Founder populations and their uses for breast cancer genetics
© Current Science Ltd 2000
Received: 19 December 1999
Accepted: 14 January 2000
Published: 1 April 2000
Numerous founder mutations have been reported in BRCA1 and BRCA2. For genetic screening of a population with a founder mutation, testing can be targeted to the mutation, allowing for a more rapid and less expensive test. In addition, more precise estimates of the prior probability of carrying a mutation and of the likelihood of a mutation carrier developing cancer should be possible. For a given founder mutation a large number of carriers are available, so that focused scientific studies of penetrance, expression, and genetic and environmental modifiers of risk can be performed. Finally, founder populations may be a powerful resource to localize additional breast cancer susceptibility loci, because of the reduction in locus heterogeneity.
KeywordsBRCA1 BRCA2 breast cancer genes founder mutations genetic epidemiology
Ethnic differences in the prevalences of many diseases have been observed. For example, sickle-cell anemia in individuals of African descent, Tay-Sachs disease in Ashkenazi Jews , and approximately 30 diseases in Finland  are more prevalent than in other populations. A likely reason for a preponderance of a disease in a specific population is a founder effect. Founder effects occur when a population is established by a small number of people or when a bottleneck occurs that reduces the population to a small number. When population expansion occurs, the mutation in a founder becomes prevalent in a larger proportion of the population. There may also be a selective advantage to the mutation carrier. By following genetic relationships over many generations, the significance of founder effects can be studied. Diamond and Rotter  reviewed studies of the Afrikaner population of South Africa. In 1652, one founding immigrant carried a gene for Huntington's chorea and one brother-sister pair carried a gene for lipoid proteinosis. The result of founder effects is that these diseases are more common in South Africa than in Holland from where the carriers emigrated.
Founder populations can be useful in genetic studies, particularly for genetic mapping of complex traits. There is little genetic heterogeneity, so that the majority of individuals with disease will carry the same gene mutation. Linkage disequilibrium between the site of the gene and close markers will exist, so that shared regions of the genome cosegregating with disease can be more readily discerned. As an example, Hirschprung's disease has been described in individuals of many different backgrounds. Using a Mennonite population, in which all affected individuals could be traced to a single common ancestral couple, one of the genes for the disease was localized and subsequently identified .
Once founder mutations are identified, researchers are able to examine prevalence of mutations in different populations and mutation-specific effects on penetrance and disease phenotype. Possibly, better estimates of risk for individuals in populations with founder mutations can be calculated. This editorial focuses on founder populations in genetic studies of breast cancer.
Prevalence of mutations in BRCA1 and BRCA2
BRCA1 and BRCA2, two genes predisposing to breast and ovarian cancers, were isolated in 1994 and 1995, respectively [5,6]. Since that time, researchers have been screening for mutations in high-risk breast and/or ovarian cancer families and in population-based samples of women with these cancers to determine the prevalence and range of mutations. Over 1300 distinct variants have been found across all population groups, of which approximately 700 are identified as causal [7,8]. A number of these mutations have been identified multiple times . Many of these common mutations have been classified as founder mutations on the basis of a shared haplotype in the genomic region containing the gene. Founder mutations for BRCA1 and BRCA2 have been described in numerous populations (Table 1), as well as across populations. For example, BRCA1 5382insC has been reported in individuals of Jewish, Dutch, Lithuanian, Russian, Hungarian, Germanic, French, Italian, British, and French-Canadian ancestry . This suggests that this is a relatively old mutation that has spread through migration.
Relative ages of several founder mutations have been investigated by examining the distance over which haplotypes are conserved [9,10]. Based on the general age of a mutation and historic data on migration and social patterns, the origin and subsequent migration of specific mutations may be described. Now that a large number of mutation carriers have been identified the Breast Cancer Linkage Consortium is undertaking such a study for a set of founder mutations.
Assessment of risk
Since the isolation of BRCA1 and BRCA2, genetic testing for mutations is becoming more common in clinical genetic practice. Important considerations are who should be offered predictive testing and when it should be done. In general, mutations in BRCA1 and BRCA2 are rare, probably accounting for less than 5% of breast cancers and 10% of ovarian cancers in the population [11,12]. The frequency of BRCA1 and BRCA2 mutation carriers in women with breast and/or ovarian cancer is dependent on the study population, and is highest in young women with breast cancer who have a strong family history of breast and/or ovarian cancers. An essential issue for testing is the probability that an individual, with breast or ovarian cancer or with a family history of cancer, will carry a mutation in BRCA1 or BRCA2. Probability models have been developed to predict the likelihood of being a mutation carrier before testing [13,14,15,16]. Prior probabilities vary depending on the model used.
