Screening for genomic rearrangements in BRCA1 and BRCA2 genes in Czech high-risk breast/ovarian cancer patients: high proportion of population specific alterations in BRCA1 gene

Abstract

Large genomic rearrangements (LGR) represent substantial proportion of pathogenic mutations in the BRCA1 gene, whereas the frequency of rearrangements in the BRCA2 gene is low in many populations. We screened for LGRs in BRCA1 and BRCA2 genes by multiplex ligation-dependent probe amplification (MLPA) in 521 unrelated patients negative for BRCA1/2 point mutations selected from 655 Czech high-risk breast and/or ovarian cancer patients. Besides long range PCR, a chromosome 17-specific oligonucleotide-based array comparative genomic hybridization (aCGH) was used for accurate location of deletions. We identified 14 patients carrying 8 different LGRs in BRCA1 that accounted for 12.3% of all pathogenic BRCA1 mutations. No LGRs were detected in the BRCA2 gene. In a subgroup of 239 patients from high-risk families, we found 12 LGRs (5.0%), whereas two LGRs were revealed in a subgroup of 282 non-familial cancer cases (0.7%). Five LGRs (deletion of exons 1-17, 5-10, 13-19, 18-22 and 21-24) were novel; two LGRs (deletion of exons 5-14 and 21-22) belong to the already described Czech-specific mutations; one LGR (deletion of exons 1-2) was reported from several countries. The deletions of exons 1-17 and 5-14, identified each in four families, represented Czech founder mutations. The present study indicates that screening for LGRs in BRCA1 should include patients from breast or ovarian cancer families as well as high-risk patients with non-familial cancer, in particular cases with early-onset breast or ovarian cancer. On the contrary, our analyses do not support the need to screen for LGRs in the BRCA2 gene. Implementation of chromosome-specific aCGH could markedly facilitate the design of primers for amplification and sequence analysis of junction fragments, especially in deletions overlapping gene boundaries.

Characterization of four novel BRCA2 large genomic rearrangements in Spanish breast/ovarian cancer families: review of the literature, and reevaluation of the genetic mechanisms involved in their origin

“…For instance, LGRs account for 2% of all BRCA2 and 12.5% of all BRCA1 disease-causing mutations detected in a Danish cohort [4]. Similar findings are observed in Australian (2.3% vs. 14.9%), Malaysian (4% vs. 8%), Italian (0% vs. 10.5%), Czech Republic (0% vs. 12.3%), or USA (6% vs. 22%) cohorts [5][6][7][8][9]. In Spain, previous studies detected BRCA2 LGRs in 1.5%, and BRCA1 LGRs in 2.8% of the families analyzed [10,11].…”

“…Overall, we have detected BRCA2 LGRs in 7 out of 836 HBOC families analyzed, supporting a low proportion of these alterations in our population. Indeed, a low proportion (ranging from 0 to 2.5%) has been reported in most populations analyzed [3,[5][6][7][8][9]30]. Some authors have reported male breast cancer patients in most families harboring BRCA2 LGRs, thus suggesting a strong association with this malignancy [4,5,21].…”

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

“…Genomic rearrangements accounted for 18.2% (4/22) of the BRCA1 mutations detected in these patients. 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].…”

Alu elements mediate large SPG11 gene rearrangements: further spatacsin mutations

“…34 The majority of these elements lost their transposition ability a long time ago, although some of them, in particular, LINE-1 and Alu, have been shown to maintain this capacity, thus contributing to recent evolutionary history of the primate genomes 35 and also to the genomic instability found to be involved in cancer and several genetic disorders. 36 Similar to what happens with the BRCA1 gene, often known to suffer Alu-mediated deletions, 37,38 analysis of SPG11 also shows a high density of interspersed repeats, namely Alu elements, which together with the large size of this gene (~101 kb) favors the occurrence of various rearrangements. In addition, and similar to what seems to be happening with the SPG11 deletions, the Alu-mediated BRCA1 rearrangements arise from nonallelic homologous recombination.…”