Abstract P2-09-13: Is there a male breast cancer cluster region in the <i>BRCA2</i> gene?
Authors: Pedro Simões, Teresa Duarte, Joana Parreira, Ana Luís, Sandra Bento, Sofia Fragoso, Sidónia Santos, Fátima Vaz, Saudade André
Journal: Cancer Research (2022)

Abstract Background: The location of the variant in the BRCA2 gene may have a role on the differential risk of hereditary breast-ovarian cancer (HBOC) families. Three Breast Cancer Cluster Regions (BCCR) have been previously identified in BRCA2: BCCR1- c.1-c.596; BCCR1’- c.772-c.1806; BCCR2- c.7394-c.8904. BCCR1 includes the Portuguese founder pathogenic variant (c.156_157insAlu), which explains up to 1/3 of hereditary breast cancer. As previously described one of the associated phenotypes of c.156_157insAlu is male breast cancer (MBC). We analyzed all MBC BRCA2 families registered in our program searching for a possible association between variant location in the BRCA2 gene and MBC. Methodology: This is a Portuguese, single-center, cross-sectional study, including all families identified with a pathogenic variant in the BRCA2 gene between December 1999 and December 2019. BRCA2 families with MBC cases were selected for further analysis including gene mapping of identified variants. The study was approved by our center’s IRB/IEC. Results: Of a total of 452 confirmed BRCA1/2 families, 285 were diagnosed with a BRCA2 pathogenic variant. Review of these 285 genograms identified 57 families with MBC in their phenotype, including 62 men diagnosed with 69 breast cancer cases (7 bilateral). Twenty-nine (47%) MBC patients were confirmed to be carriers of a BRCA2 pathogenic variant (26 tested, 3 obligate carriers); the others were considered to be probable BRCA2 carriers based on family analysis. Besides MBC other BRCA2-associated cancers were identified in these families: female breast cancer (FBC, 82%), prostate cancer (35%), gastric cancer (18%), pancreatic cancer (16%) and ovarian cancer (12%). In 6 (2%) BRCA2 families, breast cancer was exclusively diagnosed in men.Eighteen (32%) MBC patients were diagnosed with other cancers: 9 prostate, 5 colorectal, 3 gastric, 2 kidney, 1 bladder, 1 pancreatic and 1 central nervous system.The most commonly identified variant was the c.156_157insAlu (24, 38.7%), followed by c.9097dupA (6.5%), c.793+1G&amp;gt;A (4.8%) and c.2808_2811delACAA (4.8%).Thirty-six (63%) of the identified variants were located on the previously described BCCR (46% in BCCR1, 11% in BCCR1’ and 7% in BCCR2). The remaining variants were located in other areas of the BRCA2 gene: 12% closer to BRCA2 3’ terminal (exons 23-25); 1.8% in exon 8; and the remaining scattered through exon 11 (in 14% of cases in regions previously described as associated to ovarian cancer). The proportion of BCCR variants was significantly lower on confirmed carriers compared to probable carriers (48.3% vs 78.6%, chi-square p=0.018), due to a higher proportion of variants located on exons 23-25 (17.2% vs 7.1%) and on exon 11 (31% vs 14.2%). Approximately half of the bilateral MBC cases (57% of the total sample, 50% of the confirmed carriers) were associated with BCCR variants. Conclusion: Our data suggest that BCCR1 may be a male breast cancer cluster region (MBCCR). The clustering of confirmed MBC distal to BCCR2, closer to the BRCA2 3’ terminal, raises the possibility of a specific MBCCR, and warrants further research. Citation Format: Pedro Simões, Teresa Duarte, Joana Parreira, Ana Luís, Sandra Bento, Sofia Fragoso, Sidónia Santos, Fátima Vaz, Saudade André. Is there a male breast cancer cluster region in the BRCA2 gene? [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-13.