.
Highlights
IntroductionInherited cancer-predisposition syndromes account for a significant minority of cancer diagnoses and provide important opportunities for high-impact clinical intervention (in probands and their relatives) through preventative strategies in unaffected individuals (e.g., surveillance scans, prophylactic surgery, and chemoprevention) and personalized therapies in those with cancer
Inherited cancer-predisposition syndromes account for a significant minority of cancer diagnoses and provide important opportunities for high-impact clinical intervention through preventative strategies in unaffected individuals and personalized therapies in those with cancer
Clinical Characteristics and multiple primary tumors (MPTs) Combinations 460 individuals (106 [23%] males and 354 [77%] females) in 440 families had been diagnosed with 1,143 primary tumors distributed among 87 categories according to site and cell of origin
Summary
Inherited cancer-predisposition syndromes account for a significant minority of cancer diagnoses and provide important opportunities for high-impact clinical intervention (in probands and their relatives) through preventative strategies in unaffected individuals (e.g., surveillance scans, prophylactic surgery, and chemoprevention) and personalized therapies in those with cancer. Constitutional genetic variants in cancer-predisposition genes (CPGs) can predispose to a wide spectrum of tumors and levels of risk, individual CPGs are usually associated with specific tumor types.[1]. Clinical NGS assays for possible inherited cancer predisposition generally take the form of single-gene or multigene panels of CPGs, but genome-wide analysis through wholeexome sequencing (WES) or whole-genome sequencing (WGS) is possible. More expensive than WES, WGS should provide the most comprehensive analysis because it (1) can effectively interrogate all coding and non-coding areas of the genome, (2) provides more uniform read coverage than WES, in areas where target enrichment and capture are difficult,[5,6] and (3) is able to detect a wide range of structural variations, such as deletions, translocations, and inversions.[7] WGS is still in its infancy as a clinical diagnostic tool, and few assessments of its application in hereditary cancer have appeared in the literature. We applied WGS to a large heterogeneous pre-assessed MPT cohort (460 individuals from 440 families) to investigate the potential role of comprehensive CPG analysis in this group
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