BRCA1 and BRCA2 germline mutational spectrum and evidence for genetic anticipation in Portuguese breast/ovarian cancer families

Abstract

We present the first characterisation of the mutational spectrum of the entire coding sequences and exon-intron boundaries of the BRCA1 and BRCA2 genes as well as large BRCA1 rearrangements in Portuguese families with inherited predisposition to breast/ovarian cancer. Of the 100 probands studied, pathogenic mutations were identified in 22 (24.7%) of 89 breast and/or ovarian cancer families with more than one affected member (15 in BRCA1 and seven in BRCA2), but in none of the 11 patients without family history of cancer. One (6.7%) of the BRCA1 mutations is a large deletion involving exons 11-15. Seven pathogenic point mutations are novel: 2088C>T, 2156delinsCC, and 4255_4256delCT in BRCA1 and 4608_4609delTT, 5036delA, 5583_5584insT, and 8923C>T in BRCA2. The novel 2156delinsCC was identified in three probands from different families and probably represents a founder mutation in our population. We also found a previously reported 3450_3453del4 mutation in three unrelated patients. In addition to the 22 pathogenic mutations, we identified 19 missense mutations of uncertain pathogenic significance, three of them (5241G>C in BRCA1 and IVS6+13C>T and 3731T>C in BRCA2) previously undescribed. The percentage of cases with truncating mutations in BRCA1 and BRCA2 was higher in breast/ovarian cancer (37.0%, mostly BRCA1) and male breast cancer (40%, all BRCA2) families than in families with only female breast cancer (17.5%). Interestingly, we found evidence for genetic anticipation regarding age at diagnosis of both breast and ovarian cancer in those families presenting affected members in more than one generation. These findings should be taken into consideration while planning screening and prophylactic measures in families with inherited predisposition to breast and ovarian cancer.

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

“…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).…”

“…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.…”

International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation

“…From Portugal, 149 new suspected HBOC families were selected for BRCA1 and BRCA2 mutation screening using previously described criteria (Peixoto et al, 2006;Peixoto et al, 2009a) after written informed consent. Molecular testing at the Department of Genetics of the Portuguese Oncology Institute, Porto, Portugal (IPO-Porto) started by looking for the c.156_157insAlu BRCA2 mutation, followed by full BRCA1 and BRCA2 mutation screening with the previously reported methodology (Peixoto et al, 2006;Peixoto et al, 2009a;Peixoto et al, 2009b).…”

“…From Portugal, 149 new suspected HBOC families were selected for BRCA1 and BRCA2 mutation screening using previously described criteria (Peixoto et al, 2006;Peixoto et al, 2009a) after written informed consent. Molecular testing at the Department of Genetics of the Portuguese Oncology Institute, Porto, Portugal (IPO-Porto) started by looking for the c.156_157insAlu BRCA2 mutation, followed by full BRCA1 and BRCA2 mutation screening with the previously reported methodology (Peixoto et al, 2006;Peixoto et al, 2009a;Peixoto et al, 2009b). The c.156_157insAlu BRCA2 mutation was additionally screened in 5,291 suspected HBOC families living in countries other than Portugal in whom no deleterious BRCA1/BRCA2 mutations had previously been found, with the following Additionally, predictive testing was performed in four individuals from two additional families (two relatives from each family living in Rhode Island, USA, and in Villejuif, France, respectively) with the c.156_157insAlu BRCA2 mutation identified elsewhere.…”

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

“…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].…”