Examples of BRCA1 and BRCA2 founder mutations
BRCA1 IVS5 +3A>G
BRCA1 IVS 21-36del510
BRCA1 IVS 12-1643 del3835
BRCA1 IVS 11-2 A>G
Once an unaffected mutation carrier is identified, the question becomes what is the likelihood that she will develop cancer by a given age (age-specific penetrance). It is especially difficult to answer, because not all factors that contribute to the development of cancer are known. A proportion of individuals who carry mutations will not develop breast cancer or any other cancer. On the basis of estimates from population-based studies of women aged 40 years or younger to estimates from high-incidence breast cancer families of Northern European descent, the cumulative risk of breast cancer by age 70 years for BRCA1 and BRCA2 mutation carriers is between 40 and 80% [18,19,20]. Mutation-specific differences may also be important. There are regions in BRCA1 and BRCA2 in which mutations confer higher risks for developing ovarian cancer: 5' of codon 1435 in exon 13 of BRCA1  and a 3.3 kilobase region of exon 11 in BRCA2 (denoted the Ovarian Cancer Cluster Region) . It is unclear whether the differences in risk for ovarian cancer are due to a difference in penetrance of the mutations for breast cancer or ovarian cancer, or both. For BRCA2, it has been suggested that the breast cancer risk remains the same, but that the ovarian cancer risk increases . Expression is also variable . In a population with a defined founder mutation(s), more accurate assessment of the likelihood of developing cancer for a mutation carrier should be possible.
BRCA1 and BRCA2
An example of a recurrent, founder mutation is the BRCA2 999del5 mutation in the Icelandic population. No other BRCA2 mutations have been reported in this population. The 999del5 is approximately 20 times more prevalent (0.6%)  than the estimated allele frequency of BRCA2 in the general worldwide Caucasian population . This mutation with the same haplotype was also found in Finland [26,27]. In Iceland, it was the cause of female breast cancer in the majority (76%) of 21 high-risk breast cancer families studied . In nine of those 16 families, male breast cancer was also present . In 632 Icelandic breast cancer cases unselected for a family history, 7.7% of female breast cancer diagnosed at any age and 24% of those diagnosed at age 40 years or younger carried the BRCA2 999del5 mutation . This mutation is also responsible for a proportion of prostate cancer, as it accounted for 3.1% (in two out of 65 individuals) of prostate cancer cases in a population-based series of cases . Because this is the only BRCA2 mutation found in Iceland, genetic testing can be targeted to this mutation. Second, because there are a large number of individuals, both symptomatic and asymptomatic, who carry this mutation, it may be possible to develop more accurate risk estimates for mutation carriers. Age-specific penetrance has been calculated to be 17% by age 50 years and 37.2% by age 70 years . This is a lower frequency than that reported in other studies of BRCA1 and BRCA2 penetrance.
Three founder mutations have been observed in Ashkenazi Jewish breast and ovarian cancer patients. The BRCA2 6174delT mutation has been seen only in Ashkenazi Jews , with a frequency of 0.9-1.5% [32,33]. The founder BRCA1 185delAG mutation, with a frequency of 0.8-1.1% in Ashkenazi Jews [32,34], is also observed in Sephardic Jews, indicating an older origin. The 185delAG mutation has also been observed in individuals of English origin but on a different haplotype, which suggests a different origin. The third founder mutation, BRCA1 5382insC, has a frequency of 0.13-0.3% in Ashkenazi Jews. The 5382insC mutation is observed in many populations, and the vast majority of carriers share the same core haplotype (Szabo C, personal communication). The population prevalences for these three mutations combined is 2-2.5% [32,33,34], which is approximately 10-50 times higher than the allele frequency in the general population. Few other BRCA1 or BRCA2 mutations have been identified in Jewish breast or ovarian cancer cases. In this population, approximately 30% of breast cancers diagnosed at less than 40 years of age and 39% of ovarian cancers diagnosed at less than 50 years of age are caused by these mutations [35,36]. Thus, Ashkenazi Jewish women with breast or ovarian cancers have a much higher probability than non-Jewish women of being BRCA1 or BRCA2 mutation carriers. Because these mutations are so common in Ashkenazi Jewish women, they are commonly tested as a panel, regardless of whether a mutation has already been identified in a family member. A woman may carry a second mutation not present in the first family member tested and, by testing the panel, it is detected. Without knowledge of the founder mutations, a false-negative test result for an individual with a mutation-specific test could result.
