Joseph Thomas, Chacko Priya, Wesley Remani, Jayaprakash P G, James Francis V, Pillai M Radhakrishna
Department of Molecular Medicine, Regional Cancer Centre, Trivandrum, India.
Gynecol Oncol. 2006 Jun;101(3):411-7. doi: 10.1016/j.ygyno.2005.10.033. Epub 2005 Dec 19.
Host genetic factors may play a role in human papillomavirus (HPV)-associated tumorigenesis, although the issue continues to be a focus of much debate. Biotransformation is critical in carcinogenic activity of numerous environmental carcinogens. It is therefore possible that polymorphisms of genes producing functional changes in xenobiotic metabolizing enzymes may be susceptible factors in cervical carcinogenesis. This study looked into possible relationships among these factors.
In this case-control study, we analyzed leukocyte DNA from a total of 312 subjects for germline polymorphisms of CYP1A1 (m1 and m2), GSTM1 and GSTT1 at various stages of the cervical tumor progression spectrum, using PCR and RFLP.
Both m1 and m2 polymorphisms of the CYP1A1 gene were more frequent among cases (36.1% for m1 and 38.1% for m2) compared to control subjects (18.2% and 17.6% respectively). The odds ratio of a subject with homozygous CYP1A1 m1 and m2 variant being a case was highest (m1 OR = 4.77 [95% CI = 1.28-17.77]; P = 0.02 and m2 OR = 5.48 [95% CI = 1.49-20.19]; P = 0.011) respectively. The distribution of m1 and m2 CYP1A1 genotypes was also studied as a function of age and in relation to the presence of HPV 16 infection. The risk due to CYP1A1 m1 genotype, when adjusted for HPV status, showed a significantly increased risk (OR = 3.58, 95% CI = 1.88-6.81; P = 0.0001). Similar results were observed in the case of CYP1A1 m2 variant and HPV 16. There was a significant over-representation of both m1 (25.9% vs. 13.9%) and m2 (27.9% vs. 13.3%) polymorphisms in older women (46 years or more). GSTM1 and GSTT1 deletions were also prominent among cases (53.7% and 16.3% respectively) compared to controls (32.7% and 9.7% respectively). A higher proportion of both GSTT1 and GSTM1 deletions were also detected in HPV-16-positive subjects.
These results suggest that polymorphisms in the CYP1A1, GSTM1 and GSTT1 genes may render women more susceptible to the development of cervical cancer. The association between this susceptibility and the presence of human papillomavirus infection further emphasizes the significance of the genetic polymorphisms.
宿主遗传因素可能在人乳头瘤病毒（HPV）相关的肿瘤发生过程中发挥作用，尽管该问题仍是众多争论的焦点。生物转化在众多环境致癌物的致癌活性中至关重要。因此，在外源生物代谢酶中产生功能变化的基因多态性可能是宫颈癌发生的易感因素。本研究探讨了这些因素之间可能存在的关系。
在这项病例对照研究中，我们使用聚合酶链反应（PCR）和限制性片段长度多态性（RFLP）技术，分析了总共312名受试者的白细胞DNA，以检测CYP1A1（m1和m2）、谷胱甘肽S-转移酶M1（GSTM1）和谷胱甘肽S-转移酶T1（GSTT1）在宫颈癌进展谱不同阶段的种系多态性。
与对照组受试者（分别为18.2%和17.6%）相比，CYP1A1基因的m1和m2多态性在病例组中更为常见（m1为36.1%，m2为38.1%）。纯合CYP1A1 m1和m2变体的受试者作为病例的比值比最高（m1比值比=4.77[95%置信区间=1.28 - 17.77]；P = 0.02，m2比值比=5.48[95%置信区间=1.49 - 20.19]；P = 0.011）。还研究了CYP1A1 m1和m2基因型的分布与年龄以及HPV 16感染情况的关系。在根据HPV状态进行调整后，CYP1A1 m1基因型导致的风险显示出显著增加（比值比=3.58，95%置信区间=1.88 - 6.81；P = 0.0001）。CYP1A1 m2变体和HPV 16的情况也观察到了类似结果。在年龄较大的女性（46岁及以上）中，m1（25.9%对13.9%）和m2（27.9%对13.3%）多态性均显著过度呈现。与对照组（分别为32.7%和9.7%）相比，GSTM1和GSTT1缺失在病例组中也很突出（分别为53.7%和16.3%）。在HPV - 16阳性受试者中也检测到较高比例的GSTT1和GSTM1缺失。
这些结果表明，CYP1A1、GSTM1和GSTT1基因的多态性可能使女性更容易患宫颈癌。这种易感性与人类乳头瘤病毒感染之间的关联进一步强调了基因多态性的重要性。
