Novel BRCA1 and BRCA2 germline mutations and assessment of mutation spectrum and prevalence in Italian breast and/or ovarian cancer families

The prevalence of unique and recurrent BRCA1 and BRCA2 pathogenic mutations and unclassified variants varies among different populations. Two hundred and thirty-six breast and/or ovarian cancer patients were analysed to clarify the role of these genes in the Basque Country. We also studied 130 healthy women from the general population from the same region. Fifteen different pathological mutations were found in 16 index cases: 10 truncating mutations, 4 missense mutations and 1 splicing mutation. c.3002_3003insT and c.5788_5789delGT, both in exon 11 of BRCA2 have not previously been described. No pathological mutations were found in cases of sporadic juvenile breast cancer. There are no recurrent mutations in our population; apart from the mutation c.9254_9258del5, which appears in only two index cases. We have also found a lot of variants whose effect is unknown. From these variants, 17 have not previously been described: 6 missenses, 6 synonymous and 5 alterations in intronic regions. We would like to highlight the fact that 14.3% of patients with 3 or more cases of breast cancer in the family, and 16.7% of patients with family history of breast and ovarian cancer, present a pathological mutation in BRCA1 or BRCA2. This manuscript demonstrates that each population can have different mutations and due to this, Genetic Counselling and selection criteria must be different for each population. Furthermore, this article describes for the first time some new mutations and unclassified variants found in our population.

Section: Discussionmentioning

confidence: 62%

Differences in the frequency and distribution of BRCA1 and BRCA2 mutations in breast/ovarian cancer cases from the Basque country with respect to the Spanish population: implications for genetic counselling

Beristain

Martínez-Bouzas

Guerra

et al. 2007

“…Therefore their significance in the settings of a standard population approaching the genetic cancer clinic, is even less established. We have recently reported the prevalence of BRCA1 and BRCA2 mutations in a population of Italian breast/ovarian cancer families consecutively enrolled according to specific and relatively broad criteria [27]. We have now extended our analysis to the search for both BRCA1 and BRCA2 rearrangements via MLPA and report on the identification of two BRCA1 deletions, one of which (BRCA1 del23-24) described in molecular details for the first time.…”

Section: Introductionmentioning

confidence: 98%

Prevalence of BRCA1 and BRCA2 genomic rearrangements in a cohort of consecutive Italian breast and/or ovarian cancer families

Buffone

Capalbo

Ricevuto

et al. 2007

Self Cite

Germline point mutations in BRCA1 and BRCA2 genes account for about 30% of the inherited breast and ovarian cancers. Germline genomic rearrangements have been found in both BRCA1 and BRCA2 genes, but the extent to which these alterations might contribute to increasing the actual mutation detection rate is still debated. Here we screened a cohort of 112 consecutive Italian families at moderate-to-high risk for breast and/or ovarian cancer for BRCA1 and BRCA2 point mutations and genomic rearrangements. Of the 83 point mutation negative probands, two (2.4%) showed BRCA1 rearrangements, accounting for 10.5% of the BRCA1 mutations. BRCA1 del18-19 has been previously described in another Italian family, while the molecular characterization of the BRCA1 del23-24 is given here for the first time. Conversely, we failed to identify any BRCA2 rearrangements even in the hereditary breast cancer families, where we detected an higher prevalence of BRCA2 compared to BRCA1 point mutations. Our results support the idea that search for BRCA1 rearrangements should be included in the genetic screening of even moderate risk breast/ovarian cancer families. In contrast, they suggest BRCA2 rearrangements might be very rare out of the high risk families including a male breast cancer.

“…A total of 367 breast and/or ovarian cancer families were enrolled at the Hereditary Tumors section of the Policlinico Umberto I, University La Sapienza (Rome, Italy) according to previously described selection criteria [5]. Probands from each family were subjected to BRCA1/BRCA2 mutation screening, and 97 (26 %) presented with BRCA1/ 2 pathogenic mutations (Table 1).…”

Section: Family Recruitmentmentioning

confidence: 99%

“…The entire coding sequence and all intron/ exon boundaries of BRCA2 were screened by direct sequencing using an ABI PRISM DyeDeoxy Terminator Cycle Sequencing Kit and an ABI 3130XL Genetic Analyzer (Applied Biosystems, Warrington, UK) as previously described [5]. Obtained sequences were compared against the BRCA2 reference sequence, GenBank NM_000059.3.…”

Section: Brca2 Mutation Screeningmentioning

confidence: 99%

“…Pathogenic BRCA2 mutations are distributed along the entire coding sequence and may include regulatory regions such as intronic splicing signals [4][5][6][7]. The spectrum of BRCA2 mutations has been shown to differ slightly in different populations [5,[8][9][10]. Meta-analyses have estimated the cumulative risks of breast and ovarian cancers for BRCA2 mutation carriers to be 45-47 % and 11-17 %, respectively, by the age of 70 years [11,12].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14

Coppa

Buffone

Capalbo

et al. 2014

Self Cite

Hereditary breast and ovarian cancer are mainly linked to mutations in BRCA1 and BRCA2 genes which confer a similar cumulative risk of developing breast cancer. Importantly, while BRCA2 mutation carriers generally have a lower cumulative risk for ovarian cancer, mutations clustered in the central portion of BRCA2 are associated with a higher proportion of ovarian compared with breast cancer cases. The boundaries of this ovarian cancer cluster region (OCCR) have been tentatively defined within a 3.3 kb region of BRCA2 exon 11, and herein, we reassessed these boundaries using our series of Italian breast/ovarian cancer families. We used direct sequencing to investigate BRCA mutations in 367 breast/ovarian cancer families. We also studied the association between the location of the mutations and the ovarian cancer phenotype in our cohort of BRCA2-mutated families. We observed the novel c.7309_7309delA frameshift mutation and the c.7007G>A deleterious mutation in BRCA2 exons 14 and 13, respectively, in five independent Italian families characterized by a high proportion of ovarian cancer cases. Of note, a significantly higher proportion of ovarian versus breast cancer cases was associated not only with mutations in the previously defined OCCR (OR = 5.91; p = 0.004), but also with the exon 13-14 region (OR = 7.37; p = 0.001) in our BRCA2-mutated families. Our data provide initial evidence for a novel putative OCCR in BRCA2 exons 13-14.