Even among families with founder mutations, there appear to be differences in age of onset of cancer and in the type of cancers that develop [28,37,38,39]. This suggests that there are both genetic and lifestyle factors that modify penetrance of BRCA1 and BRCA2. By studying a cohort of individuals with the same mutation, one may be able to distinguish factors that affecting penetrance, because there will not be a confounding effect from genotype-phenotype correlations from location of the BRCA1/BRCA2 mutation in the individual. Once a risk factor is identified in one subgroup of mutation carriers it would need to be tested across other mutation carriers. Subsequently, it would need to be tested in a population-based case-control study, in order to determine how important the risk factor is in the general population.
BRCA1 and BRCA2 mutations are certainly important determinants of risk for breast and/or ovarian cancers, but they are not the only ones. Many women, who have a family history of breast and/or ovarian cancer and do not have a BRCA1 or BRCA2 mutation, may have a mutation in undiscovered genes. After accounting for BRCA1 and BRCA2, Peto et al  suggested that there are several other genes, possibly of lower risk, that account for a proportion of breast cancers. This complexity makes localizing additional genes problematic. Studying families identified from populations in which there are likely to be founder mutations may be extremely useful for localizing additional genes. For example, in Iceland researchers may have been able to localize BRCA2 by studying male breast cancer cases from high-risk families and looking for regions of the genome with excess sharing. Researchers have suggested studying high-risk Ashkenazi Jewish breast cancer families that do not have a BRCA1 or BRCA2 mutation in order to localize BRCA3. Localization will be promoted by minimizing the effects of genetic heterogeneity.
Founder mutations allow for focused scientific studies of penetrance, expression, and genetic and environmental modifiers of risk. The results from these studies may be very useful for understanding the role that these genes play in the incidence of breast cancer in order to target genetic testing, to provide individual risk assessment, and to design better therapeutic strategies. Localization studies to find BRCA3, using founder populations, may be more successful than traditional linkage studies, which have not yet yielded positive localization results. These types of studies, utilizing founder populations and mutations, are not unique to breast cancer genetics, and are being used successfully to understand other diseases.
Work by the author and cited in this editorial was supported by grants from the National Cancer Institute (R01 CA-74415), the Department of Defense (DAMD17-96-I-6266), and the American Cancer Society (RPG-99-181-01CCE)
- Kaback M, Lim-Steele J, Dabholkar D, et al: Tay-Sachs disease: carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. JAMA. 1993, 270: 2307-2315. 10.1001/jama.270.19.2307.View ArticlePubMedGoogle Scholar
- de la Chapelle A: Disease gene mapping in isolated human populations: the example of Finland. J Med Genet. 1993, 30: 857-865.View ArticlePubMedPubMed CentralGoogle Scholar
- Diamond JM, Rotter JI: Observing the founder effect in human evolution [news]. Nature. 1987, 329: 105-106. 10.1038/329105a0.View ArticlePubMedGoogle Scholar
- Puffenberger EG, Kauffman ER, Bolk S, et al: Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum Mol Genet. 1994, 3: 1217-1225.View ArticlePubMedGoogle Scholar
- Miki Y, Swensen J, Shattuck-Eidens D, et al: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994, 266: 66-71.View ArticlePubMedGoogle Scholar
- Wooster R, Bignell G, Lancaster J, et al: Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995, 378: 789-792. 10.1038/378789a0.View ArticlePubMedGoogle Scholar
- Shen D, Vadgama JV: BRCA1 and BRCA2 gene mutation analysis: visit to the Breast Cancer Information Core (BIC). Oncol Res. 1999, 11: 63-69.PubMedGoogle Scholar
- Breast Cancer Information Core Database:. [http://www.nhgri.nih.gov/Intramural-research/Lab-transfer/Bic/]
