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

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.

Keywords: cancer-predisposition syndromes; genetic testing; inherited cancer genetics; whole-genome sequencing.

Figure 1

Study Design Abbreviations are as follows: SV, structural variant; SNV, single-nucleotide variant; SO, Sequence Ontology; HGMD, Human Gene Mutation Database; ACMG, American College of Medical Genetics; and IGV, Integrated Genomics Viewer.

Figure 2

Molecular Investigations Initiated by Clinical Services with Inferred Reasons for Non-detection of Variants

Figure 3

Most Frequent Tumor Combination Types Combination types occurring fewer than three times are not included. Abbreviations are as follows: pheo, pheochromocytoma; GI NET, gastrointestinal neuroendocrine tumor; hem myeloid, hematological myeloid; PNET, pancreatic neuroendocrine tumor; hem lymphoid, hematological lymphoid; and NMSC, non-melanoma skin cancer (including basal cell carcinoma and squamous cell carcinoma).