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 (χ = 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.

Germline mutations and new copy number variants among 40 pediatric cancer patients suspected for genetic predisposition

“…Genetic tests are available for many CPS, but have been traditionally performed on just one or few genes selected according to clinical suspicion. Recently, the application of next‐generation sequencing (NGS) has improved the diagnostic rate . The main aim of this study is to validate an integrated workflow for the genetic diagnosis of pediatric cancer patients by proposing as first tier either a candidate gene analysis or a genomic test (whole exome sequencing or array‐CGH) depending on phenotype and family history.…”

Fumarate hydrataseFHc.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma

“…A recent study identified this variant in three individuals with multiple primary tumors, so the presumption of pathogenicity is stronger. However, none of whom had typical hereditary leiomyoma or renal cell carcinoma tumors (Whitworth et al, 2018). Although it is a well-established pathogenic variant for autosomal recessive FH deficiency, its association with renal cell carcinoma is less well defined.…”

“…Two patients reported a history of uterine fibroids but not cutaneous leiomyomas. Uterine fibroids are the most common benign tumors in women worldwide (Merrill, 2008;Zimmermann, Bernuit, Gerlinger, Schaefers, & Geppert, 2012), and in isolation are not indicative of HLRCC by themselves (Menko et al, 2014;Pithukpakorn & Toro 1993-2018-2018 which is predicted to affect the protein function using in silico prediction tools, hence the role of the c.1431_1433dupAAA, in this case, remains unclear (Chen et al, 2014).…”

Characterization of renal cell carcinoma‐associated constitutional chromosome abnormalities by genome sequencing

“…The second non‐chromosome 3 translocation t(10;17)(q11.22;p12) underwent sequencing as part of the NIHR BioResource Rare Diseases project (see methods) and was analyzed previously as part of a multiple primary tumor cohort with a history of facial fibrofolliculomas, recurrent pneumothoraces, and RRC. At that time, no abnormality was detected but subsequently reanalysis identified candidate translocation breakpoints that were supported by two overlapping Manta calls for the chromosome 10 and chromosome 17 breakpoints at chr17:17218211‐17 218 214 (17p11.2) and chr10:43236047‐43 236 050 ( 10q11.21) that were supported by 22 spanning and 10 split reads and a secondary call at chr17:17218216‐17 218 217 and chr10:43236058‐43 236 059 by 15 spanning and 18 split reads (Table S3).…”

“…Genome‐wide variant calling was jointly performed on all samples using GATK unified genotyper (version 3.7‐0‐gcfedb67) . DNA from one proband underwent GS as part of the NIHR BioResource Rare Diseases study with sequencing and primary bioinformatics performed as previously described . Data were aligned to genome build GRCh37 and all analyses were performed identically with appropriate adjustments for differences in genome build.…”