- Neuhausen SL, Mazoyer S, Friedman L, 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: 271-280.PubMedPubMed CentralGoogle Scholar
- Neuhausen SL, Godwin AK, Gershoni-Baruch R, et al: Haplotype and phenotype analysis of nine recurrent BRCA2 mutations in 111 families: results of an international study. Am J Hum Genet. 1998, 62: 1381-1388. 10.1086/301885.View ArticlePubMedPubMed CentralGoogle Scholar
- Claus EB, Schildkraut JM, Thompson WD, Risch NJ: The genetic attributable risk of breast and ovarian cancer. Cancer. 1996, 77: 2318-2324. 10.1002/(SICI)1097-0142(19960601)77:11<2318::AID-CNCR21>3.0.CO;2-Z.View ArticlePubMedGoogle Scholar
- Peto J, Collins N, Barfoot R, et al: Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst. 1999, 91: 943-949. 10.1093/jnci/91.11.943.View ArticlePubMedGoogle Scholar
- Couch FJ, DeShano ML, Blackwood MA, et al: BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med. 1997, 336: 1409-1415. 10.1056/NEJM199705153362002.View ArticlePubMedGoogle Scholar
- Berry DA, Parmigiani G, Sanchez J, Schildkraut J, Winer E: Probability of carrying a mutation of breast-ovarian cancer gene BRCA1 based on family history. J Natl Cancer Inst. 1997, 89: 227-238. 10.1093/jnci/89.3.227.View ArticlePubMedGoogle Scholar
- Frank TS, Manley SA, Olopade OI, et al: Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998, 16: 2417-2425.PubMedGoogle Scholar
- Schmidt S, Becher H, Chang-Claude J: Breast cancer risk assessment: use of complete pedigree information and the effect of mis-specified ages at diagnosis of affected relatives. Hum Genet. 1998, 102: 348-356. 10.1007/s004390050704.View ArticlePubMedGoogle Scholar
- Petrij-Bosch A, Peelen T, van Vliet M, et al: BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nature Genet. 1997, 17: 341-345.View ArticlePubMedGoogle Scholar
- Struewing JP, Hartge P, Wacholder S, et al: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med. 1997, 336: 1401-1408. 10.1056/NEJM199705153362001.View ArticlePubMedGoogle Scholar
- Hopper JL, Southey MC, Dite GS, et al: Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev. 1999, 8: 741-747.PubMedGoogle Scholar
- Ford D, Easton DF, Stratton M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998, 62: 676-689. 10.1086/301749.View ArticlePubMedPubMed CentralGoogle Scholar
- Gayther SA, Warren W, Mazoyer S, et al: Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation. Nature Genet. 1995, 11: 428-433.View ArticlePubMedGoogle Scholar
- Gayther SA, Mangion J, Russell P, et al: Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nature Genet. 1997, 15: 103-105.View ArticlePubMedGoogle Scholar
- Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst. 1999, 91: 1310-1316. 10.1093/jnci/91.15.1310.
- Thorlacius S, Sigurdsson S, Bjarnadottir H, et al: Study of a single BRCA2 mutation with high carrier frequency in a small population. Am J Hum Genet. 1997, 60: 1079-1084.PubMedPubMed CentralGoogle Scholar
- Claus EB, Risch N, Thompson WD: Genetic analysis of breast cancer in the cancer and steroid hormone study. Am J Hum Genet. 1991, 48: 232-242.PubMedPubMed CentralGoogle Scholar
- Vehmanen P, Friedman LS, Eerola H, et al: A low proportion of BRCA2 mutations in Finnish breast cancer families. Am J Hum Genet. 1997, 60: 1050-1058.PubMedPubMed CentralGoogle Scholar
- Huusko P, Paakkonen K, Launonen V, et al: Evidence of founder mutations in Finnish BRCA1 and BRCA2 families [letter]. Am J Hum Genet. 1998, 62: 1544-1548. 10.1086/301880.View ArticlePubMedPubMed CentralGoogle Scholar
- Thorlacius S, Olafsdottir G, Tryggvadottir L, et al: A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nature Genet. 1996, 13: 117-119.View ArticlePubMedGoogle Scholar
- Sigurdsson S, Thorlacius S, Tomasson J, et al: BRCA2 mutation in Icelandic prostate cancer patients. J Mol Med. 1997, 75: 758-761. 10.1007/s001090050162.View ArticlePubMedGoogle Scholar
- Thorlacius S, Struewing JP, Hartge P, et al: Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet. 1998, 352: 1337-1339. 10.1016/S0140-6736(98)03300-5.View ArticlePubMedGoogle Scholar
