Haplotype analysis suggest common founders in carriers of the recurrent BRCA2mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families

Oros, Kathleen Klein; Leblanc, Guy; Arcand, Suzanna L.; Shen, Zhen; Perret, Chantal; Mes-Masson, Anne-Marie; Foulkes, William D.; Ghadirian, Parviz; Provencher, Diane; Tonin, Patricia N.

doi:10.1186/1471-2350-7-23

Cited by 18 publications

(24 citation statements)

References 19 publications

(32 reference statements)

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“…A recombination event around BRCA2 could account for the latter haplotype difference, whereas the variance in allele size of one tetranucleotide repeat unit within the D13S1701 allele in two families may have been [16] caused by slippage during DNA replication of this repeat sequence. It is not possible to determine if this marker exhibits a higher mutation rate than other markers in the BRCA2 region, as it was suggested by other studies [25], or if that mutation occurred early on during in the spreading of the population carrying the c.156_157insAlu BRCA2 mutation. If we compare the D13S1701 genotypes for all 14 c.156_157insAlu positive probands, it is tempting to say that all mutation carriers with unphased genotypes harbored the same 299 allele, but in two out of three informative families we observed that this allele did not segregate with the mutation.…”

Section: Discussionmentioning

confidence: 88%

The c.156_157insAlu BRCA2 rearrangement accounts for more than one-fourth of deleterious BRCA mutations in northern/central Portugal

Peixoto

Santos

Rocha

et al. 2008

Breast Cancer Res Treat

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We evaluated the contribution of an Alu insertion in BRCA2 exon 3 (c.156_157insAlu) to inherited predisposition to breast/ovarian cancer in 208 families originated mostly from northern/central Portugal. We identified the c.156_157insAlu BRCA2 mutation in 14 families and showed that it accounts for more that one-fourth of deleterious BRCA1/BRCA2 mutations in breast/ovarian cancer families originated from this part of the country. This mutation originates BRCA2 exon 3 skipping and we demonstrated its pathogenic effect by showing that the BRCA2 full length transcript is derived only from the wild type allele in carriers, that it is absent in 262 chromosomes from healthy blood donors, and that it co-segregates with the disease. Polymorphic microsatellite markers were used for haplotype analysis in three informative families. In two of the three families one haplotype was shared for all but two markers, whereas in the third family all markers telomeric to BRCA2 differed from that observed in the other two. Although the c.156_157insAlu BRCA2 mutation has so far only been identified in Portuguese breast/ovarian cancer families, screening of this rearrangement in other populations will allow evaluation of whether or not it is a population-specific founder mutation and a more accurate estimation of its distribution and age.

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Section: Discussionmentioning

confidence: 88%

The c.156_157insAlu BRCA2 rearrangement accounts for more than one-fourth of deleterious BRCA mutations in northern/central Portugal

Peixoto

Santos

Rocha

et al. 2008

Breast Cancer Res Treat

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“…The probability of BRCA1/2 mutation carrier status was determined for descriptive purposes using the Manchester BRCA1/2 mutation analysis in French Canadian cancer families 509 scoring system [40] which has been shown to be highly predictive of carrier status in French Canadian cancer families, [7,12], which also included consideration of information from third degree relatives [7]. Given our inclusion criteria included affected third-degree relatives, information from first-, second-and third-degree relatives to the index case that occurred in the same branch of the family was included in the determining the score.…”

Section: Methodsmentioning

confidence: 99%

“…We have reported a mutation frequency of about 40% for French Canadian families from the Province of Quebec fulfilling this criteria [2][3][4], although a comprehensive mutation analysis including the investigation of large deletions or rearrangements was not performed in these early studies. More than 15 different mutations have been identified in this defined cohort where a significant majority ([80%) of mutationpositive families had one of five specific mutations in these genes [2][3][4][5][6][7]. This has been attributed to a shared ancestry of mutation carriers due to common founders of the French Canadian population of Quebec [1,8,9].…”

Section: Introductionmentioning

confidence: 98%

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

et al. 2010

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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.

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“…Specific BRCA1 and BRCA2 mutations have been found to recur in French Canadian cancer families [2][3][4][5], and this has been attributed to common founders in the Quebec population [1,[6][7][8][9][10]. Mutation-negative families could be due to unidentified BRCA1/BRCA2 mutations, chance clustering of cancer cases or other genes conferring increased risk to breast cancer [11].…”

Section: Introductionmentioning

confidence: 96%

Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families

Arcand

Maugard

Ghadirian

et al. 2007

Breast Cancer Res Treat

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About 40% of French Canadian breast and/or ovarian cancer families harbor germline BRCA1 or BRCA1 mutations where common mutations account for about 84% of all mutations identified in cancer families. Within a series of BRCA1 and BRCA2 mutation-negative families, a germline TP53 13398 G>A (Arg213Gln) mutation was identified, which was selected for mutation analysis in this gene because of a family history consistent with Li-Fraumeni syndrome (LFS). Given the founder effects in this population, the 13398 G>A mutation was screened in series of 52 BRCA1 and BRCA2 mutation-negative cancer families, and a mutation-positive family was identified. However, pedigree inspection and expansion of mutation-positive families with the same mutation revealed that they were closely related to each other. To further characterize the contribution of TP53 in cancer families, mutation analysis was performed in the remaining BRCA1 and BRCA2 mutation-negative cancer families. Thirty sequence variants were identified, the majority of which occur in intronic sequences and are not predicted to affect the functionality of TP53. However, the 14538 G>A (Arg290His) mutation was identified in a family which did not exhibit features consistent with LFS or Li-Fraumeni-like (LFL) syndrome. Neither of the TP53 mutations was detected in 381 French Canadian women with breast cancer diagnosed before 50 years of age not selected for family history of cancer. In all, germline TP53 mutations were identified in two of 52 (3.8%) cancer families, suggesting that TP53 is not a major contributor to BRCA1 and BRCA2 mutation-negative breast and/or ovarian cancer families of French Canadian descent.

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Haplotype analysis suggest common founders in carriers of the recurrent BRCA2mutation, 3398delAAAAG, in French Canadian hereditary breast and/ovarian cancer families

Cited by 18 publications

References 19 publications

The c.156_157insAlu BRCA2 rearrangement accounts for more than one-fourth of deleterious BRCA mutations in northern/central Portugal

The c.156_157insAlu BRCA2 rearrangement accounts for more than one-fourth of deleterious BRCA mutations in northern/central Portugal

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

Germline TP53 mutations in BRCA1 and BRCA2 mutation-negative French Canadian breast cancer families

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