類胰島素生長因子家族之基因多型性與子宮頸癌之相關性探討

根據行政院衛生署統計指出，子宮頸癌在女性癌症死亡率位居第七名。經研究指出99.7 % 的子宮頸癌，都是感染人類乳突病毒 Human Papillomavirus (HPV) 所導致。而主要造成子宮頸癌的HPV病毒又以16、18型最常見，佔70％。零期的子宮頸癌在臨床上沒有特殊的自覺症狀，絕大多數都是在子宮頸抹片檢查意外地被發現。子宮頸癌最常見的症狀是不正常的陰道出血。類胰島素生長因子 (insulin-like growth factor ; IGF) 在過去被認為與細胞的增生和分化有關，也被認為與嬰幼兒的生長遲緩有關。研究指出，透過訊息傳遞之後，類胰島素生長因子能夠同時藉由刺激細胞增生以及抑制細胞凋亡的機制誘使細胞走向癌化。也有文獻指出在部份癌症病人中，其血清中存在著較高濃度的IGF-1表現。而IGF-1及其接受器IGF-1R的基因多型性也被發現與一些癌症如肺癌、乳癌等有明顯的相關性，但是在子宮頸癌中卻少有文獻探討。因此，在本篇研究中，我們分別收集了 160 位子宮頸病變患者，其中包含高度子宮頸上皮內贅瘤共有 65 位個案；鱗狀上皮細胞癌病例共 95 位個案，以及 326 位非子宮頸癌的正常對照組檢體。利用DNA檢體以聚合酶連鎖反應-限制酶切割片段多型性技術 (PCR-RFLP) 以及即時定量聚合酶連鎖反應 (real-time PCR) 進行對IGF家族中IGF-1 +6093 (rs6219) 、+1770 (rs6220) 、IGF-1R (rs951715)以及類胰島素生長因子結合蛋白IGFBP-3 -202 (rs2854744) 基因多型性的分析。我們的研究發現 IGF -1 (rs6219、rs6220) 其基因多型性在正常人與子宮頸腫瘤患者的分佈，並不具有統計學上的意義。另外在正常人與高度子宮頸上皮內贅瘤患者的分佈，也不具有統計學上的意義。在正常人與鱗狀上皮細胞癌患者的相關性，我們發現IGF-1+6093 (rs6219) 的基因多型性在正常人與鱗狀上皮細胞癌患者的分布，不具有統計學上的意義。但是在IGF-1 +1770 (rs6220) 的基因多型性與罹患鱗狀上皮細胞癌則是有顯著的相關性。我們發現IGF-1 +1770 (rs6220) 基因型中攜帶TC基因型會比帶有TT基因型有1.793倍 ( 95％信賴區間1.012-3.178) 的機會罹患鱗狀上皮細胞癌 ( p＝0.044)。帶有CC基因型會比帶有TT基因型有2.110倍 ( 95％信賴區間1.079-4.124) 的機會罹患鱗狀上皮細胞癌 ( p＝0.027) 。至少帶有一個突變核甘酸的基因TC+CC相較於TT基因者具有1.884倍 ( 95％信賴區間1.093-3.246) 的機會罹患鱗狀上皮細胞癌 ( p＝0.021) 。另外在我們的研究中IGF-1R (rs951715) 無論是在子宮頸腫瘤患者、高度子宮頸上皮內贅瘤患者或是鱗狀上皮細胞癌基因多型性的分布則沒有明顯的相關性。而IGFBP-3 (rs2854744) 無論是在子宮頸腫瘤患者、高度子宮頸上皮內贅瘤患者或是鱗狀上皮細胞癌基因多型的分布，皆無明顯的相關性。

