BackgroundGenetic testing for BRCA1/2 genes is widely used as a strategy to reduce incidence and morbidity of hereditary breast and ovarian cancer (HBOC). The purpose of this study is to analyse the demographic and molecular characteristics of BRCA germline mutations in Navarra, Spain, and to investigate the clinical profile of hereditary and sporadic breast cancer (BC) and ovarian cancer (OC) in the Community.MethodsThe study includes 1246 individuals assessed for BRCA1/2 genetic testing in Navarra, during 2000–2016, and a cohort of BC (n = 4384) and OC (n = 561) from the population-based Navarra Cancer Registry. Distribution and molecular characteristics of BRCA1/2 mutations, as well as, comparative analysis of the clinical course, pathologic features and overall survival (OS) of patients in different risk groups were investigated.ResultsBRCA mutation detection rate was 16%, with higher proportion (63%) of BRCA2 families. Nineteen per cent of mutations were recurrent, one of which, BRCA2 c.6024dupG, showed high association to OC. BRCA carriers had double risk (95% CI = 1.04–4.33) of developing multiple malignancies than low risk families and were diagnosed at a much earlier age (16.6 and 11.7 years difference for BC and OC, respectively) when compared to the general population. For BC, BRCA carriers showed a more advanced histological stage, higher risk of bilateral neoplasms (OR = 4.3; 95% CI = 1.3–11.4, for BRCA2 carriers) and worse OS rate at 5-, 10- and 15- years, than women with sporadic tumors. For OC, over 70% of patients of all risk groups showed advanced stages at diagnosis, with the highest among BRCA1 carriers (91%). Furthermore, they also had higher probability of developing ovarian bilateral tumors (OR = 7.8, 95% CI = 1.7–55.7, for BRCA1 carriers) than the general population. Five-year OS rate was worse among women with sporadic OC than BRCA carriers, but it levelled out over the 15-year period.ConclusionsIn addition to national similarities in the HBOC-BRCA1/2 associated mutational spectrum, we identified a recurrent BRCA2 pathogenic variant (c.6024dupG), highly associated to OC in Navarra. Carriers of BRCA1/2 mutations showed a more severe BC and OC phenotype and had a worse overall prognosis when compared to a large cohort of women with sporadic counterpart tumors.

We aimed to determine the genetic diversity and molecular characteristics of the Huntington disease (HD) gene (HTT) in Spain. We performed an extended haplotype and exon one deep sequencing analysis of the HTT gene in a nationwide cohort of population-based controls (n = 520) and families with symptomatic individuals referred for HD genetic testing. This group included 331 HD cases and 140 carriers of intermediate alleles. Clinical and family history data were obtained when available. Spanish normal alleles are enriched in C haplotypes (40.1%), while A1 (39.8%) and A2 (31.6%) prevail among intermediate and expanded alleles, respectively. Alleles ≥50 CAG repeats are primarily associated with haplotypes A2 (38.9%) and C (32%), which are also present in 50% and 21.4%, respectively, of HD families with large intergenerational expansions. Non-canonical variants of exon one sequence are less frequent, but much more diverse, in alleles of ≥27 CAG repeats. The deletion of CAACAG, one of the six rare variants not observed among smaller normal alleles, is associated with haplotype C and appears to correlate with larger intergenerational expansions and early onset of symptoms. Spanish HD haplotypes are characterised by a high genetic diversity, potentially admixed with other non-Caucasian populations, with a higher representation of A2 and C haplotypes than most European populations. Differences in haplotype distributions across the CAG length range support differential germline expansion dynamics, with A2 and C showing the largest intergenerational expansions. This haplotype-dependent germline instability may be driven by specific cis-elements, such as the CAACAG deletion.

Following publication of the original article [1], the authors reported an error in Figure 2, where the color code of the text boxes is reversed. Figure 2-amended shows the correct color association between the text boxes and the different areas in the map: Navarra, neighbouring communities and other Spanish communities.

Background Genetic testing for BRCA1/2 genes is widely used as a strategy to reduce incidence and morbidity of hereditary breast and ovarian cancer. The purpose of this study is to analyse the demographic and molecular characteristics of BRCA germline mutations in Navarra, Spain, and to investigate the clinical profile of hereditary and sporadic breast cancer (BC) and ovarian cancer (OC) in the Community. Methods The study includes 1246 individuals assessed for BRCA1/2 genetic testing in Navarra, during 2000-2016, and a cohort of BC (n=4384) and OC (n=561) from the population-based Navarra Cancer Registry. Distribution and molecular characteristics of BRCA1/2 mutations, as well as, comparative analysis of the clinical course, pathologic features and overall survival of patients in different risk groups were investigated. Results BRCA mutation detection rate was 16%, with higher proportion (63%) of BRCA2 families. Nineteen per cent of mutations were recurrent, one of which, BRCA2 c.6024dupG, showed high association to OC. BRCA carriers had double risk (95% CI=1.04-4.33) of developing multiple malignancies than low risk families and were diagnosed at a much earlier age (16.6 and 11.7 years difference for BC and OC, respectively) when compared to the general population. For BC, BRCA carriers showed a more advanced histological stage, higher risk of bilateral neoplasms (OR=4.3; 95% CI=1.3-11.4, for BRCA2 carriers) and worse overall survival rate at 5-, 10- and 15- years, than women with sporadic tumors. For OC, over 70% of patients of all risk groups showed advanced stages at diagnosis, with the highest 91% among BRCA1 carriers (91%). Furthermore, they also had higher probability of developing bilateral tumors (OR=7.8, 95%CI=1.7-55.7) than the general population. Five-year overall survival rate was worse among women with sporadic OC than in BRCA carriers, but it levelled out over the 15-year period. Conclusions This study describes the molecular features of BRCA1/2 mutations in Navarra and defines the clinical course and outcomes of BRCA associated tumors compared with those of sporadic origin. Long term assessment of mortality and survival will be required to evaluate the impact of BRCA genetic testing program on the health of target population in our community.