2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/645044摘要：研究背景：乳癌術後抗賀爾蒙治療與是否追加化學治療，已成為原發性賀爾蒙接受體（HR)陽性及表皮 生長因子第二型受體(HER2)陰性乳癌病人的一項重要治療利器。除了臨床病理特徵外，目前有很多乳 癌腫瘤基因分子檢測方法，包括Oncotype DX，可預測賀爾蒙接受體(HR)陽性乳癌病人預後，並進一 步幫助臨床醫師及病人選擇是否追加術後化學治療。然而這些基因分析工具，只能偵測腫瘤組織基因 的改變，並無考慮病人本身所存在的基因差異性。初步研究成果：我們之前已證實與雌性激素和tamoxifen代謝有關之單一核甘酸基因體多形性（SNP)， 例如CYP19 (TTTA重複），CYP19 AASA單型性和SULT1A1，與停經前HR陽性早期乳癌病人預後 有高相關性（Oncologist 2008;13:751-60; Biomed Res Int 2013;2013:562197)。我們也證實從全基因組關聯分析中（GWAS)所找出與乳癌發生相關SNP，例如：MAP3K1 rs889312和FGFR2 rs2981582，以及與 tamoxifen 和 cyclophosphamide 代謝之相關 SNP，例如：CYP2B6 rs3211371，均會影響HR陽性早期乳癌病人預後。我們藉由次世代定序方法（NGS)分析80位HR陽性早期乳癌 病人，發現五個新的基因體多形性，例如：FGFR2 rs2981460和MAP3K1 rs3822625, rs702689, rs832567和rs9687226，這些SNP均與病人之不好預後呈高相關性。研究假說：基於我們的研究結果，我們認為在台灣早期HR陽性及HER2陰性乳癌病人（腫瘤大小為 T1至T3期，且腋下淋巴結0至3顆），從全基因關聯分析及次世代基因定序所找出SNP及參與雌性 激素、tamoxifen和化學治療藥物代謝相關之宿主基因多形差異性，可能影響術後追加治療的效果，進 而影響病人預後，因此本研究我們的主要目標如下：(1)持續探討及確認我們從GWAS所找出SNP與雌性激素、tamoxifen和化學治療藥物代謝相關 之SNP，是否與450位早期HR陽性及HER2陰性乳癌病人預後呈相關性(2)剖析我們從NGS所找出與FGFR2和MAP3K1相關新SNP，去分析這些SNP是否與上述早 期HR陽性及HER2陰性乳癌病人預後有關，而後調整術後治療的策略(3)藉由相關轉譯研究(細胞株及組織檢體研究）去功能性分析和釐清上述所證實與預後相關SNP 之生物特性預期研究結果：我們預期宿主基因體多形性變異會影響早期HR陽性及HER2陰性乳癌病人預後，且 可幫助我們決定是否需追加術後化學治療。且從進一步的功能性分析和釐清上述重要SNP及相對應的 生物特性，將可幫助我們發展新策略來治療這群乳癌病人。<br> Abstract: Background: Postoperative adjuvant anti-hormonal treatment with and without systemic chemotherapy is considered an integral component of the management of primary breast cancer patients with positive hormone receptor (HR) and negative HER2 status. In addition to clinicopathologic features, several multiple gene assays, including Oncotype DX, have been demonstrated to predict the survival of HR-positive patients, and help physicians and patients the decision of giving adjuvant chemotherapy or not. However, these assays only test the alteration of gene expression from tumor tissues but do not test the underling host genetic variants from patients. Preliminary results: We have previously shown that single nucleotide polymorphisms (SNPs) of estrogen and tamoxifen metabolizing genes, such as CYP19 (TTTA repeat), CYP19 haplotype AASA, and SULT1A1, are closely associated with the survival of premenopausal HR+ early breast cancer patients (Oncologist 2008;13:751-60; Biomed Res Int 2013;2013:562197). Our preliminary results showed that SNPs identified from genome-wide association studies (GWAS) that are associated with breast cancer risk, such as MAP3K1 rs889312 and FGFR2 rs2981582, and SNPs involved in tamoxifen and cyclophosphamide metabolism, such as CYP2B6 rs3211371, may affect HR+ early breast cancer outcome. Through the next-generation sequencing (NGS) methods, we identified 5 new discovered SNPs, FGFR2 rs2981460, and MAP3K1 rs3822625, rs702689, rs832567, and rs9687226 that were significantly associated with poor prognosis of 80 HR+ early breast cancer patients.Hypothesis: Based on our results, we hypothesize that, in HR+/HER2- Taiwanese early breast cancer patients (T1-T3 and axillary LN: 0 to 3), host factors as shown by SNPs identified from GWAS and NGS, and SNPs of genes involved in metabolism of estrogen, tamoxifen, and chemotherapeutic agents may influence the effect of adjuvant treatment, and thus affect the survival of these patients.In the present study, our specific aims are:(1)Continue exploration and validation our identified SNPs from GWAS and those involved in metabolism of estrogen, tamoxifen, and chemotherapeutic agents in the determination of prognosis of 450 HR+/HER2- early breast cancer.(2)Exploration of newly discovered SNPs (FGFR2 and MAP3K1) from NGS in prognostication of HR+/HER2- early breast cancer patients—determination of adjuvant treatment strategies.(3)Functionally analysis and clarification of aforementioned SNPs and their biologic significances in HR+/HER2- early breast cancer patients through translation study (cell lines and tumor samples).Major anticipated achievements: We expect that genetic variants of host SNPs may affect the prognosis of HR+/HER2- early breast cancer patients, and help use determine whether chemotherapy or not. Further, functionally analysis and clarification of biologic significances of theseSNPs may help us develop new strategies to treat this subtype of breast cancer patients.基因體多形性全基因組關聯分析次世代定序賀爾蒙接受體陽性HER2陰性乳癌SNPsGWASNGSHR-positiveHER-negativeBreast cancer