Shen Yinchen, Wang Jianfei, Han Xiaohong, Yang Hongying, Wang Shuai, Lin Dongmei, Shi Yuankai
Department of Medical Oncology, Cancer Institute/Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China ; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
PLoS One. 2013 Dec 10;8(12):e81628. doi: 10.1371/journal.pone.0081628. eCollection 2013.
Mutations in KRAS oncogene are recognized biomarkers that predict lack of response to anti- epidermal growth factor receptor (EGFR) antibody therapies. However, some patients with KRAS wild-type tumors still do not respond, so other downstream mutations in BRAF, PIK3CA and NRAS should be investigated. Herein we used direct sequencing to analyze mutation status for 676 patients in KRAS (codons 12, 13 and 61), BRAF (exon 11 and exon 15), PIK3CA (exon 9 and exon 20) and NRAS (codons12, 13 and 61). Clinicopathological characteristics associations were analyzed together with overall survival (OS) of metastatic colorectal cancer patients (mCRC). We found 35.9% (242/674) tumors harbored a KRAS mutation, 6.96% (47/675) harbored a BRAF mutation, 9.9% (62/625) harbored a PIK3CA mutation and 4.19% (26/621) harbored a NRAS mutation. KRAS mutation coexisted with BRAF, PIK3CA and NRAS mutation, PIK3CA exon9 mutation appeared more frequently in KRAS mutant tumors (P = 0.027) while NRAS mutation almost existed in KRAS wild-types (P<0.001). Female patients and older group harbored a higher KRAS mutation (P = 0.018 and P = 0.031, respectively); BRAF (V600E) mutation showed a higher frequency in colon cancer and poor differentiation tumors (P = 0.020 and P = 0.030, respectively); proximal tumors appeared a higher PIK3CA mutation (P<0.001) and distant metastatic tumors shared a higher NRAS mutation (P = 0.010). However, in this study no significant result was found between OS and gene mutation in mCRC group. To our knowledge, the first large-scale retrospective study on comprehensive genetic profile which associated with anti-EGFR MoAbs treatment selection in East Asian CRC population, appeared a specific genotype distribution picture, and the results provided a better understanding between clinicopathological characteristics and gene mutations in CRC patients.
KRAS癌基因的突变是公认的生物标志物，可预测对抗表皮生长因子受体（EGFR）抗体治疗无反应。然而，一些KRAS野生型肿瘤患者仍然没有反应，因此应研究BRAF、PIK3CA和NRAS的其他下游突变。在此，我们使用直接测序法分析了676例患者KRAS（密码子12、13和61）、BRAF（外显子11和外显子15）、PIK3CA（外显子9和外显子20）和NRAS（密码子12、13和61）的突变状态。分析了临床病理特征关联以及转移性结直肠癌患者（mCRC）的总生存期（OS）。我们发现35.9%（242/674）的肿瘤存在KRAS突变，6.96%（47/675）存在BRAF突变，9.9%（62/625）存在PIK3CA突变，4.19%（26/621）存在NRAS突变。KRAS突变与BRAF、PIK3CA和NRAS突变共存，PIK3CA外显子9突变在KRAS突变肿瘤中出现频率更高（P = 0.027），而NRAS突变几乎存在于KRAS野生型中（P<0.001）。女性患者和老年组KRAS突变率更高（分别为P = 0.018和P = 0.031）；BRAF（V600E）突变在结肠癌和低分化肿瘤中频率更高（分别为P = 0.020和P = 0.030）；近端肿瘤PIK3CA突变率更高（P<0.001），远处转移肿瘤NRAS突变率更高（P = 0.010）。然而，在本研究中，mCRC组的OS与基因突变之间未发现显著结果。据我们所知，这是东亚CRC人群中关于与抗EGFR单克隆抗体治疗选择相关的综合基因谱的首次大规模回顾性研究，呈现出特定的基因型分布情况，结果有助于更好地理解CRC患者的临床病理特征与基因突变之间的关系。
