Management of BRCA Tumour Testing in an Integrated Molecular Tumour Board Multidisciplinary Model

Abstract

Tumour testing of the BRCA1/2 genes is routinely performed in patients with different cancer histological subtypes. To accurately identify patients with tumour-detected germline pathogenic variants (PVs) is a relevant issue currently under investigation. This study aims at evaluating the performance of the tumour-to-germline diagnostic flowchart model defined at our Institutional Molecular Tumour Board (MTB). Results from tumour BRCA sequencing of 641 consecutive unselected cancer patients were discussed during weekly MTB meetings with the early involvement of clinical geneticists for appropriate referral to genetic counselling. The overall tumour detection rate of BRCA1/2 PVs was 8.7% (56/641), ranging from 24.4% (31/127) in high-grade ovarian cancer to 3.9% (12/304) in tumours not associated with germline BRCA1/2 PVs. Thirty-seven patients with PVs (66%) were evaluated by a clinical geneticist, and in 24 of them (64.9%), germline testing confirmed the presence of the PV in blood. Nine of these patients (37.5%) were not eligible for germline testing according to the criteria in use at our institution. Cascade testing was subsequently performed on 18 relatives. The tumour-to-germline diagnostic pipeline, developed in the framework of our institutional MTB, compared with guideline-based germline testing following genetic counselling, proved to be effective in identifying a higher number of germline BRCA PVs carriers.

Prevalence of BRCA homopolymeric indels in an ION Torrent-based tumour-to-germline testing workflow in high-grade ovarian carcinoma

“…Since NGS BRCA1/2 tumour testing was not available before 2017 in our Institution, 19 of 222 subjects underwent germline testing before tumour sequencing based on personal (very early age at diagnosis/previous breast cancer) or family history. According to the workflow used by our Molecular Tumour Board (MTB), in 73 out of 203 patients with upfront tumour testing subsequently received genetic counselling, either for targeted germline sequencing of a tumour-detected PV or for large genomic rearrangement analysis 14 .…”

“…Moreover, this multidisciplinary approach proved effective also when applied to tumours for which clinical, molecular, pathology and immunohistochemistry data have to be integrated, as in the case of colorectal cancer 13 . In our previous study, we showed that the tumour-to-germline approach could detect and overcome potential technical limitations of tumour sample analysis in identifying putative germline variants 14 , which may lead to low sensitivity for large genomic rearrangements detection, misinterpretation of secondary “reverse” mutations or reduced sequencing accuracy at loci with homopolymeric repeats.…”