攝護腺癌二代賀爾蒙療法療效與基因變異之相關性分析

Abstract

攝護腺癌是男性第二常見的惡性腫瘤，全球每年新診斷的攝護腺癌患者超過100萬人。攝護腺癌的病生理學主要與雄性激素受體有關，雖然雄性激素剝奪療法對晚期攝護腺癌在初期治療效果顯著，但數年內疾病會進展為去勢抗性攝護腺癌。 在初代雄性激素剝奪療法藥物基礎上，二代荷爾蒙療法已被證實對於接受化療前或化療後的晚期攝護腺癌患者具有療效。然而，二代荷爾蒙療法之療效在不同患者間存在差異，這主要取決於患者對二代荷爾蒙療法之抗藥程度。過去已提出多種不同的二代荷爾蒙療法抗藥性機轉，包括雄性激素受體基因變異、DNA損傷修復機制的變化、信號傳導通路的改變、蛋白激酶PI3K/AKT/mTOR通路的改變、Wnt-β-catenin通路之變異、神經內分泌分化異常等，這些機制的改變都可能導致對二代荷爾蒙療法產生抗藥性，從而影響治療效果。 全基因組關聯研究（genome-wide association study, GWAS）可分析癌症臨床表徵與基因變異之間的相關性，研究疾病預後及治療療效與單核苷酸多型性（single nucleotide polymorphism, SNP）基因位點變異之相關性。 本研究之研究假設為（1）基因變異會造成攝護腺癌二代賀爾蒙療法預後之影響，（2）基因變異會造成二代賀爾蒙藥物抗藥性之差異並對治療結果造成改變，（3）基因變異具有二代賀爾蒙療法療效之預測角色並提供藥物選擇之參考。 本研究之研究目的為（1）闡明基因變異對於攝護腺癌二代賀爾蒙療法療效及癌症預後之影響，（2）研究基因變異對於攝護腺癌二代賀爾蒙療法療效之預測價值，提供個人化醫療之藥物選擇。本研究以全基因組關聯分析（GWAS）進行攝護腺癌二代賀爾蒙療法病患之基因分析，識別攝護腺癌二代賀爾蒙治療預後相關因子於單核苷酸多型性位點之基因變異表現。 共有82位晚期攝護腺癌接受二代賀爾蒙療法於高雄醫學大學附設醫院之病患納入本研究中，包括 Abiraterone 28位及Enzalutamide 54位病患，收集分析病患之攝護腺癌臨床資料及二代賀爾蒙治療之相關資料，以全基因組關聯研究分析攝護腺癌二代賀爾蒙療法預後因子與基因變異之相關性。 全基因組關聯研究分析顯示，以PSA nadir < 2 ng/ml為預後因子（> 2 ng/ml, n = 37; < 2 ng/ml, n = 43），可顯示出五個位於Chromosome 1上WNT4 gene之SNP有較高的關聯強度; 以PSA下降比例 > 50%為預後因子（> 50%, n = 58; < 50%, n = 22），呈現出位於Chromosome 1上AGT CAPN9 gene之SNP有較高的關聯強度。於連續性狀分析中，PSA nadir與基因分析比較，7個位於染色體Chromosome 1、4、13、15、20上之SNP，其基因位置分別位於AJAP1、AL645474.1、AC093607.1、AC017091.1、MTCL1P1、OCA2、RNU6-929P，達統計顯著關聯強度。 此研究結果顯示，基因變異對於攝護腺癌二代賀爾蒙療法造成預後之影響，識別出數個不同的基因位點變異，呈現出二代賀爾蒙治療後預後因子基因表現之差異。此次研究所呈現出的基因變異位點位於WNT4 gene、AJAP1 gene與其他特定的癌症相關訊息傳遞路徑，進一步且更大規模的基因研究以及更深入關於癌症的路徑機轉研究為未來之研究努力目標，為個人化精準醫療提供更有力的資訊。

Prostate cancer is the second common cancer in male, and more than 1 million patients were newly diagnosed each year among the world. The pathophysiologies of the prostate cancer were mainly related to the androgen receptors (ARs). Although androgen deprivation therapies (ADT) were efficacious for the initial treatment of the advanced prostate cancer, the diseases progress into the castration resistant prostate cancer (CRPC) within years. Upon ADT, novel hormone agents (NHAs) have been proved the survival benefits for the advanced prostate cancer with the pre- or the post-chemotherapy regimen. The therapeutic effect of the NHAs varies among the patients according to the degrees of the NHA resistance. Several mechanisms of the NHA resistance had been proposed, including the genomic alterations of the androgen receptors, DNA damage repair, and several signaling pathway alterations in phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, Wnt–β-catenin pathway and neuroendocrine differentiation pathways. Genome-wide association study (GWAS) provides the genetic information for the correlation between the characters of the cancers and the genetic variants and examines the single nucleotide polymorphism (SNP) variants related to the prognosis of the diseases and oncological outcome of the therapies. Under the hypothesis that genetic variants might (1) contribute to the progression and the prognosis of the advanced prostate cancer under novel hormone therapy, (2) play the role for the novel hormone agent resistance and alter the therapeutic effects and (3) provide predictive values for the choice of the novel hormone therapies, the purposes of the studies are to (1) elucidate the prognostic value of the genetic variants in the efficacy of novel hormone therapy in the advanced prostate cancer, and (2) provide the predictive values for the prostate cancer patient receiving novel hormone agents with the genome-wide association study (GWAS) for the purpose of the precision medicine. 82 patients with advanced prostate cancer under NHA with Abiraterone (n = 28) and Enzalutamide (n = 54) were enrolled from Kaohsiung Medical University hospital. The patient’s oncological profiles were recorded retrospectively. GWAS were analyzed for the prognostic factors related to the outcome of the NHA response. For the prognostic factor of PSA nadir < 2 ng/ml as good NHA response, ( > 2 ng/ml, n = 37; < 2 ng/ml, n = 43), 5 SNPs at chromosome 1 related to WNT4 gene were found. For the prognostic factor of PSA decline > 50% as good NHA response ( > 50%, n = 58; < 50%, n = 22), 1 SNP at chromosome 1 near AGT CAPN9 gene was found. Regarding GWAS for the PSA nadir quantitative trait, several SNPs at chromosome 1, 4, 13, 15, and 20 near AJAP1, AL645474.1, AC093607.1, AC017091.1, MTCL1P1, OCA2 and RNU6-929P gene were identified. In conclusion, for the advanced prostate cancer patients under NHA with Abiraterone and Enzalutamide, GWAS revealed the correlation of the genetic variants with the oncological outcome of the NHA therapies. Several SNPs were showed the correlation with the therapeutic prognosis of NHA, including the SNPs at WNT4 gene, and AJAP1 gene which were correlated with the signaling pathways related to the cancer. These findings provide the genetic parameters for the precision medicine. Further studies were warranted.