RESUMEN
Even though male breast cancer (MBC) risk encompasses both genetic and environmental aetiologies, the primary risk factor is a germline pathogenic variant (PV) or likely pathogenic variant (LPV) in BRCA2, BRCA1 and/or PALB2 genes. To identify new potential MBC-specific predisposition genes, we sequenced a panel of 585 carcinogenesis genes in an MBC cohort without BRCA1/BRCA2/PALB2 PV/LPV. We identified 14 genes carrying rare PVs/LPVs in the MBC population versus noncancer non-Finnish European men, predominantly coding for DNA repair and maintenance of genomic stability proteins. We identified for the first time PVs/LPVs in PRCC (pre-mRNA processing), HOXA9 (transcription regulation), RECQL4 and WRN (maintenance of genomic stability) as well as in genes involved in other cellular processes. To study the specificity of this MBC PV/LPV profile, we examined whether variants in the same genes could be detected in a female breast cancer (FBC) cohort without BRCA1/BRCA2/PALB2 PV/LPV. Only 5/109 women (4.6%) carried a PV/LPV versus 18/85 men (21.2%) on these genes. FBC did not carry any PV/LPV on 11 of these genes. Although 5.9% of the MBC cohort carried PVs/LPVs in PALLD and ERCC2, neither of these genes were altered in our FBC cohort. Our data suggest that in addition to BRCA1/BRCA2/PALB2, other genes involved in DNA repair/maintenance or genomic stability as well as cell adhesion may form a specific MBC PV/LPV signature.
RESUMEN
Immunohistochemistry (IHC) and/or MSI-PCR (microsatellite instability-polymerase chain reaction) tests are performed routinely to detect mismatch repair deficiency (MMR-D). Classical MMR-D tumors present a loss of MLH1/PMS2 or MSH2/MSH6 with MSI-High. Other profiles of MMR-D tumors have been described but have been rarely studied. In this study, we established a classification of unusual MMR-D tumors and determined their frequency and clinical impact. All MMR-D tumors identified between 2007 and 2017 were selected. Any profile besides the classical MMR-D phenotype was defined as unusual. For patients with unusual MMR-D tumors, IHC, and PCR data were reviewed, the tumor mutation burden (TMB) was evaluated and clinical and genetic features were collected. Of the 4948 cases of MMR testing, 3800 had both the available IHC and MSI-PCR results and 585 of these had MMR-D. After reviewing the IHC and PCR, 21% of the cases initially identified as unusual MMR-D were reclassified, which resulted in a final identification of 89 unusual MMR-D tumors (15%). Unusual MMR-D tumors were more often associated with non-CRC than classical MMR-D tumors. Unusual MMR-D tumors were classified into four sub-groups: i) isolated loss of PMS2 or MSH6, ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI, iii) four MMR proteins retained with MSI and, iv) complex loss of MMR proteins, with clinical characteristics for each sub-group. TMB-high or -intermediate was shown in 96% of the cancers studied (24/25), which confirmed MMR deficiency. Genetic syndromes were identified in 44.9% (40/89) and 21.4% (106/496) of patients with unusual and classical MMR-D tumors, respectively (P < 0.001). Five patients treated with an immune checkpoint inhibitor (ICI) had a prolonged clinical benefit. Our classification of unusual MMR-D phenotype helps to identify MMR deficiency. Unusual MMR-D phenotype occurs in 15% of MMR-D tumors. A high frequency of genetic syndromes was noted in these patients who could benefit from ICI.