The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families?

Until recently, the molecular diagnosis of hereditary breast and ovarian cancer (HBOC) was mostly based on BRCA1/2 testing. Next generation sequencing and the recent discovery of new genes involved in HBOC now permit the transfer of genomic capture targeting multiple candidate genes from research to clinical use. However, the implications for the management of patients and their families have not been extensively studied, in particular since some of these genes are not well-established cancer predisposing genes. We studied 583 consecutive patients from Burgundy (France) fulfilling the criteria for BRCA testing using a next generation sequencing 25-genes panel including 20 well-established high-risk cancer genes as well as more recently identified predisposing HBOC cancer. A pathogenic BRCA1/2 mutation was found in 51 patients (9%). Besides, we found 37 pathogenic or likely pathogenic mutations in 10 different high to low-risk genes in 34 patients (6%). The most frequently mutated genes were CHEK2 (n = 12; 2%), ATM (n = 9; 1.5%), and PALB2 (n = 4; 0.6%). Three patients had a mutation in two different predisposing genes. The analysis of clinical actionability conducted in mutation-positive individuals revealed that additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone had been recommended in 69% of cases. In conclusion, multigene panel testing is a powerful tool to identifying high to low-risk HBOC susceptibility genes. The penetrance and spectrum of cancers with these other genes are sometimes undefined, and further collaborative work is crucial to address this question.

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene.

Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.