Background
Breast cancer (BC) remains the most common form of cancer and the second leading cause of cancer death among women and about 5–10% have hereditary breast cancer, explained by genetic susceptibility [
1,
2]. Germline mutations in the tumor suppressor gene
BRCA1 account for the largest proportion of BC susceptibility to date and confer a 55–65% lifetime risk of developing breast cancer [
2,
3].
BRCA1 has a very heterogeneous mutation spectrum, often having high frequency of founder mutations in isolated populations such as the Ashkenazi Jewish or the Icelandic population, where few founder mutations account for most
BRCA1 carriers [
4,
5].
Among Hispanic populations from Iberia and the Americas,
BRCA1 c.3331_3334delCAAG (Breast Cancer Information Core designation: 3450del4 or rs80357903) is one of the most widely distributed founder mutation and reaches its highest frequency in admixed populations from Central Colombia [
6].
BRCA1 c.3331_3334delCAAG was first described in a Canadian BC family [
7], and since then reported in Europe, Latin American, the Middle Eastern, and North African patients [
8‐
15]. The occurrence of
BRCA1 c.3331_3334delCAAG in different populations may be indicative of a mutational hotspot associated with multiple origins or a founder effect from a single ancient mutation. Although haplotype analysis has been carried out for
BRCA1 c.3331_3334delCAAG in some of these countries, they have been limited to a few intragenic markers and to a limited number of populations, often using a single individual from a carrier family [
8‐
10]. Moreover, the
BRCA1 c.3331_3334delCAAG mutation haplotype has not been assessed on an international scale, and the ancestral origin of
BRCA1 c.3331_3334delCAAG remains to be determined. To gain insights into its origin, extensive haplotype analysis of
BRCA1 c.3331_3334delCAAG was completed in carriers from six different countries, and the age of the mutation was estimated in Colombia and Iberia. We utilized genome-wide and targeted SNP data followed by imputation, haplotype phasing, linkage disequilibrium analyses, genetic admixture estimation, and mutation dating to comprehensively assess genetic variation, spanning the entire chromosome 17, where
BRCA1 resides. Our results indicated that
BRCA1 c.3331_3334delCAAG had a single origin in Iberia.
Discussion
The comparison of haplotypes between individuals with the same mutation can distinguish whether high-frequency alleles derive from an older or more recent single mutational event and can also determine whether the mutation had arisen independently from multiple individuals. Our study suggests that the BRCA1 c.3331_3334delCAAG was introduced to Colombia and South America early in the colonization of the country, resulting in a high mutation prevalence in the population. The estimated age of this mutation in Colombia is consistent with this historical account.
Haplotype length is inversely correlated with the number of generations separating the common ancestor from cases with the mutation in the present time. Our approach revealed a shared mutation haplotype by carriers of six countries, multiple continents, and numerous families. These findings depict a history of immigration that is consistent with ancestral links between these populations. The estimated ages from our study and ancestry estimates in Colombian mutation carriers are consistent with the country’s history and origin of the mutation, in addition to the genetic demography of Colombia. The mutation was likely introduced to the region during early colonial times during the early 1500s, and our findings in Iberia are consistent with previous dating estimates for other mutations [
31]. Moreover, our studies suggest an early recombination event in Spain, which results in the two main haplotypes around the mutation. Spanish and Portuguese colonization of Brazil, Chile, and Colombia during the early 1500s is consistent with the mutation distribution found in our study. In fact, the differences in time periods of Spanish colonization and conquest can be represented by the two main mutation haplotypes found in this study. Interestingly, we also found the same haplotype in a carrier from Angola, a former Portuguese colony, and thus our findings are consistent with the European colonization of Africa and the Americas.
