Impact of deleterious variants in other genes beyond BRCA1/2 detected in breast/ovarian and pancreatic cancer patients by NGS-based multi-gene panel testing: looking over the hedge

Abstract

Background Hereditary breast cancer (BC), ovarian cancer (OC), and pancreatic cancer (PC) are the major BRCA -associated tumours. However, some BRCA1/2 -wild-type (wt) patients with a strong personal and/or family history of cancer need a further genetic testing through a multi-gene panel containing other high- and moderate-risk susceptibility genes. Patients and methods Our study was aimed to assess if some BC, OC, or PC patients should be offered multi-gene panel testing, based on well-defined criteria concerning their personal and/or family history of cancer, such as earliness of cancer onset, occurrence of multiple tumours, or presence of at least two or more affected first-degree relatives. For this purpose, 205 out of 915 BC, OC, or PC patients, resulted negative for BRCA1/2 and with significant personal and/or family history of cancer, were genetically tested for germline pathogenic or likely pathogenic variants (PVs/LPVs) in genes different from BRCA1/2 . Results Our investigation revealed that 31 (15.1%) out of 205 patients harboured germline PVs/LPVs in no- BRCA genes, including PALB2 , CHEK2 , ATM , MUTYH , MSH2 , and RAD51C . Interestingly, in the absence of an analysis conducted through multi-gene panel, a considerable percentage (15.1%) of PVs/LPVs would have been lost. Conclusions Providing a multi-gene panel testing to BRCA1/2 -wt BC/OC/PC patients with a strong personal and/or family history of cancer could significantly increase the detection rates of germline PVs/LPVs in other cancer predisposition genes beyond BRCA1/2. The use of a multi-gene panel testing could improve the inherited cancer risk estimation and clinical management of patients and unaffected family members.

Precision Medicine for BRCA/PALB2-Mutated Pancreatic Cancer and Emerging Strategies to Improve Therapeutic Responses to PARP Inhibition

“…Four of these mutations were found in non-BRCA genes, with two affecting ATM, one affecting PALB2, and one affecting RAD50 [ 37 ]. Consistent with these observations, our recent study using an expanded panel of 22 genes associated with HR, demonstrated an overall mutation frequency of 15% [ 35 ], with similar results observed in a study using a more focused molecular panel of six genes [ 38 ]. Accordingly, a large-scale meta-analysis evaluated several surrogate markers of HRD in PDAC, focusing on BRCA1 , BRCA2 , PALB2 , ATM , ATR , CHEK2 , RAD51 , and FANC .…”

“…Similarly, in relapsed platinum-sensitive high-grade ovarian cancer patients, therapeutic responses to Rucaparib were not restricted to BRCA -mutated tumors, and were observed in several patients with mutations to other HR genes including ATM , NBN , RAD51C , and RAD51D [ 132 ]. In PDAC, several studies now suggest that the true rates of HRD in PDAC patients may be underreported using only BRCA and PALB2 mutations as the defining criteria [ 35 , 38 , 39 ]. Hence, mutations to non-classic HR genes warrant continued exploration as a predictor of drug responses, particularly as PARP inhibitors advance in the treatment of other cancers, often in combination with chemotherapy or radiation [ 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 ].…”

Hereditary Ovarian Carcinoma: Cancer Pathogenesis Looking beyond BRCA1 and BRCA2

“…Pathogenic variants in PALB2, ATM and BARD1 are recognized by the NCCN as involved in hereditary breast and ovarian cancer syndrome but have insufficient evidence to determine their ovarian cancer risk [74].…”

Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, pancreatic, and prostate cancer: a position paper of Italian Scientific Societies

“… 45 However, the evaluation of sole BRCA in the cancer tissue does not allow the identification of deleterious variants in other genes associated with hereditary ovarian cancer risk, which are mutated in 4%-7% of patients with ovarian cancer. 46 Notably, although BRCA1/2 gene PVs account for the vast majority of the hereditary breast and ovarian cancer, PVs of other genes can be involved, and could explain an HRD status when no BRCA1/2 PVs are identified. BRCA1 methylations status should be also considered for a better understanding of HRD status.…”