Genome-Wide Association Studies (GWAS) breast cancer susceptibility loci in Arabs: susceptibility and prognostic implications in Tunisians

Abstract

Genome-wide Association Studies (GWAS) revealed novel genetic markers for breast cancer susceptibility. But little is known about the risk factors and molecular events associated with breast cancer in Arab Population. Therefore, we designed a broad study to investigate the susceptibility and prognostic implications of the GWAS breast cancer loci in the Tunisian population. In a cohort of 640 unrelated patients with breast cancer and 371 healthy control subjects, we characterized the variation of 9 single nucleotide polymorphisms (SNPs), namely rs1219648, rs2981582; rs8051542, rs12443621, and rs3803662; rs889312; rs3817198; rs13387042 and rs13281615. Only 5 out of 9 GWAS breast cancer loci were found to be significantly associated with breast cancer in Tunisians: The rs1219648 (G vs. A allele: OR = 1.36, P = 1 9 10 -3 ) and rs2981582 (A vs. G allele: OR = 1.55, P = 3 9 10 -6 ) of FGFR2 gene; the rs8051542 of the TNRC9 gene (T vs. C allele: OR = 1.40, P = 4 9 10 -4 ); the rs889312 of the MAP3K1 gene (C vs. A allele: OR = 1.33, P = 3 9 10 -3 ) and the rs13281615 located on 8q24 (G vs. A allele: OR = 1.21, P = 0.03). Homozygous variant genotypes of rs2981582 were strongly related to lymph node negative breast cancer (OR = 3.33, P = 6 9 10 -7 ) and the minor allele of rs2981582 was associated with increased risk of ER? tumors (OR = 1.57, P = 0.02; OR = 2.15, P = 0.001, for heterozygous and homozygous variant genotypes, respectively) and increased risk of distant metastasis development (OR = 2.30, P = 4 9 10 -3 ; OR = 3.57, P = 6 9 10 -5 , for heterozygous and homozygous variant genotypes, respectively) in a dose dependent manner. The association for rs8051542 was stronger for high-grade SBR tumors (OR = 2.54, P = 2 9 10 -4 ). GG genotype of rs13387042 on 2q35 showed a significant association with the risk of developing distant metastasis (OR = 1.94, P = 0.02). The G allele of rs1219648 in FGFR2 and the A allele of rs13387042 on 2q35 indicated a better prognosis by showing a significantly higher overall survival rates (P = 0.013 and P = 0.005, respectively). In conclusion, GWAS breast cancer FGFR2, TNRC9, MAP3K1, and 8q24 loci are associated with an increased risk of breast cancer and genetic variation in FGFR2 gene may predict the aggressiveness of breast cancer in Tunisians.

Increased risk of breast cancer in individuals carrying the TNRC9 rs3803662 C>T polymorphism: a meta-analysis of case-control studies

“…In total, 18 studies involving 44,820 cases and 58,316 controls met the inclusion criteria and were used in pooled analyses (Antoniou et al, 2008;Garcia-Closas et al, 2008;Li et al, 2009;Mcinerney et al, 2009;Gorodnova et al, 2010;Latif et al, 2010;Liang et al, 2010;Tamimi et al, 2010;Campa et al, 2011;Han et al, 2011;Slattery et al, 2011;Harlid et al, 2012;Shan et al, 2012;Mizoo et al, 2013;Ottini et al, 2013;Chen et al, 2014;Elematore et al, 2014). The primary features of these investigations are shown in Table 1.…”

Single Nucleotide Polymorphism 8q24 rs13281615 and Risk of Breast Cancer: Meta-Analysis of More than 100,000 Cases

“…In the end, 14 articles were found to satisfy the inclusion criteria and were included in the meta-analysis [21]–[34]. These articles involved a total of 44,283 cases and 55,756 controls, of which 5,170 cases and 5,589 controls were Chinese [25]–[27], [32], and the remaining 39,113 cases and 50,167 controls were of mixed ethnicity (>95% Caucasian) [21]–[24], [28]–[31], [33], [34]. In one study [22], 95.6% of cases and 96.7% of controls were European, while 4.4% of cases and 3.3% of controls were Asian.…”

“…Several studies included in the meta-analysis demonstrate that rs13281615 polymorphisms can interact with environmental factors to modulate BC risk [23]–[27], [29], [32], [34]. In fact, rs13281615 polymorphisms were not found to interact with BRCA1 or BRCA2 in BC risk, though only one study [30] examined the possibility of such genetic interactions.…”

Association of Trinucleotide-Repeatcontaining 9 (Tnrc9) SNP With the Risk of Breast Cancer in Egyptians

“…The rs12443621 SNP of the TNRC9 gene (also named TOX3) is located at chromosome 16q12. The function of TNRC9 is still unclear, but a previous study conducted by Shan et al, (2012) has reported that TNRC9 down-regulates BRCA1 expression through altering the methylation status of its promoter and promotes breast cancer aggressiveness. Other risk factors for breast cancer may include population differences that vary by ethnicity, family history, menopausal status and each of estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) tumor statuses.…”