Prevalence ofBRCA1 genomic rearrangements in a large cohort of Italian breast and breast/ovarian cancer families without detectableBRCA1 andBRCA2 point mutations

Agata, Simona; Viel, Alessandra; Puppa, Lara Della; Cortesi, Laura; Fersini, G.; Callegaro, Monia; Palma, Maurizia Dalla; Dolcetti, Riccardo; Fédérico, Massimo; Venuta, Salvatore; Miolo, Gianmaria; D’Andrea, Emma; Montagna, Marco

doi:10.1002/gcc.20342

Cited by 52 publications

(49 citation statements)

References 24 publications

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“…Adding the three BRCA1 del (ex 9-12) mutations found among the sequence negative cases brings the overall prevalence of BRCA mutations in the cohort to 34% (37 of 110)-the large rearrangement representing 8.8% (3 of 37) of all BRCA carriers. This proportion of rearrangements among BRCA1-positive individuals is consistent with previous studies in European and American populations (3,4,6,(28)(29)(30)(31).…”

Section: Discussionsupporting

confidence: 92%

“…Five of eight BRCA1 rearrangements (five deletions, two duplications, and one amplification) identified in this cohort were novel; one has been reported to be a French founder mutation (deletion of exons 8-13; ref. 32) and two others (deletion of exons 11-15 and duplication of exon 20) were also reported in Portuguese (31) and Italian cohorts (28). However, the BRCA1 del (9-12) mutation has not been reported in any other study population to date.…”

Section: Discussionmentioning

confidence: 83%

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Evidence for Common Ancestral Origin of a Recurring BRCA1 Genomic Rearrangement Identified in High-Risk Hispanic Families

Weitzel

Lagos

Herzog

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

103

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Background: Large rearrangements account for 8% to 15% of deleterious BRCA mutations, although none have been characterized previously in individuals of Mexican ancestry. Methods: DNA from 106 Hispanic patients without an identifiable BRCA mutation by exonic sequence analysis was subjected to multiplexed quantitative differential PCR. One case of Native American and African American ancestry was identified via multiplex ligation-dependent probe amplification. Long-range PCR was used to confirm deletion events and to clone and sequence genomic breakpoints. Splicing patterns were derived by sequencing cDNA from reverse transcription-PCR of lymphoblastoid cell line RNA. Haplotype analysis was conducted for recurrent mutations. Results: The same deletion of BRCA1 exons 9 through 12 was identified in five unrelated families. Long-range PCR and

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 83%

Evidence for Common Ancestral Origin of a Recurring BRCA1 Genomic Rearrangement Identified in High-Risk Hispanic Families

Weitzel

Lagos

Herzog

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

103

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“…This rate is somewhat higher than those previously recorded in other populations such as in Spain (8.2%) [19], Germany (9.6%) [20], France (12.0%) [5], Czech Republic (12.3%) [21] and Denmark (12.5%) [22], but is lower than that recorded in the Netherlands (27.3%) [13]. Our reported percentage is in agreement with the results of Agata et al in Italy, who reported about 19% of LGRs in a large cohort of breast and breast/ovarian cancer families without BRCA1 and BRCA2 point mutations detectable by conventional scanning methods [14].…”

Section: Discussionsupporting

confidence: 82%

“…Indeed, the incidence of BRCA1 LGRs in patients with strong family history of breast cancer ranges from 0.8%-23%, which represents around 8%-40% contribution to the BRCA1 mutation spectrum in different ethnic groups [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Screening for BRCA1 large genomic rearrangements in female Egyptian hereditary breast cancer patients

Hagag¹,

Shwaireb²,

Coffa³

et al. 2013

East Mediterr Health J

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Approximately 5%-10% of all breast cancers are inherited as the result of germline mutations in the BRCA1 gene. Large genomic rearrangements (LGRs) in BRCA1 have not been well-researched in the Egyptian population. Using multiplex ligation-dependent probe amplification, we showed BRCA1 rearrangements in 4/22 cases (18.2%) of familial breast cancer. No influence of having multiple breast cancer cases within the family was observed in patients diagnosed at < or ≥ 45 years and having BRCA1-positive LGRs. However, focusing on cases with first-and second-degree relatives affected, we observed a significant difference between the percentage of patients with BRCA1-positive versus BRCA1-negative LGRs. Our results provide the first evidence that LGRs in BRCA1 exist in the Egyptian population. Screening for these alterations may be desirable when breast cancer patients are diagnosed at an early age, especially if these cases have first-and second-degree of relatives with breast cancer.