We used genome-wide SNP data to capture the mutation haplotype and estimate mutation age rather than traditional microsatellite markers, which allowed us to comprehensively assess the mutation haplotype via IBD analysis and multiple sequence alignment. A similar approach can be exploited for mapping new variants [
32]. We recognize that there may be more to explore surrounding this mutation. While we were able to date the mutation in Iberia and Colombia, we lacked sufficient control data for other countries, such as Chile or Brazil, to allow us to date the mutation in such countries. We anticipate that the mutation age in the other countries will be related to the time of Spanish and Portuguese colonization. We also cannot exclude that the mutation may have multiple ancestral origins in countries without a history of colonization by those countries, such as Canada or Norway, where this mutation has been also reported [
7,
33]. Furthermore, while our study in Colombia focused on communities from the central Andean region, where we have shown that they have a predominant European and Indigenous American ancestry [
16,
34‐
40], a recent study in Afro-Colombian populations from the west of the country also identified
BRCA1 c.3331_3334delCAAG carriers, which may suggest additional origins in other Colombian groups [
41]. A similar analysis with carriers from these populations would be necessary to confirm this hypothesis.
Acknowledgements
We are grateful to all of the individuals who participated in the current study.
COLUMBUS Consortium contributors (in alphabetical order): Fernando Bolaños (Hospital Hernando Moncaleano Perdomo, Neiva, Colombia), Raúl Murillo (Pontificia Universidad Javeriana, Bogotá, Colombia), Yesid Sánchez (Universidad del Tolima, Ibagué, Colombia), Carolina Sanabria (Instituto Nacional de Cancerología, Bogotá, Colombia), Martha Lucia Serrano (Instituto Nacional de Cancerología, Bogotá, Colombia), John Jairo Suarez (Universidad del Tolima, Ibagué, Colombia).
The Brazilian Familial Cancer Network contributors (in alphabetical order):, Barbara Alemar (Medical Genomics Laboratory, Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil), Cristina Brinckmann Oliveira Netto (Medical Genetics Service, Porto Alegre, Brazil), Dirce Maria Carraro (Laboratory of Genomics and Molecular Biology, International Research Center, A.C. Camargo Cancer Center, São Paulo, Brazil;, Laboratory of Genomic Diagnostics, Anatomic Pathology Department, A.C. Camargo Cancer Center, São Paulo, Brazil), Fernando Regla Vargas (Birth Defects Epidemiology Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation and Medical Genetics Service, Gaffrée Guinle Hospital, Federal University of Rio de Janeiro State, Rio de Janeiro, Brazil.), Gustavo Stumpf da Silva (Medical Genomics Laboratory, Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil), Ivana Lúcia Oliveira Nascimento (Laboratory of Immunology and Molecular Biology (LABIMUNO). Federal University of Bahia (UFBA), Salvador, Bahia, Brazil; Oncology Nucleus of Bahia, NOB, Salvador, Bahia, Brazil), Kelly Rose Lobo de Souza (Genetics Program. National Cancer Institute, Rio de Janeiro, Brazil), Kiyoko Abe-Sandes (Laboratory of Immunology and Molecular Biology (LABIMUNO). Federal University of Bahia (UFBA), Salvador, Bahia, Brazil), Maria Isabel Achatz (Hospital Sírio-Libanês (HSL), São Paulo, São Paulo, Brazil), Miguel Angelo Martins Moreira (Genetics Program. National Cancer Institute, Rio de Janeiro, Brazil), Maria Betânia Torrales (Laboratory of Immunology and Molecular Biology (LABIMUNO). Federal University of Bahia (UFBA), Salvador, Bahia, Brazil), Maristela Pimenta (Laboratory of Genomic Diagnostics, Anatomic Pathology Department, A.C. Camargo Cancer Center, São Paulo, Brazil), Patricia Santos da Silva (Medical Genomics Laboratory, Hospital de Clinicas de Porto Alegre (HCPA), Porto Alegre, Brazil)), Taisa Manuela Bonfim Machado-Lopes (Laboratory of Immunology and Molecular Biology (LABIMUNO). Federal University of Bahia (UFBA), Salvador, Bahia, Brazil).
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