232P - Identification of ‘secondary’ germline cancer predisposition variants from somatic tumour testing: Should we evolve towards universal screening?

Background

In recent years, the use of Next Generation Sequencing based gene panels for the management of solid tumours has become almost routine testing in many Cancer Genomics Laboratories. In most cases, the purpose of the analysis is to identify biomarkers with potential predictive value. However, the mutations identified in the tissue may also have a hereditary origin. The objective of this study was to analyse the pathogenic germline variants identified as a somatic secondary finding in genes that have not been established to confer an increased risk for this specific tumour (‘off-tumour’).

Methods

A retrospective analysis was carried out on 330 patients in whom a tumour genomic analysis (somatic testing) had been performed in our institution between February 2022 and 2023. The genomic analysis tool was Oncomine ^TM Comprehensive Assay in all cases (500 gene panel). Germline-focused analysis was performed to variants with a variant allele frequency >30% (or >20% if small insertions/deletions) in genes consistent with hereditary predisposition to cancer.

Results

In the solid biopsies from 330 patients studied, 58 pathogenic variants of potential germline origin were identified in 54 patients (16.3%). In 23 of these patients (42.5%) the pathogenic variant was an ‘off-tumour’ finding. The median age at diagnosis of these 23 patients was 56 years-old, 21 patients (91.3%) had a metastatic or recurrent tumour and 11 (47.8%) did not meet any criteria of inherited predisposition to cancer. The results of the germline study are available in 10 of these 23 patients and the germline pathogenic variant was confirmed in 7 cases (70%): 4 BRCA1, 1 ATM, 1 MUTYH and 1 PMS2. The most frequent related tumour was lung cancer, in 3 cases.

Conclusions

In our series of 330 cases tested for tumour genomics, 23 patients harboured an "off-tumour" pathogenic variant with potential germline origin, that was confirmed in 7 out of 10 patients. Detected germline mutations included high penetrance cancer predisposing genes as BRCA1. This detection rate reflects the clinical utility, for patients and their families, of using the somatic genomic analysis as a source of information about a potential hereditary cancer predisposition syndrome.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M.F. Sanmamed: Financial Interests, Personal, Advisory Board: Numab, Pieris, MSD; Financial Interests, Personal, Speaker’s Bureau: MSD, Replimune; Financial Interests, Personal, Research Grant: Roche, BMS, AZ. A. Gonzalez Martin: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Clovis, GSK, Genmab, Alkermes, Sutro, Roche, Sotio, PharmaMar, Oncoinvent, Novartis, Mersana, MSD, Macrogenics, Eisai, Inmunogen, Regeneron, HederaDx, Illumina; Financial Interests, Personal, Invited Speaker: GSK, AstraZeneca, Clovis, Roche, Novocure, MSD, Takeda, Zaylab; Financial Interests, Institutional, Coordinating PI, PI of ANITA trial: GSK, Roche; Financial Interests, Personal, Steering Committee Member, Member of ENGOT ov43-SC: MSD; Financial Interests, Institutional, Coordinating PI, ENGOT PI of EPIK-O trial: Novartis; Financial Interests, Institutional, Coordinating PI, ENGOT PI of AVB-500 phase III trial: ARAVIVE. All other authors have declared no conflicts of interest.