Significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor 1 of 5 BRCA1 and BRCA2 mutations

Abstract

In 1998, we reported that a significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor specific germline mutations in BRCA1 or BRCA2 attributed to common founders. Here we report the frequency of previously described mutations (n ‫؍‬ 7) and 13 mutations identified in French Canadian families since 1998, in a new group of families (n ‫؍‬ 88). Four of the previously described mutations, 4446C>T, 2953delGTAinsC, 8765delAG and 6085C>T, account for 72% and 69% of mutation-positive families in previously (n ‫؍‬ 81) and recently ascertained groups, respectively. Only 2 of 13 recently identified mutations were found in more than 1 family: 3875delGTCT (n ‫؍‬ 2) and 3398delAAAAG (n ‫؍‬ 4). The 2 groups (ascertained pre-and post-gene discovery) did not differ significantly when distribution of mutations based on cancer syndrome phenotype and age of diagnosis or number of breast cancer cases were compared. Five common mutations accounted for a significant proportion (84%) of all mutationpositive families. The age of diagnosis of female breast cancer in mutation-negative families was significantly higher than that of the mutation-positive families (p<0.0001). The total number of cases of cancer per family was significantly lower in mutation-negative than mutation-positive families (p<0.001). Our results define a new mutation panel for screening BRCA1/2 mutations and the phenotype of mutation-positive families harboring the common mutations in the French Canadian population. © 2004 Wiley-Liss, Inc. Key words: BRCA1; BRCA2; French Canadian; founder mutationIn 1998, our group was the first to report that a significant proportion of breast and/or ovarian cancer families of French Canadian descent harbor specific mutations in BRCA1 and BRCA2 1 genes that confer a significantly increased lifetime risk of developing both breast cancer and ovarian cancer. [2][3][4][5] In the initial study that comprised 97 hereditary breast cancer (HBC) and hereditary breast and ovarian cancer (HBOC) families screened for only 4 specific variations in each gene, the BRCA1 4446CϾT and BRCA2 8765delAG mutations accounted for 68% (28 of 41) of mutation-positive families. 1 The BRCA1 2953delGTAinsC and 3768insA mutations, and BRCA2 2816insA and 6085GϾT mutations, were also identified more than once in independently ascertained families and were observed at similar frequencies, accounting for 4 to 10% of mutation-positive families. Although only specific mutations were screened in this analysis, the overall proportion of mutation-positive families was consistent with those observed in other reports in the general population where a comprehensive analysis of BRCA1 and/or BRCA2 was conducted. 6 -11

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).…”

“…French Canadian families with breast cancer and breast-ovarian cancer syndrome present with recurrent mutations in the BRCA1, BRCA2 or PALB2 breast cancer susceptibility genes (1)(2)(3). This has been attributed to common founders in the Quebec provincial population (4,5).…”

High frequency of exon deletions and putative founder effects in French Canadian Lynch syndrome families

“…In hereditary breast and ovarian cancer pedigrees, such recurrent mutations have been identified in BRCA1 and BRCA2 where five founder mutations account for 75-85% of all mutations present in the French Canadian population of Quebec (Oros et al, 2004;Simard et al, 2007). More recently, a single mutation in PALB2, p.Q775X, has been described as a founding mutation in French Canadian breast cancer families (Foulkes et al, 2007).…”

The BRCA2 c.9004G>A (E2003K) variant is likely pathogenic and recurs in breast and/or ovarian cancer families of French Canadian descent

“…About 40% of French Canadian cancer families with at least three or more cases of breast and/ovarian cancer carry a pathogenic BRCA1/2 mutation [4,[9][10][11]. Although 15 different BRCA1/2 mutations have been reported in French Canadian cancer families, five specific frameshift or nonsense mutations in BRCA1 (c.4327C[T (R1443X), c.2834_2836delGTAinsC); and BRCA2 (c.8537_8538de-lAG, c.5857G[T (E1953X), c.3167_3171delAAAAG) have been shown to account for a significant majority of mutation-positive families [9][10][11][12][13]. This has been attributed to a shared ancestry of mutation carriers due to common founders of the French Canadian population of Quebec [14][15][16][17][18].…”