表皮生长因子受体通路在化疗±西妥昔单抗治疗的晚期结直肠癌患者肿瘤中的体细胞谱分析。
Somatic profiling of the epidermal growth factor receptor pathway in tumors from patients with advanced colorectal cancer treated with chemotherapy ± cetuximab.
机构信息
Institute of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, Wales, United Kingdom.
出版信息
Clin Cancer Res. 2013 Aug 1;19(15):4104-13. doi: 10.1158/1078-0432.CCR-12-2581. Epub 2013 Jun 5.
PURPOSE
To study the somatic molecular profile of the EGF receptor (EGFR) pathway in advanced colorectal cancer, its relationship to prognosis, the site of the primary and metastases, and response to cetuximab.
EXPERIMENTAL DESIGN
We used Sequenom and Pyrosequencing for high-throughput somatic profiling of the EGFR pathway in 1,976 tumors from patients with advanced colorectal cancer from the COIN trial (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). Correlations between mutations, clinicopathologic, response, and survival data were carried out.
RESULTS
Sequenom and Pyrosequencing had 99.0% (9,961/10,063) genotype concordance. We identified 13 different KRAS mutations in 42.3% of advanced colorectal cancers, 2 BRAF mutations in 9.0%, 4 NRAS mutations in 3.6%, and 5 PIK3CA mutations in 12.7%. 4.2% of advanced colorectal cancers had microsatellite instability (MSI). KRAS and PIK3CA exon 9, but not exon 20, mutations cooccurred (P = 8.9 × 10(-4)) as did MSI and BRAF mutations (P = 5.3 × 10(-10)). KRAS mutations were associated with right colon cancers (P = 5.2 × 10(-5)) and BRAF mutations with right (P = 7.2 × 10(-5)) and transverse colon (P = 9.8 × 10(-6)) cancers. KRAS mutations were associated with lung-only metastases (P = 2.3 × 10(-4)), BRAF mutations with peritoneal (P = 9.2 × 10(-4)) and nodal-only (P = 3.7 × 10(-5)) metastases, and MSI (BRAF(WT)) with nodal-only metastases (P = 2.9 × 10(-4)). MSI (BRAF(WT)) was associated with worse survival (HR = 1.89, 95% CI 1.30-2.76, P = 8.5 × 10(-4)). No mutations, subsets of mutations, or MSI status were associated with response to cetuximab.
CONCLUSIONS
Our data support a functional cooperation between KRAS and PIK3CA in colorectal tumorigenesis and link somatic profiles to the sites of metastases. MSI was associated with poor prognosis in advanced disease, and no individual somatic profile was associated with response to cetuximab in COIN.
目的
研究晚期结直肠癌表皮生长因子受体（EGFR）通路的体细胞分子谱，及其与预后、原发灶和转移灶部位以及对西妥昔单抗的反应之间的关系。
实验设计
我们使用 Sequenom 和 Pyrosequencing 对 COIN 试验（奥沙利铂和氟嘧啶化疗±西妥昔单抗）中 1976 例晚期结直肠癌患者的 EGFR 通路进行高通量体细胞分析。对突变、临床病理、反应和生存数据进行了相关性分析。
结果
Sequenom 和 Pyrosequencing 的基因型一致性为 99.0%（9961/10063）。我们在 42.3%的晚期结直肠癌中发现了 13 种不同的 KRAS 突变，2 种 BRAF 突变，4 种 NRAS 突变，5 种 PIK3CA 突变。4.2%的晚期结直肠癌存在微卫星不稳定性（MSI）。KRAS 和 PIK3CA 外显子 9，而非外显子 20 的突变同时发生（P = 8.9×10(-4)），MSI 和 BRAF 突变也同时发生（P = 5.3×10(-10)）。KRAS 突变与右结肠癌有关（P = 5.2×10(-5)），BRAF 突变与右（P = 7.2×10(-5)）和横结肠癌（P = 9.8×10(-6)）有关。KRAS 突变与仅肺转移有关（P = 2.3×10(-4)），BRAF 突变与腹膜（P = 9.2×10(-4)）和淋巴结仅转移有关（P = 3.7×10(-5)），而 MSI（BRAF(WT)）与淋巴结仅转移有关（P = 2.9×10(-4)）。MSI（BRAF(WT)）与生存不良相关（HR = 1.89，95%CI 1.30-2.76，P = 8.5×10(-4)）。没有突变、突变亚群或 MSI 状态与西妥昔单抗的反应相关。
结论
我们的数据支持 KRAS 和 PIK3CA 在结直肠肿瘤发生中的功能协同作用，并将体细胞谱与转移部位联系起来。MSI 与晚期疾病预后不良有关，而 COIN 中没有单个体细胞谱与西妥昔单抗的反应相关。
Zotero 插件