Abstract
BackgroundBreast cancer is the most common cancer in women worldwide. Around 50% of breast cancer familial risk has been so far explained by known susceptibility alleles with variable levels of risk and prevalence. The vast majority of these breast cancer associated variations reported to date are from populations of European ancestry. In spite of its heterogeneity and genetic wealth, North-African populations have not been studied by the HapMap and the 1000Genomes projects. Thus, very little is known about the genetic architecture of these populations.MethodsThis study aimed to investigate a subset of common breast cancer loci in the general Tunisian population and to compare their genetic composition to those of other ethnic groups. We undertook a genome-wide haplotype study by genotyping 135 Tunisian subjects using the Affymetrix 6.0-Array. We compared Tunisian allele frequencies and linkage disequilibrium patterns to those of HapMap populations and we performed a comprehensive assessment of the functional effects of several selected variants.ResultsHaplotype analyses showed that at risk haplotypes on 2p24, 4q21, 6q25, 9q31, 10q26, 11p15, 11q13 and 14q32 loci are considerably frequent in the Tunisian population (> 20%). Allele frequency comparison showed that the frequency of rs13329835 is significantly different between Tunisian and all other HapMap populations. LD-blocks and Principle Component Analysis revealed that the genetic characteristics of breast cancer variants in the Tunisian, and so probably the North-African populations, are more similar to those of Europeans than Africans.Using eQTl analysis, we characterized rs9911630 as the most strongly expression-associated SNP that seems to affect the expression levels of BRCA1 and two long non coding RNAs (NBR2 and LINC008854). Additional in-silico analysis also suggested a potential functional significance of this variant.ConclusionsWe illustrated the utility of combining haplotype analysis in diverse ethnic groups with functional analysis to explore breast cancer genetic architecture in Tunisia. Results presented in this study provide the first report on a large number of common breast cancer genetic polymorphisms in the Tunisian population which may establish a baseline database to guide future association studies in North Africa.
Highlights
Breast cancer is the most common cancer in women worldwide
-GMA Global Minor Allele, GMAF Global Minor Allele Frequency, TUN the frequency of the global minor allele in the Tunisian population, Score: from the RegulomeDB database and score significance provided in the predicted function column, eQTL association provided by the Genotype-Tissue Expression (GTEx) database, p the p value of the variants’ eQTL association, TF Transcription factor -The highlighted rows indicate polymorphisms that showed the highest RegulomeDB scores, significant eQTL associations and other functional evidence -rs1494961 is the only exonic variant in this list, we provided its predicted functional significance using the Sift software -In bold, Single nucleotide polymorphism (SNP) previously identified as associated with breast cancer risk in the Tunisian population tool showed that rs9911630 is a haplotype tagging SNP in the Tunisian population (Fig. 2c)
With the principal components analysis (PCA) results, we showed that Yoruba in Ibadan (YRI), Luhya in Webuye (LWK) and Japanese in Tokyo (JPT) populations are the most contributors to variability between African and non-Africans (Dim 1), and TUN, Mexicans living in Los Angeles (MEX) and Gujarati Indians in Houston (GIH) are those who contributed less to this variability (Additional file 2: Figure S4A)
Summary
Breast cancer is the most common cancer in women worldwide. Around 50% of breast cancer familial risk has been so far explained by known susceptibility alleles with variable levels of risk and prevalence. Half of the inherited susceptibility to breast cancer is explained by a combination of high, intermediate, and low-risk alleles [2]. Rare high risk alleles such as BRCA1 [3, 4], BRCA2 [5, 6], TP53 [7], STK11, PTEN and CDH1 explain approximately 20–30% of the inherited susceptibility, intermediate-risk alleles in genes such as CHEK2, ATM, BRIP1(FANCJ) [8,9,10] and PALB2 (FAN CN) [11,12,13,14,15] explain an additional 5%, while common lower penetrance alleles explain approximately 16% of the breast cancer risk [16,17,18,19,20,21,22,23]. It is reported that breast cancer is more aggressive in North Africa than in Western countries with notably large proportions of young patients [30,31,32]
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