黏液性上皮卵巢癌第17號染色體多套畸形對HER2狀態的影響

Assessing the influence of polysomy-17 on HER2 status in mucinous epithelial ovarian cancer

蔡孟潔(MENG-CHIEH TSAI)

指導教授 ： 曾淑玲 ； 韓志平

中山醫學大學/醫學院/醫學研究所/碩士(2017年)

摘要

目的：評估黏液性上皮卵巢癌組織中，第17號染色體多套畸形(polysomy-17)對HER2狀態所造成的影響。 研究設計：在49例黏液性上皮卵巢癌組織晶片中，我們根據2010年全球胃癌第三期臨床研究(ToGA trial)對小切片檢體的評分基準，以4B5抗體免疫組織化學染色(immunohistochemistry; IHC)方法，分析HER2受體蛋白表現強度;以Abbott/Vysis, PathVysion Her2 DNA Probe Kit螢光原位雜交(fluorescence in situ hybridization; FISH)方法，分析Her2基因數量擴增比例。橘色螢光訊號代表「Her2基因」；綠色螢光訊號代表「第17號染色體著絲粒區(chromosome 17 centromere locus，CEP17)」;也間接作為「第17號染色體」的計數標誌。 結果：我們的數據顯示:「Her2基因數量擴增比例(FISH)」與「HER2受體蛋白表現強度(IHC)」二者的整體一致性非常好(34/35=97.14%; kappa=0.9224)。Her2基因FISH比例擴增個案百分比，隨者HER2受體蛋白IHC表現強度(陰性、模糊、陽性) 三個等級，呈現漸增趨勢(0%，14.29%，88.89%，P<0.001)。第17號染色體著絲粒區「校正前」之Her2基因數目中位數，也隨者HER2受體蛋白IHC表現強度三個等級，呈現漸增趨勢(1.80，1.90，9.90；P<0.001); 而「校正後」之Her2基因數量比例(又稱為FISH)中位數，同樣隨者HER2受體蛋白IHC表現強度三個等級，呈現漸增趨勢 (1.13，1.09，5.73; P<0.001)。此外;在「第17號染色體多套畸形」亞群體中，其「校正前」Her2基因中位數，顯著高於「非第17號染色體多套畸形」亞群體中者(2.50 vs. 1.85，P=0.009);但在前述二亞群體中，其個別「校正後」Her2基因比例(FISH)中位數相比較，則無顯著差異(1.14 vs. 1.19，P=1.000)。 結論：第17號染色體多套畸形本身並不會顯著影響HER2受體蛋白IHC表現及Her2基因數目擴增。理由是：第17號染色體多套畸形經第17號染色體著絲粒區校正後，伴隨增加具功能性的Her2基因數目，僅呈現簡單算數級數增加，實際擴增之Her2基因數目有限，因此，HER2受體蛋白表現強度增加，也相對很有限。然而，「Her2基因數量比例(FISH)擴增」與「HER2受體蛋白表現強度(IHC)增加」兩個現象，是現今預測HER2單株抗體藥物對乳房、胃、胃食道交界處等癌症患者療效預後與藥物敏感評估的重要因子。未來希望對黏液性上皮卵巢癌病患開發其它拮抗HER2標靶藥物提供參考，針對晚期或復發黏液性上皮卵巢癌病患，有機會被納入開發拮抗HER2新藥臨床試驗；一旦HER2標靶抗癌新藥研發成功後，對於此類病患的治療，將有很大的助益。

關鍵字

黏液性上皮卵巢癌 ； HER2狀態 ； 第17號染色體多套畸形(polysomy-17) ； 第17號染色體著絲粒區(chromosome 17 centromere locus, CEP17) ； 亞群體(subgroup) ； 免疫組織化學染色(immunohistochemistry, IHC) ； 螢光原位雜交(fluorescence in situ hybridization, FISH)

並列摘要

Objective: Her2 gene amplification and protein over-expression are important factors in predicting clinical sensitivity to anti-HER2 monoclonal antibody therapy in breast, gastric or gastroesophageal junction (GEJ) cancer patients. However, little information addresses chromosome 17 centromere CEP17 in mucinous epithelial ovarian cancer (EOC). The purpose of this study was to assess the influence of CEP17 polysomy on HER2 status in patients with mucinous EOC.

Study Design: Of the 49 tissue microarray (TMA) samples of mucinous EOC, we applied 2010 ToGA trial biopsy scoring criteria to analyze the HER2 protein expression by an immunohistochemistry (IHC) test with 4B5 antibody (Ventana medical system Inc.), and the Her2 gene amplification by the fluorescence in situ hybridization (FISH) test with an Abbott/Vyzsis, PathVysion Her2 DNA Probe Kit.

Results: Our data revealed a favorable overall concordance (34/35=97.14%) between Her2 FISH and HER2 IHC assays (kappa=0.9224). The percentage of Her2 FISH amplified cases showed a significant increasing trend through their corresponding HER2 IHC ordinals (0%,14.29%,88.89%,P<0.001). The medians of Her2 gene copies (before CEP17 correction) increased significantly through 3 HER2 IHC orders (1.80, 1.90, 9.90; P<0.001); and the medians of the Her2 FISH ratios (after CEP17 correction) also did so (1.13, 1.09, 5.73; P<0.001). Additionally, the median of Her2 gene copies was significantly higher in the CEP17 polysomy subgroup than that in the CEP17 nonpolysomy subgroup (2.50 vs. 1.85, P=0.009), but the medians of Her2 FISH ratios were not (1.14 vs. 1.19, P=1.000).

Conclusion: The CEP17 polysomy did not significantly influence the HER2 IHC and Her2 FISH results in mucinous EOC. The arithmetic raise of CEP17 per se did not reflect a substantial increase in functional Her2 gene copies and HER2 protein overexpression. Verifying HER2 status in mucinous EOC is indispensable to select potentially candidates for novel anti-HER2 drug therapies in the future.

並列關鍵字

mucinous epithelial ovarian cancer ； HER2 status ； CEP17 polysomy ； chromosome 17 centromere locus (CEP17) ； subgroup ； immunohistochemistry (IHC) ； fluorescence in situ hybridization(FISH)

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