Abstract 766P
Background
Despite the increasing number of genes associated with hereditary breast/ovarian cancer (HBOC), BRCA1/2 explain most cases of this entity. Both BRCA1 and BRCA2 contribute to ovarian cancer (OC), cumulative risk of 25-40% and 11-18%, respectively. In contrast to other populations, HBOC Portuguese patients (pts) have a higher prevalence of BRCA2 variants, partially due to the effect of the founder BRCA2 variant: c.156_157insAlu. The aim of this study was to map and analyze BRCA1/2 variants from OC pts in our HBOC program.
Methods
From 502 OC index pts tested between Jan 2000-Dec 2020, 86 were diagnosed with a BRCA1/2 pathogenic variant (PV) (17%). In these HBOC families further 21 OC pts were confirmed as BRCA1/2 carriers. Frequency and spectrum of BRCA1/2 variants were analyzed. Variants were mapped across the gene and the previously described ovarian cancer cluster region (OCCR), for the 107 BRCA1/2 OC pts.
Results
We observed 52 PV in BRCA1 (48.6%) and 55 in BRCA2 (51.4%). The Portuguese BRCA2 founder variant c.156_157insAlu was the most frequent event (16/55: 29.1%), almost 3 times the most frequent BRCA1 variant: c.5266dup (6/52: 11.5%). Although BRCA1 and BRCA2 prevalence were rather similar, copy number variations (CNVs) had a higher contribution for BRCA1 (10/52: 19.2%) than for BRCA2 (3/55: 5.5%). Mapping revealed that exon 11 of BRCA2 harbored 32.7% of all variants while BRCA1 exon 10 included 55.8% of PVs in this gene. While 46.2% of BRCA1 variants (29/52) fall within the previously described OCCR, this proportion was lower for BRCA2 (8/55: 15.4%). BRCA1 variants were not restricted to a particular functional domain, while for BRCA2 20% of PVs were localized within the BRC repeats domain.
Conclusions
In contrast to data from other populations, this study unveils a balanced ratio between BRCA1 and BRCA2 PV in OC pts, probably the result of the BRCA2 Portuguese founder effect. This PV (c.156_157insAlu) is located in exon 3, not previously described as an OCCR. BRCA2 variants were scattered through the gene, while BRCA1 variants were mostly localized in the OCCR. Also, BRC repeats region in BRCA2 appears to be more relevant than the OCCR and CNVs may play a more influential role in BRCA1 than BRCA2 in OC pts, in our cohort.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Instituto Portugues de Oncologia de Lisboa Francisco Gentil.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.