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“…Pathogenic alterations in BRCA1 include mutations in the regulatory regions of the gene, splice site mutations, nonsense/ frameshift/missense mutations, and large chromosomal rearrangements, estimated to account for ~19% of all BRCA1 mutations in Italian patients (13).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the c.190T>C missense mutation in BRCA1 codon 64 (Cys64Arg)

Willems

Magri²,

Čretnik³

et al. 2009

Int J Oncol

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Abstract. In the Milan area (Northern Italy), we identified a family characterized by a high prevalence of ovarian and breast cancer cases (5 out of 6 subjects, over 3 generations), and a predominant prevalence of ovarian lesions (4 out of 5 patients). Analysis of BRCA1 and BRCA2 genes allowed the identification of the missense c.190T>C mutation in codon 64 (Cys64Arg) of BRCA1. The aims of the present investigation were to characterize the functional implications of the c.190T>C mutation at the molecular level, and to search whether additional polymorphisms might be linked to the peculiar phenotypic features observed in the Italian pedigree. Molecular modelling studies suggested that substitution of the cysteine 64 with an arginine likely disrupts the architecture of the BRCA1 RING finger domain, responsible for the interaction with BARD1, essential for the tumor-suppressor activity of the BRCA1-BARD1 complex. By splicing site information analysis, exonic splicing enhancer site characterization, and analysis of transcript fragment length and sequence, we showed that the c.190T>C mutation was able to modulate the splicing of exon 5 in a fashion opposite to the c.190T>G transversion, responsible for the functionally-related Cys64Gly amino acid substitution. Genotyping of BRCA1 and BRCA2 in the Italian family revealed the presence of two significant polymorphisms: the cancer-associated c.2612C>T SNP in BRCA1, and the c.-26G>A SNP in the BRCA2 gene, acting as an ovarian cancer risk modifier in carriers of deleterious BRCA1 mutations. Analysis of these SNPs in a genotypically-unrelated Polish family, characterized by prevalent breast neoplasms in carriers of the c.190T>C mutation, revealed a genetic profile consistent with the hypothetic role of both polymorphisms. IntroductionHereditary breast cancer accounts for 5-10% of all breast cancers worldwide. Prevalence of BRCA1 and BRCA2 mutations among high-risk cancer patients may vary by ethnicity, study inclusion criteria and mutation detection techniques. Since their early characterization, inherited BRCA1 mutations were found to be responsible for ~45% of inherited early-onset breast cancers, and for >80% of inherited breast and ovarian cancers (1). In Europe, BRCA1 mutation frequencies in breast cancer populations show considerable variability and range between 0.4% in Finland and 7% in Sweden (2). Meta-analytic mean cumulative cancer risks for mutation carriers at age 70 years are 57% for BRCA1 and 49% for BRCA2 mutation carriers; ovarian cancer risk is 40% for BRCA1 and 18% for BRCA2 mutation carriers (3). In Italy, breast cancer penetrance, estimated in a series of 568 families, was found to be 27% at age 50 and 39% at age 70 in BRCA1 mutation carriers, and 26% at age 50 and 44% at age 70 in BRCA2 mutation carriers (4). Ovarian cancer penetrances in Italy were estimated to be 14% at age 50 and 43% at age 70 in BRCA1 mutation carriers, and 3% at age 50 and 15% at age 70 in BRCA2 mutation carriers (4).BRCA1 is a gene with a coding sequence spanning over 23 exons, i...

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Prevalence ofBRCA1 genomic rearrangements in a large cohort of Italian breast and breast/ovarian cancer families without detectableBRCA1 andBRCA2 point mutations

Cited by 52 publications

References 24 publications

Evidence for Common Ancestral Origin of a Recurring BRCA1 Genomic Rearrangement Identified in High-Risk Hispanic Families

Evidence for Common Ancestral Origin of a Recurring BRCA1 Genomic Rearrangement Identified in High-Risk Hispanic Families

Screening for BRCA1 large genomic rearrangements in female Egyptian hereditary breast cancer patients

Characterization of the c.190T>C missense mutation in BRCA1 codon 64 (Cys64Arg)

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