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Evidence for a BRCA1 Founder Mutation in Families of West African Ancestry

1999; Elsevier BV; Volume: 65; Issue: 2 Linguagem: Inglês

10.1086/302511

1537-6605

Heather C. Mefford, Lisa Baumbach, Ramesh C. K. Panguluri, Carolyn Whitfield-Broome, Csilla I. Szabo, Selena Smith, Mary‐Claire King, Georgia M. Dunston, Dominique Stoppa-Lyonnet, Fernando Arena,

Chromosomal and Genetic Variations

To the Editor: Inherited mutations in the BRCA1 gene (MIM 113705; GenBank U14680) (Miki et al. Miki et al., 1994Miki Y Swensen J Shattuck-Eidens D Futreal PA Harshman K Tavtigian S Liu Q et al.A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.Science. 1994; 266: 66-71Crossref PubMed Scopus (5047) Google Scholar) are less common among breast cancer patients of African American ancestry than among those of white ancestry. For example, in a population-based series of breast cancer patients from North Carolina, the prevalence of BRCA1 mutations was 3.3% among white women and 0% among African American women (Newman et al. Newman et al., 1998Newman B Mu H Butler LM Millikan RC Moorman PG King M-C Frequency of breast cancer attributable to BRCA1 in a population-based series of American women.JAMA. 1998; 279: 915-921Crossref PubMed Scopus (316) Google Scholar). Nonetheless, inherited BRCA1 mutations have been identified in families of African and African American ancestry at high risk of breast cancer (Gao et al. Gao et al., 1997Gao Q Neuhausen S Cummings S Luce M Olopade OI Recurrent germ-line BRCA1 mutations in extended African American families with early-onset breast cancer.Am J Hum Genet. 1997; 60: 1233-1236PubMed Google Scholar; Stoppa-Lyonnet et al. Stoppa-Lyonnet et al., 1997Stoppa-Lyonnet D Laurent-Puig P Essioux L Pagès S Ithier G Ligot L Fourquet A et al.BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic.Am J Hum Genet. 1997; 60: 1021-1030PubMed Google Scholar; Panguluri et al. Panguluri et al., in pressPanguluri RCK, Brody LC, Modali R, Utley K, Adams-Campbell L, Day AA, Whitfield-Broome C, et al. BRCA1 mutations in African Americans. Hum Genet (1999) (in press)Google Scholar [in press]). To provide effective genetic testing for African American families at high risk for breast and ovarian cancer, it would be helpful to identify ancient BRCA1 mutations of African origin analogous to ancient mutations in other populations (Simard et al. Simard et al., 1994Simard J Tonin P Durocher F Morgan K Rommens J Gingras S Samson C et al.Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families.Nat Genet. 1994; 8: 392-398Crossref PubMed Scopus (287) Google Scholar; Peelen et al. Peelen et al., 1997Peelen T van Vliet M Petrij-Bosch A Mieremet R Szabo C van den Ouweland AMW Hogervorst F et al.A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families.Am J Hum Genet. 1997; 60: 1041-1049PubMed Google Scholar; Petrij-Bosch et al. Petrij-Bosch et al., 1997Petrij-Bosch A Peelen T van Vliet M van Eijk R Olmer R Drusdau M Hogervorst FBL et al.BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients.Nat Genet. 1997; 17: 341-345Crossref PubMed Scopus (357) Google Scholar). Here we have described one apparently ancient, African BRCA1 mutation. BRCA1 mutation 943ins10 was detected in breast cancer patients from the Ivory Coast (Stoppa-Lyonnet et al. Stoppa-Lyonnet et al., 1997Stoppa-Lyonnet D Laurent-Puig P Essioux L Pagès S Ithier G Ligot L Fourquet A et al.BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic.Am J Hum Genet. 1997; 60: 1021-1030PubMed Google Scholar), the Bahamas, and the United States (Arena et al. Arena et al., 1997Arena JF Smith S Vincek V Gayol L Villegas F Perera E King MC et al.A BRCA1 founder mutation in African-Americans.Am J Hum Genet Suppl. 1997; 61: A14Google Scholar; Panguluri et al. Panguluri et al., in pressPanguluri RCK, Brody LC, Modali R, Utley K, Adams-Campbell L, Day AA, Whitfield-Broome C, et al. BRCA1 mutations in African Americans. Hum Genet (1999) (in press)Google Scholar [in press]) (fig. 1). To confirm the identity of the mutation for the five probands and their relatives, the critical region of BRCA1 was genotyped by fluorescent sequencing with dRhodamine-dye terminators (Applied Biosystems). Primers 5′-GGAATTAAATGAAAGAGTATGAGC-3′ and 5′-CTTCCAGCCCATCTGTTATGTTG-3′ revealed the heterozygous frameshift mutation 943ins10, a 10-bp insertion in exon 11, leading to a stop at codon 289. The mutation is a tandem duplication, in a repeated-sequence motif, that could have occurred atany site between BRCA1 nucleotides 926 and 943(fig. 2). The notation “943ins10” designates the most-3′ site of insertion possible (Antonarakis et al. Antonarakis, 1998Antonarakis SE Recommendations for a nomenclature system for human gene mutations: Nomenclature Working Group.Hum Mutat. 1998; 11: 1-3Crossref PubMed Scopus (833) Google Scholar).The 943ins10 variant can be easily detected on agarosegel by amplification of genomic DNA or cDNA with BRCA1 primers 5′-CTGCTTGTGAATTTTCTGAGACGG-3′ and 5′-TGCTGTAATGAGCTGGCATGAG-3′ under standard conditions. Wild-type BRCA1 sequence yields a product of 184 bp, and 943ins10 yields a product of 194 bp.Figure 2Sequence of the BRCA1 943ins10 mutation. A duplication and insertion of 10 bp causes a frameshift and premature truncation at amino acid 289.