印度东北部人群中DNA修复与细胞周期基因变异与乳腺癌风险的关联：多重交互分析
Association of DNA repair and cell cycle gene variations with breast cancer risk in Northeast Indian population: a multiple interaction analysis.
作者信息
Wasson Mishi Kaushal, Chauhan Pradeep Singh, Singh L C, Katara Dheeraj, Dev Sharma Jagannath, Zomawia Eric, Kataki Amal, Kapur Sujala, Saxena Sunita
机构信息
National Institute of Pathology, ICMR, Safdarjung Hospital Campus, New Delhi, 110029, India.
出版信息
Tumour Biol. 2014 Jun;35(6):5885-94. doi: 10.1007/s13277-014-1779-2. Epub 2014 Mar 7.
Polymorphisms in DNA repair and cell cycle genes contribute to increased breast cancer (BC) risk. Their association and interaction in relation to betel quid and tobacco chewing habits need exhaustive multi-analytical investigation to explain BC predisposition due to DNA damage. Polymorphism in TP53-72Arg>Pro, RAD51-135G>C, BRCA2, and CCND1-G870A were examined in 204 BC cases and 217 controls from Northeast Indian population. Multifaceted analytic approaches were used to explore relationships between polymorphisms, tobacco history, and BC susceptibility. Betel quid chewing was identified as the predominant risk factor. CCND-AA and dominant model showed protection towards BC in betel quid chewer (BQC) [(0.28 (0.10-0.77), 0.01 and 0.32 (0.12-0.81), 0.01)] and non-betel quid chewers (NBQC) [(0.26 (0.09-0.78), 0.01 and 0.37 (0.16-0.87), 0.02)]. TP53-Pro/Pro genotype showed protection towards BC in NBQC (0.29 (0.10-0.81), p=0.01) and (0.51 (0.32-0.80), p=0.003, respectively). RAD51-C allele was associated with BC risk (2.03 (1.26-3.30) 0.002) in BQC. Two BQC cases had BRCA2 8415G>T:K2729N mutation in Exon18. MDR analysis showed best four locus model with TBA 0.6765 (0.005) and CVC of 10/10 in NBQC. Interaction diagram concurred the interactions between TP53 and RAD51 (1.32 %) with independent effect (1.89 %) of CCND1in NBQC. In CART analysis, BQC with CCND1 GG genotype were at risk (OR=33.0; 95 % CI=6.08-179.07), p<0.001) followed by combination of BQC, CCND1, No-Smk, and Alc (OR=42.00; 95 % CI=5.11-345.11, p<0.001). Risk was also observed in BQC, CCND1, No-Smk, Non-Alc, and TP53 combination (OR=14.84; 95 % CI=3.13-70.34, p<0.001) and BQC, CCND1, No-Smk, Non-Alc, TP53 (OR=9.40; 95 % CI=1.99-44.34, p<0.001). NBQC group showed risk with combination of NBQC and TP53 (OR=5.54; 95 % CI=1.11-27.42, p=0.03). Genetic variants in DNA repair and cell cycle genes contribute to BC risk through gene-gene and gene-environmental interactions.
DNA修复和细胞周期基因的多态性会增加患乳腺癌（BC）的风险。它们与槟榔和烟草咀嚼习惯的关联及相互作用需要进行详尽的多分析研究，以解释因DNA损伤导致的BC易感性。在来自印度东北部人群的204例BC病例和217例对照中，检测了TP53 - 72Arg>Pro、RAD51 - 135G>C、BRCA2和CCND1 - G870A的多态性。采用多方面的分析方法来探究多态性、烟草史与BC易感性之间的关系。嚼槟榔被确定为主要危险因素。CCND - AA和显性模型在嚼槟榔者（BQC）[(0.28(0.10 - 0.77), 0.01和0.32(0.12 - 0.81), 0.01)]和非嚼槟榔者（NBQC）[(0.26(0.09 - 0.78), 0.01和0.37(0.16 - 0.87), 0.02)]中对BC具有保护作用。TP53 - Pro/Pro基因型在NBQC中对BC具有保护作用（分别为0.29(0.10 - 0.81), p = 0.01和0.51(0.32 - 0.80), p = 0.003）。RAD51 - C等位基因与BQC中的BC风险相关（2.03(1.26 - 3.30) 0.002）。两名BQC病例在第18外显子中有BRCA2 8415G>T:K2729N突变。多因素降维分析显示，在NBQC中最佳的四位点模型的TBA为0.6765(0.005)，CVC为10/10。相互作用图显示，在NBQC中TP53与RAD51之间存在相互作用（1.32%），CCND1具有独立作用（1.89%）。在分类回归树分析中，CCND1 GG基因型的BQC有风险（OR = 33.0；95%CI = 6.08 - 179.07），p < 0.001），其次是BQC、CCND1、不吸烟和饮酒的组合（OR = 42.00；95%CI = 5.11 - 345.11，p < 0.001）。在BQC、CCND1、不吸烟、不饮酒和TP53的组合（OR = 14.84；95%CI = 3.13 - 70.34，p < 0.001）以及BQC、CCND1、不吸烟、不饮酒、TP53（OR = 9.40；95%CI = 1.99 - 44.34，p < 0.001）中也观察到风险。NBQC组中NBQC与TP53的组合有风险（OR = 5.54；95%CI = 1.11 - 27.42，p = 0.03）。DNA修复和细胞周期基因中的遗传变异通过基因 - 基因和基因 - 环境相互作用导致BC风险。
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