Feng Qingyang, Liang Li, Ren Li, Chen Jingwen, Wei Ye, Chang Wenju, Zhu Dexiang, Lin Qi, Zheng Peng, Xu Jianmin
Department of General Surgery, Zhongshan Hospital, Fudan University Shanghai, China.
Department of Internal Medicine/Oncology, Zhongshan Hospital, Fudan University Shanghai, China.
Am J Cancer Res. 2015 Jan 15;5(2):674-88. eCollection 2015.
In colorectal cancer, there are significant differences between synchronous and metachronous distant metastases. However in recent studies, synchronous and metachronous metastases were always lumped together, neglecting their clinical and molecular differences. The mechanism of the latency of metachronous metastases is still unclear. We conducted this study to reveal the relationship between EGFR pathways and metachronous metastases, and try to find efficient predictors.
PCRs and pyrosequencing were used to detect KRAS, BRAF, PIK3CA and PTEN mutations in primary tumor tissues in a total of 281 patients from 2002 to 2008. Patients were identified into three groups: no-metastases group, synchronous-metastases group and metachronous-metastases group. Clinical and survival data were collected from a prospective database.
KRAS codon 13 mutation was an independent predictor only for metachronous distant metastases (OR = 11.857, P < 0.001), but not for synchronous metastases. Male gender (OR = 2.233, P = 0.024), primary tumor located at rectum (OR = 0.404, P = 0.041), and primary pN2 stage (OR = 3.361, P = 0.01) were also independent predictors for metachronous distant metastases. Different SNPs in KRAS worked significantly different in determining synchronous or metachronous metastases. BRAF mutation (Univariate, OR = 11.5, P = 0.039) and > 200 ng/ml preoperative CEA (Univariate, OR = 41, P = 0.011) potentially predicted metastases within 6 months after primary tumor resection. After metachronous metastases, radical resection (HR = 0.280, P = 0.002) was the most important protective factor for long-term survival.
There were significant clinical and molecular differences between synchronous and metachronous metastases. As an independent predictor, KRAS codon 13 mutation might be the key to explain the mechanism of colorectal cancer metachronous distant metastases. Together with clinical characteristics, it could aid in the early detection of metachronous metastases.
在结直肠癌中，同时性和异时性远处转移之间存在显著差异。然而，在最近的研究中，同时性和异时性转移总是被混在一起，忽略了它们在临床和分子方面的差异。异时性转移潜伏期的机制仍不清楚。我们开展这项研究以揭示表皮生长因子受体（EGFR）通路与异时性转移之间的关系，并试图找到有效的预测指标。
采用聚合酶链反应（PCR）和焦磷酸测序法检测2002年至2008年间共281例患者原发肿瘤组织中的KRAS、BRAF、PIK3CA和PTEN基因突变。将患者分为三组：无转移组、同时性转移组和异时性转移组。从一个前瞻性数据库收集临床和生存数据。
KRAS密码子13突变仅是异时性远处转移的独立预测指标（比值比[OR]=11.857，P<0.001），而不是同时性转移的预测指标。男性（OR=2.233，P=0.024）、原发肿瘤位于直肠（OR=0.404，P=0.041）以及原发肿瘤pN2期（OR=3.361，P=0.01）也是异时性远处转移的独立预测指标。KRAS基因中的不同单核苷酸多态性（SNP）在确定同时性或异时性转移方面作用显著不同。BRAF突变（单因素分析，OR=11.5，P=0.039）和术前癌胚抗原（CEA）>200 ng/ml（单因素分析，OR=41，P=0.011）可能预测原发肿瘤切除后6个月内发生转移。异时性转移发生后，根治性切除（风险比[HR]=0.280，P=0.002）是长期生存的最重要保护因素。
同时性和异时性转移之间存在显著的临床和分子差异。作为独立预测指标，KRAS密码子13突变可能是解释结直肠癌异时性远处转移机制的关键。结合临床特征，其有助于早期发现异时性转移。