- Neuhausen S, Gilewski T, Norton L, et al: Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nature Genet. 1996, 13: 126-128.View ArticlePubMedGoogle Scholar
- Roa BB, Boyd AA, Volcik K, Richards CS: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nature Genet. 1996, 14: 185-187.View ArticlePubMedGoogle Scholar
- Oddoux C, Struewing JP, Clayton CM, et al: The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nature Genet. 1996, 14: 188-190.View ArticlePubMedGoogle Scholar
- Struewing JP, Abeliovich D, Peretz T, et al: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nature Genet. 1995, 11: 198-200.View ArticlePubMedGoogle Scholar
- Levy-Lahad E, Catane R, Eisenberg S, et al: Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet. 1997, 60: 1059-1067.PubMedPubMed CentralGoogle Scholar
- Abeliovich D, Kaduri L, Lerer I, et al: The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997, 60: 505-514.PubMedPubMed CentralGoogle Scholar
- Friedman LS, Szabo CI, Ostermeyer EA, 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: 1284-1297.PubMedPubMed CentralGoogle Scholar
- Tonin P, Serova O, Lenoir G, et al: BRCA1 mutations in Ashkenazi Jewish women [letter]. Am J Hum Genet. 1995, 57: 189-PubMedPubMed CentralGoogle Scholar
- Simard J, Tonin P, Durocher F, et al: Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nature Genet. 1994, 8: 392-398.View ArticlePubMedGoogle Scholar
- Mefford HC, Baumbach L, Panguluri RC, et al: Evidence for a BRCA1 founder mutation in families of West African ancestry [letter]. Am J Hum Genet. 1999, 65: 575-578. 10.1086/302511.View ArticlePubMedPubMed CentralGoogle Scholar
- Gao Q, Neuhausen S, Cummings S, Luce M, Olopade OI: Recurrent germ-line BRCA1 mutations in extended African American families with early-onset breast cancer [letter]. Am J Hum Genet. 1997, 60: 1233-1236.PubMedPubMed CentralGoogle Scholar
- Claes K, Machackova E, De Vos M, et al: Mutation analysis of the BRCA1 and BRCA2 genes in the Belgian patient population and identification of a Belgian founder mutation BRCA1 IVS5 + 3A > G. Dis Markers. 1999, 15: 69-73.View ArticlePubMedPubMed CentralGoogle Scholar
- Peelen T, van Vliet M, Petrij-Bosch A, 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: 1041-1049.PubMedPubMed CentralGoogle Scholar
- Tonin PM, Mes-Masson AM, Narod SA, Ghadirian P, Provencher D: Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history. Clin Genet. 1999, 55: 318-324. 10.1034/j.1399-0004.1999.550504.x.View ArticlePubMedGoogle Scholar
- Backe J, Hofferbert S, Skawran B, et al: Frequency of BRCA1 mutation 5382insC in German breast cancer patients. Gynecol Oncol. 1999, 72: 402-406. 10.1006/gyno.1998.5270.View ArticlePubMedGoogle Scholar
- Csokay B, Tihomirova L, Stengrevics A, Sinicka O, Olah E: Strong founder effects in BRCA1 mutation carrier breast cancer patients from Latvia. Mutation in brief no. 258. Online. Hum Mutat. 1999, 14: 92-10.1002/(SICI)1098-1004(1999)14:1<92::AID-HUMU23>3.0.CO;2-2.View ArticlePubMedGoogle Scholar
- Andersen TI, Borresen AL, Moller P: A common BRCA1 mutation in Norwegian breast and ovarian cancer families? [letter]. Am J Hum Genet. 1996, 59: 486-487.PubMedPubMed CentralGoogle Scholar
- Borg A, Dorum A, Heimdal K, et al: BRCA1 1675delA and 1135insA account for one third of Norwegian familial breast-ovarian cancer and are associated with later disease onset than less frequent mutations. Dis Markers. 1999, 15: 79-84.View ArticlePubMedPubMed CentralGoogle Scholar
- Dorum A, Hovig E, Trope C, Inganas M, Moller P: Three per cent of Norwegian ovarian cancers are caused by BRCA1 1675delA or 1135insA. Eur J Cancer. 1999, 35: 779-781. 10.1016/S0959-8049(99)00050-7.View ArticlePubMedGoogle Scholar
- Gayther SA, Harrington P, Russell P, et al: Frequently occurring germ-line mutations of the BRCA1 gene in ovarian cancer families from Russia [letter]. Am J Hum Genet. 1997, 60: 1239-1242.PubMedPubMed CentralGoogle Scholar
- Johannsson O, Ostermeyer EA, Hakansson S, et al: Founding BRCA1 mutations in hereditary breast and ovarian cancer in southern Sweden. Am J Hum Genet. 1996, 58: 441-450.PubMedPubMed CentralGoogle Scholar