上皮性卵巢癌组织脆性组氨酸三联基因甲基化和3p14的等位基因丢失

Hypermethylation of fragile histidine triad gene and 3p14 allelic deletion in ovarian carcinomas

目的 探讨肿瘤抑制基因脆性组氨酸三联(FHIT)基因在上皮性卵巢癌(简称卵巢癌)组织中的甲基化状态以及该基因定位的3p14位点的等位基因丢失及其在卵巢癌的发生发展中的作用。方法 采用甲基化特异性聚合酶链反应(MSP)方法检测61例卵巢癌组织及10例交界性上皮性卵巢肿瘤(简称交界性卵巢肿瘤)组织FHIT基因启动子CpG岛的甲基化频率,并采用微卫星多态性标志D3S1287检测45例卵巢癌组织3p14位点杂合子丢失(LOH)和纯合子丢失(HD)状态。结果 卵巢癌组织中FHIT基因甲基化频率为39 3% (24 /61),其中浆液性囊腺癌为45 2% ( 19 /42 ),黏液性囊腺癌为14 3% (1 /7),子宫内膜样癌为33 3% (4 /12);交界性卵巢肿瘤组织中FHIT基因甲基化为6 /10,其中交界性浆液性囊腺瘤1 /3,交界性黏液性囊腺瘤5 /7。卵巢癌组织甲基化频率与临床分期、细胞分化程度相关性无统计学意义。交界性卵巢肿瘤与卵巢癌之甲基化频率差异无统计学意义。43 5% (10 /23)卵巢癌显示LOH;有信息的浆液性囊腺癌中33 3% (6 /18)检测到HD。FHIT基因甲基化与基因丢失之间无明显相关性。结论 首次证实卵巢癌FHIT基因启动子有较高的甲基化频率,这可能是FHIT基因沉默的重要原因,在卵巢癌的发生与发展过程中起着重要的作用;同时3p14位点等位基因的丢失可使基因?

Objective The FHIT( fragile histidine triad) is a candidate tumor suppressor gene (TSG) located on chromosome 3p14.2. Hypermethylation and loss of heterozygosity (LOH) are major mechanisms in the inactivation of tumor suppressor genes. In this study, the methylation status of FHIT and LOH of 3p14 in 61 cases of human sporadic ovary carcinomas were investigated.Methods Sixty-one primary ovary carcinomas and 10 borderline ovarian tumors were analyzed with methylation specific PCR (MSP) to detect the CpG island methylation status in the FHIT promoter region. In addition, 45 cases of ovary carcinomas and their corresponding non-tumor ovary tissues were investigated with D3S1287 microsatellite polymorphic marker for LOH.Results Hypermethylation of FHIT gene was observed in 39.3%(24/61) of ovarian carcinomas. The frequencies of hypermethylation in serous ovarian carcinoma, mucinous ovarian carcinoma, endometrioid ovarian carcinoma and ovary borderline tumor were 45.2%(19/42), 14.3%(1/7), 33.3%(4/12) and 60.0%(6/10), respectively. Ten of twenty-three (43.5%) informative tumors showed LOH and 6 of 18 (33.3%) informative cases showed homozygous deletions. The status of FHIT methylation was not associated with clinical stage and differentiation grade, there was no significant difference between the malignant and borderline tumors. Conclusion Hypermethylation and allelic deletion of FHIT are frequent events in ovarian carcinomas and are important mechanisms for the loss of expression of this gene.