Siddiqui Sarah, Chattopadhyay Shilpi, Akhtar Md Salman, Najm Mohammad Zeeshan, Deo S V S, Shukla N K, Husain Syed Akhtar
Department of Biotechnology, Jamia Millia Islamia, New Delhi, India.
Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India.
PLoS One. 2014 Oct 21;9(10):e110426. doi: 10.1371/journal.pone.0110426. eCollection 2014.
Genome-Wide Association Studies (GWAS) have identified Fibroblast growth factor receptor 2 (FGFR2) as a candidate gene for breast cancer with single nucleotide polymorphisms (SNPs) located in intron 2 region as the susceptibility loci strongly associated with the risk. However, replicate studies have often failed to extrapolate the association to diverse ethnic regions. This hints towards the existing heterogeneity among different populations, arising due to differential linkage disequilibrium (LD) structures and frequencies of SNPs within the associated regions of the genome. It is therefore important to revisit the previously linked candidates in varied population groups to unravel the extent of heterogeneity. In an attempt to investigate the role of FGFR2 polymorphisms in susceptibility to the risk of breast cancer among North Indian women, we genotyped rs2981582, rs1219648, rs2981578 and rs7895676 polymorphisms in 368 breast cancer patients and 484 healthy controls by Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) assay. We observed a statistically significant association with breast cancer risk for all the four genetic variants (P<0.05). In per-allele model for rs2981582, rs1219648, rs7895676 and in dominant model for rs2981578, association remained significant after bonferroni correction (P<0.0125). On performing stratified analysis, significant correlations with various clinicopathological as well as environmental and lifestyle characteristics were observed. It was evident that rs1219648 and rs2981578 interacted with exogenous hormone use and advanced clinical stage III (after Bonferroni correction, P<0.000694), respectively. Furthermore, combined analysis on these four loci revealed that compared to women with 0-1 risk loci, those with 2-4 risk loci had increased risk (OR = 1.645, 95%CI = 1.152-2.347, P = 0.006). In haplotype analysis, for rs2981578, rs2981582 and rs1219648, risk haplotype (GTG) was associated with a significantly increased risk compared to the common (ACA) haplotype (OR = 1.365, 95% CI = 1.086-1.717, P = 0.008). Our results suggest that intron 2 SNPs of FGFR2 may contribute to genetic susceptibility of breast cancer in North India population.
全基因组关联研究（GWAS）已将成纤维细胞生长因子受体2（FGFR2）确定为乳腺癌的候选基因，位于内含子2区域的单核苷酸多态性（SNP）作为与风险密切相关的易感位点。然而，重复研究往往未能将这种关联外推到不同的种族地区。这暗示了不同人群之间存在异质性，这是由于基因组相关区域内SNP的连锁不平衡（LD）结构和频率不同所致。因此，有必要在不同人群组中重新审视先前关联的候选基因，以了解异质性的程度。为了研究FGFR2基因多态性在北印度女性乳腺癌易感性中的作用，我们通过聚合酶链反应-限制性片段长度多态性（PCR-RFLP）分析，对368例乳腺癌患者和484例健康对照进行了rs2981582、rs1219648、rs2981578和rs7895676多态性的基因分型。我们观察到所有这四个基因变异与乳腺癌风险均存在统计学上的显著关联（P<0.05）。在rs2981582、rs1219648、rs7895676的等位基因模型以及rs2981578的显性模型中，经Bonferroni校正后关联仍具有显著性（P<0.0125）。进行分层分析时，观察到与各种临床病理以及环境和生活方式特征存在显著相关性。很明显，rs1219648和rs2981578分别与外源性激素使用和晚期临床III期相互作用（经Bonferroni校正后，P<0.000694）。此外，对这四个位点的联合分析显示，与具有0-1个风险位点的女性相比，具有2-4个风险位点的女性风险增加（OR = 1.645，95%CI = 1.152-2.347，P = 0.006）。在单倍型分析中，对于rs2981578、rs2981582和rs1219648，与常见的（ACA）单倍型相比，风险单倍型（GTG）与风险显著增加相关（OR = 1.365，95%CI = 1.086-1.717，P = 0.008）。我们的结果表明，FGFR2内含子2的SNP可能导致北印度人群乳腺癌的遗传易感性。
