Breast cancer (BC) in men is a rare disease, whose etiology appears to be largely associated with genetic risk factors. Inherited germ-line mutations in known susceptibility genes, such as BRCA1/2 and PALB2 account for about 15% of all male BCs (MBCs). Currently, more than 25 genes have been associated with familial BC in women, most of them being involved in DNA repair and genome maintenance pathways connected with BRCA1 and BRCA2. Little is known about these emerging genes, or other genes involved in genetic syndromes, in relation to increased risk of BC in men.
Next-generation sequencing (NGS) technology offers a valuable opportunity for cancer risk assessment, allowing the analysis of multiple genes simultaneously, but unexpected findings pose challenges for clinical management. As the use of gene-panel testing is becoming widespread, there is an urgent need for well-designed case-control studies in diverse populations providing reliable estimates of risk for the purpose of counseling, since for nearly all of these emerging susceptibility genes, it is currently not possible to provide accurate risk estimates.
In our ongoing extensive genomic screening by gene-panel on MBC cases, we found unexpected mutations in cancer-related genes involved in DNA repair pathway, not yet studied in relation to MBC risk.
In this project, we aim to perform a case-control study on a large series of BRCA1/2 mutation negative MBCs, by genotyping selected pathogenic variants in DNA repair genes, including ATM, BARD1, FANCM, MUTYH, NBN and RAD51D, identified through our gene-panel screening.
Results from this study are expected to add important information to the knowledge accumulating worldwide to date, in order to help evaluating more precise and robust estimates of the MBC risk associated with these mutations. Eventually, the findings may be useful in the identification of high-risk cancer families and may eventually improve clinical management of all family members.
With this project we aim to better understand the genetic basis of MBC susceptibility. With the exception of BRCA1, BRCA2, and PALB2, little is known about other genes conferring moderate/low-penetrance susceptibility in MBC, or those genes that are involved in other genetic syndromes but that are also likely to be responsible of an increased risk of BC in men. The discovery of unexpected genetic variants associated with MBC may be useful in the identification of high-risk breast cancer families and may eventually improve clinical management of all family members, including female relatives.
The potential for genetics to enable precision prevention initially depends on empirical studies to discover risk variants and describe their association with cancer risk. To date, the usefulness of multi-gene panel technology in the clinical management of patients may be still limited by incomplete information on cancer risk estimates, even for well-documented genes. As unexpected mutations are being identified on multi-gene panels, there is an urgent need for large, well-designed case-control studies in diverse populations providing reliable estimates of risk for the purpose of counseling. Results from the case-control study proposed here are expected to add important information to the knowledge accumulating worldwide to date, in order to help in evaluating more precise and robust estimates of the BC risk associated with these mutations and help personalized BC risk assessment in men.
Interestingly, more than 20% of MBC cases develop a second non-breast tumor, including colon cancer, suggesting that these tumors may share genetic risk factors. Evaluating a colon cancer susceptibility gene such as MUTYH in the context of MBC is an unique opportunity, which may lead to informed recommendation for colon cancer surveillance for families at increased risk.
MBC represents a good model to investigate the genetic component in BC susceptibility since it is not affected by confounding factors related the high frequency of the disease as for female BC, so that our results may be eventually extended to female BC, thus providing highlights in the comprehension of the missing additional genetic component of BC susceptibility in both sexes.
Furthermore, the identification of BC cases carrying DNA repair related pathogenic mutations is likely to have a significant impact on the treatment management. Promising data derived from the use of several PARP inhibitors in clinical settings, for the treatment of homologous recombination-deficient tumors, and novel therapeutic strategies targeting DNA repair genes are emerging.
Eventually, the findings may allow for the identification of targets that could be of significant clinical relevance, thus improving the clinical management of BC patients of both sexes and their families.