上皮性卵巢癌的流行病學與預後指標之研究

The Studies of Epidemiology and Prognostic Markers in Epithelial Ovarian Carcinoma

江盈澄(Ying-Cheng CHIANG)

指導教授 ： 陳祈安 ； 鄭文芳

國立臺灣大學/醫學院/臨床醫學研究所/博士(2016年)

https://doi.org/10.6342/NTU201610228

摘要

上皮性卵巢癌的發生率逐年升高，且其死亡率在婦女的惡性腫瘤中名列第一，在婦癌的領域中逐漸成為一個愈來愈重要的疾病，早期的上皮性卵巢癌往往沒有明確的症狀，大部分患者都已經達到晚期。上皮性卵巢癌的標準治療方式為腫瘤減積手術及輔助性化學治療通常治療後的初期反應在所有上皮性卵巢癌患者可達80%，在晚期患者可達40-60%，可是大部份患者於兩年內會復發，其中化療藥物的抗藥性在腫瘤的復發與惡化方面扮演了重要的角色，若能找出兼具預測臨床病程及代表腫瘤生物特性的因子，對於臨床診斷和治療將會很有助益。在第一個研究中，利用臺灣癌症登記系統全國資料庫的卵巢癌資料，來進行三十年來上皮性卵巢癌的發生率和預後的流行病學分析。研究發現這期間內漿液性腺癌、子宮內膜樣腺癌和明亮細胞癌的發生率增加，且最普遍的診斷年齡從60歲逐漸改變為50歲。在存活分析方面，黏液性腺癌、子宮內膜樣腺癌或明亮細胞癌患者的長期存活率比漿液性腺癌患者好(log rank test，p < 0.0001)；相反地，未分化癌或癌肉瘤患者的存活率比漿液性腺癌的患者差(log rank test，p < 0.0001)。以西元1991至1995年期間為基準，死亡的風險自西元1996至1999年期間逐漸減低(風險比：0.90，95%信賴區間：0.81-1.01，p = 0.054)，西元2000年以後更是明顯下降(風險比：0.74，95%信賴區間：0.67-0.82，p < 0.0001)。在第二個研究中，建立一個新的上皮性卵巢癌細胞株 - CA5171，它源自未接受化療的上皮性卵巢癌患者。CA5171細胞表現出上皮細胞的形態特徵，倍增時間約為24小時，CA5171有PIK3CA、PTEN和TP53基因的突變，單核苷酸多態性陣列分析顯示沒有同合性基因缺失，但有基因擴增的位點在染色體1、2、5、9、10、12、15、16、20和X。細胞毒性藥物與老鼠實驗顯示CA5171細胞對紫杉醇與阿黴素敏感，對順鉑有抗藥性。細胞所表現上皮間質轉化的特性可能是侵襲和遷移能力的原因，這些特性讓CA5171細胞株成為將來上皮性卵巢癌研究的有利工具。在第三個研究中，檢視上皮性卵巢癌患者組織CHI3L1基因表現與臨床預後的關聯性，研究發現漿液性腺癌患者、晚期患者或化療抗藥性患者有顯著較高的CHI3L1基因表現。高CHI3L1表現患者無病存活期(p<0.001)與整體存活期(p<0.001)顯著較短，高CHI3L1表現是疾病復發(風險比：2.91，95%信賴區間：1.89−4.48，p<0.001)和疾病死亡(風險比：4.03，95%信賴區間：2.37−6.87，p<0.001)的重要風險因子。細胞株研究顯示，CHI3L1基因可藉由提高Mcl-1的表現來抑制紫杉醇引起的卵巢癌細胞凋亡。由此可見CHI3L1基因可做為上皮性卵巢癌患者有潛力的預後指標。總結而言，三十年癌症登記資料庫的分析提供了台灣地區卵巢癌長期流行病學方面的資訊；所建立的CA5171細胞株是上皮性卵巢癌研究的有利工具；CHI3L1基因可做為上皮性卵巢癌患者有潛力的預後指標。

