JCO:前列腺癌预后遗传因子

西班牙国立癌症研究中心（CNIO）下属的前列腺癌和生殖泌尿系肿瘤临床研究部门的最新研究结果发现,与一般的前列腺癌患者相比,前列腺癌患者如果同时发生BRCA2基因变异,就会出现不良的预后及很低的生存机率.

Olmos是前列腺癌和生殖泌尿系肿瘤临床研究部门的领导人,他说：“大部分前列腺癌患者都有良好的预后,在日常临床实践中,我们所面临的最大的挑战就是很难确定哪些患者病情是致命的.”

为了寻找与病情发展有关的遗传标记,本研究的作者对61名前列腺癌患者进行了检测,这些患者同时伴有BRCA2基因

（该基因能抑制肿瘤生长,对DNA具有保护作用）变异,18名患者伴有BRCA1基因（该基因的功能与BRCA2的相似）变异,

本研究排除了两个基因同时发生突变的1,940名患者.

这是目前调查前列腺癌患者BRCA1或BRCA2基因突变规模最大的一项研究；这些基因与家族性乳腺癌和卵巢癌综合征有关.

调查结果显示,BRCA1和BRCA2发生变异的患者,其前列腺癌都发展得比较严重,而且还有转移的迹象.

甚至,在同一组没有检测到癌细胞转移的患者中,伴有基因突变的23%的患者在未来5年内会发生癌细胞转移,而基因正常的患者只有7%的会出现这种情况.在诊断的5年后,19% BRCA2基因突变携带者在癌症早期就死亡,而在基因正常的患者中,这种死亡率只有4%.BRCA1基因突变在这方面的差异不显著.

文章的第一作者Castro说：“这些数据表明,BRCA2是第一个可用于前列腺癌预后的遗传因子.”她还补充说：“本研究的结果表明,需要转变对伴有BRCA基因突变的前列腺癌患者的临床治疗管理.目前的治疗标准对于此类患者来说似乎是不足够的,而且没有具体的行动指南.”

“既然我们已经可以设法确定具有潜在致命疾病的患者,我们的下一个挑战就是寻找最有效而且副作用最少的治疗方法.”Olmos说.

前列腺癌是世界上第二个最常见的男性癌症类型,发达国家,它是最见的肿瘤疾病.

在过去的几十年里,由于人的寿命都有所延长以及前列腺特异性抗原（Prostate-Specific Antigen,PSA）的广泛使用,使得这种癌症的发生有上升的趋势.有幸的是,由这种癌症所引起的死亡率在下降,这都归功于发病早期的诊断以及治疗方式的改良.

虽然如此,有些情况仍有致命的危险,需要努力寻找到能识别预后不良的患者的资源,建立更合适的治疗策略.（生物谷Bioon.com）

doi: 10.1200/JCO.2012.43.1882
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Germline BRCA Mutations Are Associated With Higher Risk of Nodal Involvement, Distant Metastasis, and Poor Survival Outcomes in Prostate Cancer

Elena Castro,Chee Goh,David Olmos?,Ed Saunders,Daniel Leongamornlert,Malgorzata Tymrakiewicz,Nadiya Mahmud,Tokhir Dadaev,Koveela Govindasami,Michelle Guy,Emma Sawyer,Rosemary Wilkinson,Audrey Ardern-Jones,Steve Ellis,Debra Frost,Susan Peock,D. Gareth Evans,Marc Tischkowitz,Trevor Cole,Rosemarie Davidson,Diana Eccles,Carole Brewer,Fiona Douglas,Mary E. Porteous,Alan Donaldson,Huw Dorkins,Louise Izatt,Jackie Cook,
Shirley Hodgson,M. John Kennedy,Lucy E. Side,Jacqueline Eason,Alex Murray,Antonis C. Antoniou,Douglas F. Easton,Zsofia Kote-Jarai and Rosalind Eeles

Purpose To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes.

Patients and Methods This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1).

Results PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup.

Conclusion Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.

(责任编辑：zengchang)