Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer

Abstract

Few studies have reported on the comprehensive BRCA1/2 mutation analyses of hereditary breast cancer (HBC) families of French Canadian descent. Here we report the investigation of 82 families with at least 3 cases of breast cancer evaluated for mutations by DNA sequencing and/or multiplex ligation-dependent probe amplification (MLPA) assay. DNA sequencing identified pathogenic mutations in 37 (45.1%) families, of which 70.2% were one of three recurring mutations (BRCA1:R1443X, BRCA2:8765delAG, and BRCA2:E1953X) frequently reported in this founder population; and variants of uncertain clinical significance in 7 (8.5%) families of which two harbored BRCA2:E3002K. MLPA analysis of the 38 DNA sequence-negative families did not reveal any large rearrangements in BRCA1/2. A phenotypic characterization of the cancer families based on pathogenic mutation status revealed that there were significantly fewer very young age at diagnosis breast cancer cases (<36 years) in mutation-negative families (5.9%, 9 of 153) than in BRCA1 (22.8%, 13 of 57; P = 0.0003) or BRCA2 (22.9%, 27 of 118; P < 1× 10E5) mutation-positive families. There were significantly more mutation-positive families (29 of 36, 80.6%) with a very young age of onset of breast cancer case than those that did not (8 of 39, 20.5%) (P < 10E6). The comprehensive mutation analysis of BRCA1/2 suggests that genomic rearrangements are unlikely to account for sequence-negative HBC families and affirms that the presence of a very young age of diagnosis of breast cancer is strongly predictive of mutation carrier status of French Canadian HBC families.

Double PALB2 and BRCA1/BRCA2 mutation carriers are rare in breast cancer and breast-ovarian cancer syndrome families from the French Canadian founder population

“…In total, ~0.4% of the same cohort of breast cancer cases not selected for a family history of cancer, and who were also analyzed for the presence of recurrent BRCA1/BRCA2 mutations, were identified to be PALB2:c.2323C>T [p.Q775X] carriers, whereas no carriers were observed among newborns (7). These results are consistent with those of previous studies, which reported that ~40 and 1% of French Canadian breast cancer and breast-ovarian cancer families harbor germline BRCA1/BRCA2 or PALB2 germline mutations, respectively (2,3,8,9).…”

BRCA1 germline mutations dominate familial breast cancer patients in Henan China

“…Loss of function of BRCA by mutations might lead to abnormal cell cycle and cell growth, and then cancers. Our result in this study shown the rate of BRCA1 gene mutation is 52.54% among familiar breast cancer patients, which is higher than published result (11). A possible reason is that invasive ductal carcinoma is the main histopathologic types of breast cancer in this cohort of patients, in which the mutation rates in BRCA1 even as high as 74.19%.…”

Establishing a Clinic-Based Pancreatic Cancer and Periampullary Tumour Research Registry in Quebec

“…Most subjects with pdac were white (79.2% maternal, 80.1% paternal), with an enrichment of cases (37.4%) having French-Canadian ancestry (at least 1 parental origin, Table iii). In addition, 56.8% of pdac-affected subjects had an ancestry (that is, French-Canadian, Ashkenazi Jewish, Greek, German, Polish, or Latvian) known to harbour recurrent germline ("founder") mutations in the BRCA1, BRCA2, and PALB2 pdac predisposing genes (Table iii) [11][12][13][14][15][16][17][18][19] . Table iii also shows data describing education, environmental exposures, weight loss, and history of type 2 diabetes and pancreatitis for enrolled patients with pdac.…”

“…Notably, more than half the enrolled patients in the qpcs affected with pdac (56.8%) had an ancestry (at least 1 parental origin) known to harbour founder BRCA1 and BRCA2 mutations [11][12][13][14][15][16][17][18][19] . The founder populations represent a genetically enriched subgroup ideal for gene discovery studies 8,[37][38][39] .…”

“…The enrichment of the qpcs with participants of French-Canadian descent is particularly valuable because fpdac is prevalent in that population 40 . In addition, FrenchCanadian founder mutations in the BRCA1, BRCA2, and PALB2 genes have already been described [11][12][13] , providing the qpcs with a unique opportunity to study the prevalence of those founder mutations among French-Canadian participants with pdac. BRCA1-and BRCA2-associated pdac is of particular interest because those tumours can have beneficial treatment responses to dna cross-linking agents (that is, platinum salts) and parp inhibitors [41][42][43][44][45][46] .…”