RESUMO
In BRCA1/2 families, early-onset breast cancer (BrCa) cases may be also observed among non-carrier relatives. These women are considered phenocopies and raise difficult counselling issues concerning the selection of the index case and the residual risks estimate in negative family members. Few studies investigated the presence of potential genetic susceptibility factors in phenocopies, mainly focussing on BrCa-associated single-nucleotide polymorphisms. We hypothesized that, as for other Mendelian diseases, a revertant somatic mosaicism, resulting from spontaneous correction of a pathogenic mutation, might occur also in BRCA pedigrees. A putative low-level mosaicism in phenocopies, which has never been investigated, might be the causal factor undetected by standard diagnostic testing. We selected 16 non-carriers BrCa-affected from 15 BRCA1/2 families, and investigated the presence of mosaicism through MALDI-TOF mass spectrometry. The analyses were performed on available tumour samples (7 cases), blood leukocytes, buccal mucosa and urine samples (2 cases) or on blood only (7 cases). In one family (n.8), real-time PCR was also performed to analyse the phenocopy and her healthy parents. On the 16 phenocopies we did not detect the family mutations neither in the tumour, expected to display the highest mutation frequency, nor in the other analysed tissues. In family 8, all the genotyping assays did not detect mosaicism in the phenocopy or her healthy parents, supporting the hypothesis of a de novo occurrence of the BRCA2 mutation identified in the proband. These results suggest that somatic mosaicism is not likely to be a common phenomenon in BRCA1/2 families. As our families fulfilled high-risk selection criteria, other genetic factors might be responsible for most of these cases and have a significant impact on risk assessment in BRCA1/2 families. Finally, we found a de novo BRCA2 mutation, suggesting that, although rare, this event should be taken into account in the evaluation of high-risk families.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Mosaicismo , Adulto , Neoplasias da Mama/diagnóstico , DNA/análise , DNA/isolamento & purificação , DNA/metabolismo , Tumor do Seio Endodérmico/diagnóstico , Tumor do Seio Endodérmico/genética , Feminino , Testes Genéticos , Genótipo , Humanos , Pessoa de Meia-Idade , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/genética , Adulto JovemRESUMO
Recurrent and non-recurrent chromosomal rearrangements seem to reflect susceptibility to DNA rearrangements due to the presence of recombinogenic motifs in at least one partner chromosomal region. While specific genomic motifs such as AT-rich repeats, fragile sites and Alu repeats are often found in recurrent translocations, the molecular mechanisms underlying non-recurrent chromosomal rearrangements remain largely unknown. Here, we map the breakpoint region of a non-recurrent translocation, t(7;9)(q11.23;p24.3), present in a healthy woman who inherited the apparently balanced translocation from her mother and transmitted the same rearrangement to two sons-respectively healthy and aborted. Characterisation by a two-step FISH analysis, first with BAC clones and then with small locus-specific probes, restricted the breakpoint intervals to 8-10 kb. Both regions contained specific Alu sequences, which, together with the flanking low copy repeat block Ac in 7q11.23, might stimulate the translocation. We noted that, although the translocation is non-recurrent, 7q11.23 is recurrently involved in different chromosomal rearrangements, supporting the hypothesis that the 7q11.23 genomic structure is prone to recombination events.