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Genotypes of relatives in these five families were consistent with BRCA1 943ins10 being a founder mutation of African origin. Nine markers within and flanking BRCA1 were genotyped (Genome Database): D17S1325, D17S1326, and D17S1327 (5′ of BRCA1); D17S1323 (intron 12), D17S1322 (intron 19), and D17S855 (intron 20); and D17S1321, D17S1320, and D17S1185 (3′ of BRCA1) (Neuhausen et al. Neuhausen et al., 1996Neuhausen SL Mazoyer S Friedman L Stratton M Offit K Caligo A Tomlinson G et al.Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.Am J Hum Genet. 1996; 58: 271-280PubMed Google Scholar; Smith et al. Smith et al., 1996Smith TM Lee MK Szabo CI Jerome N McEuen M Taylor M Hood L et al.Complete genomic sequence and analysis of 117 kb of human DNA containing the gene BRCA1.Genome Res. 1996; 6: 1029-1049Crossref PubMed Scopus (233) Google Scholar). The 943ins10 mutation occurred on a single haplotype spanning D17S1320–D17S1326 (fig. 1), a distance of ∼700 kb. The families inheriting BRCA1 943ins10 were from widespread locales of Africa and the African diaspora: the Ivory Coast, the Bahamas, the southeastern United States, and Washington, DC. The families are not recently related, and the four families in North America can trace their history in this hemisphere to the slavery period. The length of the 943ins10 nonrecombinant BRCA1 region is similar to the length of the shared region flanking the BRCA1 mutation 185delAG. Hence, the ages of these mutations may be comparable (Bar-Sade et al. Bar-Sade et al., 1998Bar-Sade RB Kruglikova A Modan B Gak E Hirsh-Yechezkel G Theodor L Novikov I et al.The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim.Hum Mol Genet. 1998; 7: 801-805Crossref PubMed Scopus (106) Google Scholar). The shared BRCA1 region flanking 943ins10 is shorter than the BRCA1 regions flanking 5382insC or 2800delAA, so the African mutation is probably older than these European mutations (Neuhausen et al. Neuhausen et al., 1996Neuhausen SL Mazoyer S Friedman L Stratton M Offit K Caligo A Tomlinson G et al.Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study.Am J Hum Genet. 1996; 58: 271-280PubMed Google Scholar; Friedman et al. Friedman et al., 1995Friedman LS Szabo CI Ostermeyer EA Dowd P Butler L Park T Lee MK et al.Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families.Am J Hum Genet. 1995; 57: 1284-1297PubMed Google Scholar). West Africans were brought to North America as slaves between 1619 and 1808. Hence, the social history of the families studied indicates that the mutation is >200 years old and could be much more ancient. Figure 1 indicates additional, known cases of breast and ovarian cancer in each family. In families UM94003 and UM95027, mothers of probands were affected. In families UM96034 and HU003, in which mothers were not affected, the 943ins10 allele was inherited from the father. Age at breast and ovarian cancer diagnosis was ≤50 years for all probands and affected relatives. Family IC564 includes four women with breast or ovarian cancer, all of whom live in the Ivory Coast, where breast and ovarian cancer are rare (Parkin et al. Parkin et al., 1997Parkin DM Whelan SL Ferlay J Raymond L Young J Cancer incidence in five continents. Vol 7. International Association of Cancer Registries, Lyon1997Google Scholar). In this family, the mother of a patient with ovarian cancer remains unaffected at age 83 years, though she is likely to carry the mutation. That there are elderly carriers without cancer suggests that nongenetic factors may influence the penetrance of BRCA1 alleles in geographic regions with a low background risk for breast cancer. The geographic distribution of 943ins10 in North America is intriguing and is not completely known. BRCA1 943ins10 occurred in 3 of 96 African American patients seen at the University of Miami, who had breast cancer diagnosed at an early age, and in 1 of 55 African American patients seen at Howard University in Washington, DC, who had breast cancer diagnosed at an early age or who had families with a high incidence of breast cancer. However, in the population-based Carolina Breast Cancer Study, the mutation did not appear among 263 African American breast cancer patients, 50% of whom were aged <50 years and 50% of whom were aged ⩾50 years at diagnosis (Newman et al. Newman et al., 1998Newman B Mu H Butler LM Millikan RC Moorman PG King M-C Frequency of breast cancer attributable to BRCA1 in a population-based series of American women.JAMA. 1998; 279: 915-921Crossref PubMed Scopus (316) Google Scholar). The 943ins10 allele has not been observed in any patients with breast cancer who identify their ancestry as solely European. The migration patterns of African Americans and, hence, the current areas of residence of African American families, may explain the difference, among clinical centers, in the prevalence of the mutation. To determine, among African American women, the proportion of inherited breast or ovarian cancer attributable to BRCA1 943ins10, we would like to encourage testing for this mutation among African American breast and ovarian cancer patients from various regions of the United States. Given the increasing incidence of and higher mortality from breast cancer among African American women, it would be useful to obtain as much information as possible about the roles of BRCA1 and BRCA2 in this population. This study was supported by National Institutes of Health grants CA27632, CA55772, and RR03048, by U.S. Department of Defense grant 17-94-J4245, and by grants from the Komen Foundation and the Sylvester Comprehensive Cancer Center Developmental Program.