Abstract P3-07-04: Geographical patterns of pathogenic genetic variants associated with hereditary breast, ovarian and prostate cancer (HBOPC) in Portugal
Authors: de Oliveira Inês Calvinho , Fragoso Sofia , Santos Sidónia , Duarte Teresa , Bexiga Catarina , Mira Beatriz , Miguel Isália , Luís Ana , Vaz Fátima 
Published: March 2022

Introduction:HBOPC syndrome is mostly associated with germline pathogenic and likely pathogenic variants (PV) in BRCA1 and BRCA2 genes. Other high and moderate penetrance genes are increasingly diagnosed in these families, especially after implementation of NGS methodologies in clinical practice. In this study we analyze the global and regional mutational patterns of Portuguese HBOPC families, looking for associated phenotypes and possible clusters of specific PV. Methods:Observational study including all index patients (pts) with identified PV in genes associated with breast, ovarian and prostate cancers in our Centre, between 2000 and 2020. Geographical mapping of variants was done regarding residency and birth origin. Main cancer diagnoses of pts were also registered. Results:Between January 2000 and December 2020, 5233 index pts consented in genetic testing and 658 (12.6%) tested positive for a PV associated with HBOPC syndrome (84 were non-Portuguese residents). Regarding these 658 positive pts, 537 (81.6%) had breast (BC), 113 (17.2%) had ovarian and 9 (1.4%) had prostate cancer. BRCA2 was the most mutated gene (302 pts, 45.9%), followed by BRCA1 (179 pts, 27.2%), while PV in other genes were diagnosed in 177 (26.9%) pts (CHEK2, ATM, PALB2, RAD51C, TP53, RAD51D, MUTYH, BRIP1, RAD50, BLM and PTEN PV were identified in 54 (8.2%), 27 (4.1%), 21 (3.2%), 17 (2.6%), 16 (2.4%), 14 (2.1%), 11 (1.7%), 7 (1.1%), 4 (0.6%), 4 (0.6%) and 2 (0.3%) pts, respectively). PV in MSH2, MLH1, FAM175A and MRE11A were each described in 1 (0.15%) pt, all diagnosed with BC. Double heterozygosity was identified in 7 (1.1%) pts: BRCA1/BRCA2, BRCA1/CHEK2, BRCA2/PALB2, BRCA2/CHEK2, ATM/PALB2, ATM/RAD51C and MUTYH/MSH2. BRCA2 PV were more frequent than BRCA1 in all Portuguese regions except Algarve, where BRCA2 frequency was lower (BRCA1:BRCA2 &gt; 1). The known BRCA2 founder c.156_157insAlu was the most recurrently diagnosed PV: 36.4% of all BRCA2 families including 8 non-Portuguese families (6 from Angola, 1 from France and 1 from Brazil). Further analysis revealed 3 possible regional clusters: 1- Duplication of exon 12 (previously described as ins6KbEx13) was the only BRCA1 identified in Algarve, with 90.9% of all families with this PV originating in this region; 2- 75% of all BRCA2 c.6405_6409del; p.(Asn2135LysfsTer3) families have origin in Alentejo, being the third most diagnosed BRCA event in the region, after c.156_157insAlu and c.5266dup; p.(Gln1756ProfsTer74); 3- c.3331_3334del; (p.Gln1111AsnfsTer5) was the only BRCA1 PV identified in Madeira (6 families). When comparing Portuguese and foreign pts, similar rates of breast, ovarian and prostate cancers were found (81.5%, 17.2% and 1.2% versus 82.1%, 16.7% and 2.4%, respectively). Most foreign residents lived in Lisboa and Vale do Tejo (82,1%) and their BRCA1:BRCA2 ratio was 0,87 (versus 0,46 in Portuguese pts), while in Algarve (13,5%) their BRCA1:BRCA2 was even higher (1.5 versus 0,69 in Portuguese pts). Discussion and conclusion:Our study confirms that BRCA2 PV are more frequent than BRCA1 PV in Portugal, with the exception of the Algarve region. Our data suggests that foreign pts accessing genetic testing in this region may have imbalanced the BRCA1:BRCA2 ratio, while for the whole population the imbalance towards BRCA2 is associated with the known founder BRCA2 c.156_157insAlu. Our data identified 2 BRCA1 (Algarve and Madeira) and 1 BRCA2 (Alentejo) geographical clusters.

Citation Format: Inês Calvinho de Oliveira, Sofia Fragoso, Sidónia Santos, Teresa Duarte, Catarina Bexiga, Beatriz Mira, Isália Miguel, Ana Luís, Fátima Vaz. Geographical patterns of pathogenic genetic variants associated with hereditary breast, ovarian and prostate cancer (HBOPC) in Portugal [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 P3-07-04.