Butkiewicz D, Rusin M, Enewold L, Shields P G, Chorazy M, Harris C C
Department of Tumor Biology, Centre of Oncology, M.Sklodowska-Curie Memorial Institute, 44-101 Gliwice, Poland.
Carcinogenesis. 2001 Apr;22(4):593-7. doi: 10.1093/carcin/22.4.593.
Polymorphisms in DNA repair genes may be associated with differences in the repair efficiency of DNA damage and may influence an individual's risk of lung cancer. The frequencies of several amino acid substitutions in XRCC1 (Arg194Trp, Arg280His and Arg399Gln), XRCC3 (Thr241Met), XPD (Ile199Met, His201Tyr, Asp312Asn and Lys751Gln) and XPF (Pro379Ser) genes were studied in 96 non-small-cell lung cancer (NSCLC) cases and in 96 healthy controls matched for age, gender and cigarette smoking. The XPD codon 312 Asp/Asp genotype was found to have almost twice the risk of lung cancer when the Asp/Asn + Asn/Asn combined genotype served as reference [odds ratio (OR) 1.86, 95% confidence interval (CI), 1.02-3.40]. In light cigarette smokers (less than the median of 34.5 pack-years), the XPD codon 312 Asp/Asp genotype was more frequent among cases than in controls and was associated with an increased risk of NSCLC. Compared with the Asn/Asn carriers, the OR in light smokers with the Asp/Asn genotype was 1.70 (CI0.35 0.43-6.74) and the OR in those with the Asp/Asp genotype was 5.32 (CI0.35-21.02) (P trend = 0.01). The 312 Asp/Asp genotype was not associated with lung cancer risk in never-smokers or heavy smokers (>34.5 pack-years). The XPD-312Asp and -751Lys polymorphisms were in linkage disequilibrium in the group studied; this finding was further supported by pedigree analysis of four families from Utah. The XPD 312Asp amino acid is evolutionarily conserved and is located in the seven-motif helicase domain of the RecQ family of DNA helicases. Our results indicate that these polymorphisms in the XPD gene should be investigated further for the possible attenuation of DNA repair and apoptotic functions and that additional molecular epidemiological studies are warranted to extend these findings.
DNA修复基因中的多态性可能与DNA损伤修复效率的差异相关，并可能影响个体患肺癌的风险。我们研究了96例非小细胞肺癌（NSCLC）患者以及96名年龄、性别和吸烟情况相匹配的健康对照者中，XRCC1基因（Arg194Trp、Arg280His和Arg399Gln）、XRCC3基因（Thr241Met）、XPD基因（Ile199Met、His201Tyr、Asp312Asn和 Lys751Gln）和XPF基因（Pro379Ser）中几种氨基酸替代的频率。当以Asp/Asn + Asn/Asn联合基因型作为参照时，发现XPD基因第312位密码子Asp/Asp基因型患肺癌的风险几乎是其两倍[比值比（OR）为1.86，95%置信区间（CI）为1.02 - 3.40]。在轻度吸烟者（低于34.5包年的中位数）中，病例组中XPD基因第312位密码子Asp/Asp基因型的频率高于对照组，且与非小细胞肺癌风险增加相关。与Asn/Asn携带者相比，Asp/Asn基因型的轻度吸烟者的OR为1.70（CI0.35 0.43 - 6.74），Asp/Asp基因型者的OR为5.32（CI0.35 - 21.02）（P趋势 = 0.01）。312 Asp/Asp基因型在从不吸烟者或重度吸烟者（>34.5包年）中与肺癌风险无关。在所研究的群体中，XPD - 312Asp和 - 751Lys多态性处于连锁不平衡状态；来自犹他州的四个家族的系谱分析进一步支持了这一发现。XPD基因第312位的Asp氨基酸在进化上是保守的，位于DNA解旋酶RecQ家族的七基序解旋酶结构域中。我们的结果表明，应进一步研究XPD基因中的这些多态性对DNA修复和凋亡功能可能产生的减弱作用，并且有必要开展更多的分子流行病学研究来扩展这些发现。