關鍵字

上皮性卵巢癌 ； 流行病學 ； 卵巢癌細胞株 ； CA5171 ； CHI3L1 ； YKL-40

並列摘要

Epithelial ovarian carcinoma has the highest mortality rate among gynecologic malignancies and is an important disease in the field. Early diagnosis is difficult due to the lack of obvious initial symptoms, therefore ovarian cancer patients are usually diagnosed at advanced stage. Current treatments include debulking surgery and adjuvant chemotherapy with the regimen of platinum and paclitaxel which have a response rate of 80% for all patients and 40-60% for advanced-staged patients, but they usually relapse after initial response and ultimately die of recurrence. Chemo-resistance is an obstacle in the managements of epithelial ovarian cancer. A clinical prognostic factor reflecting the possible mechanisms and biological characteristics of oncogenesis or chemo-resistance may be helpful in the development of new therapeutic strategies. In the first study, we conducted the nationwide database analysis through Taiwan cancer registry system from 1979 to 2008 to evaluate the pattern, incidence and prognosis of epithelial ovarian carcinomas in the last three decades. The age-specific incidence rates increased especially in serous, endometrioid and clear cell carcinoma, and the age of diagnosis decreased from sixty to fifty years old in the three decades. Patients with mucinous, endometrioid, or clear cell carcinoma had better long-term survival than patients with serous carcinoma (log rank test, p<0.001). Patients with undifferentiated carcinoma or carcinosarcoma had poorer survival than those with serous carcinoma (log rank test, p<0.001). The mortality risk decreased from the period of 1996-1999 (hazard ratio [HR]: 0.90, p=0.054) to the period after 2000 (HR: 0.74, p<0.001) as compared with that from the period of 1991-1995. In the second study, we reported a new cell line, CA5171, derived from a chemotherapy-naive, epithelial ovarian carcinoma patient. The CA5171 cells presented with cobblestone morphology and a doubling time of 24 hours. Gene mutation analysis showed that the cells belonged to the type II ovarian cancer pathway with mutations of PIK3CA, PTEN and TP53. Single-nucleotide polymorphism array analysis showed no homozygous gene deletion; however, several loci of gene copy number gains were noted in chromosome 1, 2, 5, 9, 10, 12, 15, 16, 20 and X. The in vitro and in vivo experiments showed that the cells were sensitive to paclitaxel and doxorubicin, but resistant to cisplatin. The cells also presented epithelial–mesenchymal transition properties that may have been related to their invasion and migration potential. The CA5171 cells show the potential as a new cell line for studies on epithelial ovarian carcinoma. In the third study, the association of CHI3L1 expression and clinical outcomes of epithelial ovarian carcinoma patients were investigated. The expression of CHI3L1 was also higher in patients with a serous histological type, advanced stage, and chemo-resistance. Patients with high CHI3L1 expression had a shorter progression free survival (log rank test, p < 0.001) and overall survival (log rank test, p < 0.001). Patients with high CHI3L1 expression also had a high risk of recurrence (HR: 2.91, 95% CI: 1.89−4.48, p < 0.001) and death (HR: 4.03, 95% CI: 2.37−6.87, p < 0.001). In vitro studies showed that CHI3L1 up-regulated the expression of anti-apoptotic Mcl-1 protein and hampered paclitaxel-induced apoptosis of ovarian cancer cells. These results suggest that CHI3L1 shows potential as a prognostic biomarker for epithelial ovarian carcinoma. In summary, the nationwide database analysis provided the long-term epidemiological information of epithelial ovarian cancer in Taiwan. The CA5171 cell line had the potential as a new tool for studies on epithelial ovarian carcinoma. The CHI3L1 expression of ovarian cancer tissue was a potential marker for epithelial ovarian cancer patients.

並列關鍵字

epithelial ovarian cancer ； epidemiology ； ovarian cancer cell line ； CA5171 ； CHI3L1 ； YKL-40

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