關鍵字

類胰島素生長因子；基因多型性；子宮頸癌

並列摘要

According to Department of Health, Executive Yuan statistics, cervical cancer was ranked seventh in cancer mortality of women. Some studies showed that 99.7% of cervical cancers are caused by infection with HPV (Human Papillomavirus, HPV). The subtypes of 16 and 18 are the major causes of cervical cancer and accounted about 70%. Cervical cancer patients on clinical stage 0 have no particular symptoms and are almost found by the Pap smear accidentally. The most common symptom of cervical cancer is abnormal vaginal bleeding. Insulin-like growth factor (IGF) has been reported to be related with growth retardation of newborns. Recent studies indicated that IGF may stimulate several signal pathways to induce cell proliferation and inhibit cell apoptosis, leading to the transformation of normal cells to cancer cells. Some literatures indicated that high serum expression of IGF-1 was found in some cervical cancer patients. The gene polymorphisms of IGF-1 and IGF-1R had been found in some cancers, such as lung cancer, breast cancer. But there is few literatures about the correlation of polymorphisms and cervical cancer. Therefore, in this study, we collected 160 patients with cervical neoplasm, which contained 65 cases of high-grade cervical intraepithelial neoplasm and 95 cases of squamous cell carcinoma. Besides, we also collected 326 cases without cervical lesion as control group. Using the DNA samples for the IGF family, IGF-1 +6093 (rs6219), +1770 (rs6220), IGF-1R (rs951715) and insulin-like growth factor binding protein IGFBP-3 -202 (rs2854744) polymorphisms analysis by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) and real-time quantitative polymerase chain reaction (real-time PCR). Our study found that, there is no statistical difference in IGF-1 (rs6219, rs6220) polymorphism between control and cervical neoplasm groups. Besides, there is also no statistical difference in IGF-1 (rs6219, rs6220) polymorphism between control and high-grade cervical intraepithelial neoplasm groups. Comparing control and squamous cell carcinoma groups, there is no significant difference in the polymorphism of IGF-1 +6093 (rs6219) but it has significant difference in IGF-1 +1770 (rs6220) gene polymorphism distribution. According to IGF-1 +1770 (rs6220) polymorphism distribution, the cancer risk of TC genotype is 1.793 fold than TT genotype (p = 0.044, 95% CI 1.012-3.178), the cancer risk of CC genotype is 2.110 fold than TT genotype (p = 0.027, 95% CI 1.079-4.124). At least one nucleotide mutation including genotype TC and CC, the risk of cervical squamous cell carcinoma is 1.884 fold than TT genotype (p = 0.021, 95% CI 1.093-3.246). Otherwise, there is no significant difference in IGF-1R (rs951715) polymorphism distribution between control, high-grade cervical intraepithelial neoplasm and squamous cell cancer groups. There is also no significant difference in IGFBP-3 (rs2854744) polymorphism distribution between control, high-grade cervical intraepithelial neoplasm and squamous cell cancer groups.

並列關鍵字

insulin-like growth factor genes ； polymorphism ； cervical cancer

參考文獻

Benedet, J.L., H. Bender, H. Jones, 3rd, H.Y. Ngan, and S. Pecorelli. 2000. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers. FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 70:209-262.

Chen, W., S. Wang, T. Tian, J. Bai, Z. Hu, Y. Xu, J. Dong, F. Chen, X. Wang, and H. Shen. 2009. Phenotypes and genotypes of insulin-like growth factor 1, IGF-binding protein-3 and cancer risk: evidence from 96 studies. Eur J Hum Genet. 17:1668-1675.

Cheng, I., D.O. Stram, K.L. Penney, M. Pike, L. Le Marchand, L.N. Kolonel, J. Hirschhorn, D. Altshuler, B.E. Henderson, and M.L. Freedman. 2006. Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort. J Natl Cancer Inst. 98:123-134.

Cho, S.H., S.K. Kim, E. Kwon, H.J. Park, K.H. Kwon, and J.H. Chung. 2012. Polymorphism of IGF1R is associated with papillary thyroid carcinoma in a Korean population. J Interferon Cytokine Res. 32:401-406.

Clemmons, D.R. 2007. Modifying IGF1 activity: an approach to treat endocrine disorders, atherosclerosis and cancer. Nat Rev Drug Discov. 6:821-833.

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類胰島素生長因子家族之基因多型性與子宮頸癌之相關性探討

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