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

International audience; Large genomic rearrangements (LGR) represent substantial proportion of pathogenic mutations in the gene, whereas the frequency of rearrangements in the gene is low in many populations. We screened for LGRs in and genes by multiplex ligation-dependent probe amplification (MLPA) in 521 unrelated patients negative for 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 that accounted for 12.3% of all pathogenic mutations. No LGRs were detected in the 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 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 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.