Mechanic Leah E, Marrogi Aizen J, Welsh Judith A, Bowman Elise D, Khan Mohammed A, Enewold Lindsey, Zheng Yun-Ling, Chanock Stephen, Shields Peter G, Harris Curtis C
Laboratory of Human Carcinogenesis, NCI Center for Cancer Research, 37 Convent Drive, Bethesda, MD 20892-4255, USA.
Carcinogenesis. 2005 Mar;26(3):597-604. doi: 10.1093/carcin/bgh344. Epub 2004 Nov 25.
The pattern of somatic mutations in TP53 is distinct for particular cancers and carcinogenic exposures, providing clues to disease etiology, e.g. G:C-->T:A mutations in TP53 are more frequently observed in smoking-associated lung cancers. In order to investigate possible causes and mechanisms of lung cancer susceptibility differences, the TP53 gene was sequenced in a case-only study of lung cancers (206 men and 103 women). Our primary hypothesis was that the TP53 mutation spectrum is influenced by polymorphisms in genes involved in DNA repair and apoptosis. We observed a TP53 mutation frequency in exons 5-8 of 25%. Functional polymorphisms in XPD (Asp312Asn, rs1799793 and Lys751Gln, rs1052559), a protein required for nucleotide excision repair and with roles in p53-mediated apoptosis, were modestly associated with G:C-->T:A mutations in TP53 in lung tumors [Asp/Asn312 + Asn/Asn312 and/or Lys/Gln751 + Gln/Gln751 versus Asp/Asp312 + Lys/Lys751; odds ratio (OR) 2.73, 95% confidence interval (CI) 0.98-7.61], consistent with the role of this protein in repair of bulky carcinogen-DNA adducts. In addition, a TP53 polymorphism (Arg72Pro, rs1042522) with a known role in the efficiency of apoptosis was also associated with the presence of a TP53 mutation (Pro/Arg72 or Pro/Pro72 versus Arg/Arg72; OR 2.25, 95% CI 1.21-4.17) or a G:C-->T:A mutation in TP53 (Pro/Arg72 or Pro/Pro72 versus Arg/Arg72; OR 2.42, 95% CI 0.97-6.04). An interaction between the XPD variant alleles (Asn312 and Gln751) and the TP53 Pro72 allele was observed for TP53 mutations (any TP53 mutation P(int) = 0.027, G:C-->T:A TP53 mutation P(int) = 0.041). The statistical interaction observed in our study is consistent with the observed biological interaction for XPD and p53 in nucleotide excision repair and apoptosis. In conclusion, differences in TP53 mutation spectra in lung tumors are associated with several genetic factors and may reflect differences in lung cancer susceptibility and carcinogenesis.
TP53基因的体细胞突变模式在特定癌症和致癌暴露中各不相同，这为疾病病因提供了线索，例如，在与吸烟相关的肺癌中更常观察到TP53基因中G:C→T:A的突变。为了研究肺癌易感性差异的可能原因和机制，在一项仅针对肺癌患者的研究（206名男性和103名女性）中对TP53基因进行了测序。我们的主要假设是，TP53突变谱受参与DNA修复和细胞凋亡的基因多态性影响。我们观察到外显子5 - 8中TP53的突变频率为25%。XPD基因（Asp312Asn，rs1799793和Lys751Gln，rs1052559）的功能多态性与肺肿瘤中TP53基因的G:C→T:A突变存在适度关联[Asp/Asn312 + Asn/Asn312和/或Lys/Gln751 + Gln/Gln751与Asp/Asp312 + Lys/Lys751相比；优势比（OR）为2.73，95%置信区间（CI）为0.98 - 7.61]，这与该蛋白在修复大分子致癌物 - DNA加合物中的作用一致。此外，一种在细胞凋亡效率中具有已知作用的TP53多态性（Arg72Pro，rs1042522）也与TP53突变的存在（Pro/Arg72或Pro/Pro72与Arg/Arg72相比；OR为2.25，95% CI为1.21 - 4.17）或TP53基因中的G:C→T:A突变（Pro/Arg72或Pro/Pro72与Arg/Arg72相比；OR为2.42，95% CI为0.97 - 6.04）相关。对于TP53突变（任何TP53突变P(int)=0.027，G:C→T:A的TP53突变P(int)=0.041），观察到XPD变异等位基因（Asn312和Gln751）与TP53的Pro72等位基因之间存在相互作用。我们研究中观察到的统计学相互作用与在核苷酸切除修复和细胞凋亡中观察到的XPD和p53之间的生物学相互作用一致。总之，肺肿瘤中TP53突变谱的差异与多种遗传因素相关，可能反映了肺癌易感性和致癌过程的差异。
