Clustering of cancer‐related mutations in a subset of BRCA1 alleles: A study in the Spanish population

Abstract

We have observed that the frequency of D17S855 short alleles (139 bp and 141 bp) in individuals carrying BRCA1 germline mutations is higher than in controls (54% vs. 31%, p ‫؍‬ 0.0004). By unambiguously establishing mutation/ D17S855 phase in 18 BRCA1-positive families, we find that most (11 of 15 different mutations) BRCA1 defects are linked to chromosomes with short alleles (OR ‫؍‬ 8.21, 95% CI 1.97-39.32, p ‫؍‬ 0.0007). We suggest that BRCA1 mutations are not randomly distributed but clustered in a subset of BRCA1 alleles that can be identified by D17S855 genotyping. Further analysis involving a larger set of mutations and different populations are needed to clarify the relevance of this unexpected finding. © 2002 Wiley-Liss, Inc. Key words: BRCA1; D17S855; OR; CI; genetic testing; Spain BRCA1 was the first breast and ovarian cancer susceptibility gene to be identified. 1 Since then, more than 500 different cancerrelated mutations scattered all over the coding sequence and intron/exon boundaries have been identified, 2 suggesting that many independent, and randomly distributed mutational events have occurred in this gene, making genetic testing difficult, costly and time consuming. Interestingly, here we present data suggesting that mutations detected in breast/ovarian families are not randomly distributed but clustered in a subset of BRCA1 alleles.We have genotyped D17S855 (a highly informative BRCA1 intragenic marker, calculated heterozygosity of 0.8220 in Europeans 3 ) in index cases from 140 breast/ovarian Spanish families. Index cases (the youngest breast and/or ovarian cancer case available in each family) have been previously screened for BRCA1 germline mutations. 4 -7 Breast/ovarian families have been ascertained in several different areas from Spain: They have 3 or more cases of breast/ovarian cancer diagnosed in two generations (same lineage), one of them diagnosed before age 50. Families carrying BRCA1 mutations do not show any geographical clustering. More data concerning BRCA1 genetic testing is available upon request.D17S855 genotyping was performed in an Abby Prism 310 Genetic Analyzer (Applied Biosystems, Foster City, CA). Allele calling ranged from 139 bp to 151 bp in all cases. For statistical analyses we used the 2 test. Interestingly, we observed an overrepresentation of D17S855 short alleles (18% vs. 10% for the 139 alleles and 36% vs. 20% for the 141 alleles) in index cases carrying BRCA1 germline mutations (positive index cases through this text), when compared to index cases that were not demonstrated to carry a mutation (negative index cases). Observed frequency increases were equivalent in both cases (roughly 80%), and we did not detect a similar increase for any other D17S855 allele frequency (data not shown). We decided, therefore, to pool data from both 139 and 141 alleles (short alleles through this text) in all statistical analysis.As shown in Figure 1, D17S855 short alleles are overrepresented in positive index cases (54% vs. 31%, OR ϭ 2.57, 95% CI 1.46 -4.56, p ϭ 0.0004). I...

Over-representation of two specific haplotypes among chromosomes harbouring BRCA1 mutations

“…2 We confirmed that shortest alleles were concentrated in chromosomes carrying BRCA1 mutations (65 vs 40%, Po0.05); moreover, the distribution of allele À2, the less frequently associated with haplotype I in the general population, 3 was over-represented in the chromosomes with mutations associated with haplotype I (12 vs 44.4%) (OR 3.5, CI 1.14 -11.15, P ¼ 0.049).…”

“…2 So, we genotyped this marker in our cases and found that the 139 bp allele, designated as À2, was 3.5 times more frequent than expected in mutations linked to haplotype I (CI 1.14 -11.15, P ¼ 0.049). So, these results define a second haplotype, which is also overrepresented among chromosomes harbouring BRCA1 mutations.…”

“…In this way, it has recently been observed in Spanish populations that BRCA1 mutations could be more frequently found in chromosomes that are defined by the presence of short alleles (139 and 141 bp) for the BRCA1 intragenic microsatellite marker D17S855. 2 In the present study, we have determined two haplotypes associated with the BRCA1 gene in the index cases of 106 breast/ovarian cancer Spanish families by genotyping three BRCA1 SNPs included in a 200 -400 kb region that is subjected to a recombination suppression mechanism. These SNPs define two major haplotypes, designated as class I and class II, that account for nearly all chromosomes in European and Asian populations.…”

High proportion of BRCA1/2 founder mutations in Hispanic breast/ovarian cancer families from Colombia

“…Of the 26 observations in the BIC database, the majority was of European ancestry and only nine were of Latin American/Caribbean descent. This mutation has also previously been found in eleven Spanish families [33][34][35] and in a family from El Salvador [1]. The third recurrent mutation, 3034 delACAA in BRCA2 was found in two families.…”

The Impact of Acculturation on Awareness of Genetic Testing for Increased Cancer Risk among Hispanics in the Year 2000 National Health Interview Survey

“…In a national study of 646 patients who received genetic testing in community based (non-research) settings between the years 1998 and 2000, only 1% (n = 7) were Hispanic (5). As of yet, mutation prevalence, associated breast cancer risk, and the need for cancer genetic services are not well defined in Hispanics although BRCA1/2 mutations have been documented (6)(7)(8)(9)(10)(11)(12)(13)(14). For example, among 10,000 high-risk individuals undergoing mutation testing at a commercial laboratory who specified a single ancestry, the prevalence of BRCA1/2 mutations was 16% among Europeans, 19% among Africans, 18% among Latin Americans/Caribbeans, 14% among Native Americans, and 12% among Asians (15).…”