BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients.
BRAF V600E mutation and KRAS codon 13 mutations predict poor survival in Chinese colorectal cancer patients.
复制标题
BRAF V600E 突变和 KRAS 密码子 13 突变预测中国结直肠癌患者生存率较差
DOI：
10.1186/1471-2407-14-802
复制
发表时间：
2014-11-03
期刊：
影响因子：
3.8
通讯作者：
He Y
中科院分区：
文献类型：
--
作者：
Chen J;Guo F;Shi X;Zhang L;Zhang A;Jin H;He Y
inKRAS、brafand pik3ca3是西方国家结直肠癌（CRC）患者中最常见的体细胞突变；但其在亚洲患者中的患病率和预后价值尚未得到充分评估。本研究的目的是确定这些基因在中国结直肠癌患者中的突变频率，并探讨它们对预后的影响。方法从214例结直肠癌患者（结直肠：126/88）的福尔马林固定石蜡包埋（FFPE）组织中提取DNA，采用PCR和直接测序的方法对kras外显子2、braf外显子15和pik3ca9、20外显子的序列进行评价。结果在44.9%（96/214）、4.2%（9/214）和12.3%（26/212）的crc中分别检测到skras、brafand pik3突变。最常见的突变inKRAS、brafand pik3ca3分别为G12D、V600E和H1047R。所有braf和80.8%的pik3突变来自结肠癌患者。BRAFV600E与结肠癌患者的晚期TNM （P < 0.001）、更多的远处转移（P = 0.025）和更差的总生存（OS, P < 0.001；多变量HR = 4.2, P = 0.004）相关。与kraswt /BRAFwt结直肠癌患者（N = 109）相比，krascodon 13突变患者（N = 25）的OS明显较差（P = 0.016；多变量HR = 2.7, P = 0.011），而krascodon 12突变患者与生存率无显著相关性。在三种最常见的kraswt突变中，与kraswt /BRAFwt患者相比，G13D （N = 23）与不良OS有显著相关性（P = 0.024；多变量HR = 2.6, P = 0.016）。结论PI3K/RAS-RAF信号通路基因在中国结直肠癌患者中经常发生突变，但其特征与西方结直肠癌患者不同。BRAFV600E是中国患者的独立预后因素。我们发现krascodon 13突变（特别是G13D）与中国brafwild型crc患者的低生存率相关，目前尚未报道。我们的数据强调了对CRC患者分子特征进行前瞻性评估的重要性，因为单一突变类型可能代表不同的生物学效应和临床意义。
BackgroundMutations inKRAS,BRAFandPIK3CAare the most common somatic alterations found in the colorectal cancer (CRC) patients from Western countries; but their prevalence and prognostic value have not been adequately assessed in Asian patients. The aim of this study was to determine the mutation frequencies of these genes in Chinese CRC patients and to investigate their impact on prognosis.MethodsThe sequences of exon 2 ofKRAS, exon 15 ofBRAFand exons 9 and 20 ofPIK3CAwere evaluated by PCR and direct sequencing using DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues from primary CRC tumors of 214 patients (colon/rectum: 126/88).ResultsKRAS,BRAFandPIK3CAmutations were identified in 44.9% (96/214), 4.2% (9/214) and 12.3% (26/212) CRCs, respectively. The most frequent mutations inKRAS,BRAFandPIK3CAwere G12D, V600E and H1047R, respectively. AllBRAFand 80.8%PIK3CAmutations were from colon cancer patients.BRAFV600E was associated with advanced TNM (P < 0.001), more distant metastases (P = 0.025), and worse overall survival (OS, P < 0.001; multivariate HR = 4.2, P = 0.004) in colon cancer patients. Compared withKRASwt/BRAFwt CRC patients (N = 109), those withKRAScodon 13 mutations (N = 25) had significantly worse OS (P = 0.016; multivariate HR = 2.7, P = 0.011), whereasKRAScodon 12-mutated cases were not significantly associated with survival. Among the three most commonKRASmutations, G13D (N = 23) showed significant association with poor OS (P = 0.024; multivariate HR = 2.6, P = 0.016) compared withKRASwt/BRAFwt patients.ConclusionOur findings indicate that PI3K/RAS-RAF signaling pathway genes are frequently mutated in Chinese CRC patients, but have different characteristics than found in Western patients.BRAFV600E is an independent prognostic factor for Chinese patients. Our finding thatKRAScodon 13 mutations (in particular G13D) are associated with inferior survival inBRAFwild-type CRCs in Chinese patients was not reported thus far. Our data emphasizes the importance of prospective evaluation of molecular features in CRC patients, because a single mutation type may represent a distinct biologic effect and clinical implication.