Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes

Abstract

BackgroundSarcomas are a rare and diverse group of cancers occurring mainly in young individuals for which an underlying germline genetic cause remains unclear in most cases.MethodsGermline DNA from 177 children, adolescents and young adults with soft tissue or bone sarcomas was tested using multigene panels with 113 or 126 cancer predisposing genes (CPGs) to describe the prevalence of germline pathogenic/likely pathogenic variants (GPVs). Subsequent testing of a subset of tumours for loss of heterozygosity (LOH) evaluation was performed to investigate the clinical and molecular significance of these variants.ResultsGPVs were detected in 21.5% (38/177) of the patients (15.8% in children and 21.6% in adolescents and young adults), with dominant CPGs being altered in 15.2% overall. These variants were found in genes previously associated with the risk of developing sarcomas (TP53,RB1,NF1,EXT1/2) but also in genes where that risk is still emerging/limited (ERCC2,TSC2andBRCA2) or unknown (PALB2,RAD50,FANCMand others). The detection rates of GPVs varied from 0% to 33% across sarcoma subtypes and GPV carriers were more likely to present more than one primary tumour than non-carriers (21.1%×6.5%; p=0.012). Loss of the wild-type allele was detected in 48% of tumours from GPV carriers, mostly in genes definitively associated with sarcoma risk.ConclusionOur findings reveal that a high proportion of young patients with sarcomas presented a GPV in a CPG, underscoring the urgency of establishing appropriate genetic screening strategies for these individuals and their families.

Germline Genetic Mutations in Adult Patients with Sarcoma: Insight into the Middle East Genetic Landscape

“…Similarly, we observed more P/LP in patients with family history for malignancy, but the difference was not statistically significant. This conclusion is parallel to Carvalho et al, who demonstrated higher mutation rates in patients with positive family history, although this was not statistically significant either [55].…”

Clinical Impact of Comprehensive Molecular Profiling in Adolescents and Young Adults with Sarcoma

“…We add to a body of evidence demonstrating the clinical value of CMP beyond the ability to identify new treatment options [23,24]. Of major importance to AYA patients, CMP led to the identification of pathogenic germline variants in 12% of our cohort, which is similar to previous reports in this population [25,26], although this is notably less than the finding of 55% in a large multisite cohort of 1162 adult sarcoma patients [27]. Our department now advocates for referral to a familial cancer centre to offer germline testing for all patients under 40 years with sarcoma, as well as for older patients with a suggestive personal or family history.…”