Prevalence and Heterogeneity of KRAS, BRAF, and PIK3CA Mutations in Primary Colorectal Adenocarcinomas and Their Corresponding Metastases
Prevalence and Heterogeneity of KRAS, BRAF, and PIK3CA Mutations in Primary Colorectal Adenocarcinomas and Their Corresponding Metastases
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DOI：
10.1158/1078-0432.ccr-09-2446
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发表时间：
2010-02-01
影响因子：
11.5
通讯作者：
Gabbert, Helmut E.
中科院分区：
文献类型：
--
作者：
Baldus, Stephan E.;Schaefer, Karl-L.;Gabbert, Helmut E.
目的：表皮生长因子受体（EGFR）抗体治疗建立在野生型KRAS结直肠癌患者;然而，高达50%的这些患者不响应这种治疗。为了确定这种治疗失败的可能原因，我们搜索了不同EGFR依赖性信号蛋白的突变，并分析了它们在原发性肿瘤和相应转移灶中的分布模式。分别从肿瘤中心、浸润前沿（n = 100）、淋巴结（n = 55）和远处转移（n = 20）宏观解剖的肿瘤组织，结果：原发肿瘤中KRAS、BRAF和PIK 3CA的突变率分别为41%、7%和21%。通过比较肿瘤中心和浸润前沿，分别在8%、1%和5%的原发性肿瘤中观察到KRAS、BRAF和PIK 3CA突变的瘤内异质性。在31%（KRAS）、4%（BRAF）和13%（PIK 3CA）的病例中发现原发肿瘤和淋巴结转移之间的异质性。原发性肿瘤和远处转移瘤之间的异质性存在于2例KRAS患者（10%）和1例PIK 3CA患者（5%）中，但不存在于BRAF中。原发肿瘤和转移灶之间的不一致结果可以显着减少通过测试额外的肿瘤samples.Conclusions：EGFR抗体治疗野生型KRAS结直肠癌患者的失败可能是由于激活BRAF或PIK 3CA突变和假阴性测序结果引起的瘤内异质性。由于原发性肿瘤和淋巴结转移之间的异质性特别高，后者最不适合诊断突变分析。Clin Cancer Res; 16（3）; 790-9. (C)2010年AACR。
Purpose: Epidermal growth factor receptor (EGFR) antibody therapy is established in patients with wild-type KRAS colorectal carcinoma; however, up to 50% of these patients do not respond to this therapy. To identify the possible causes of this therapy failure, we searched for mutations in different EGFR-dependent signaling proteins and analyzed their distribution patterns in primary tumors and corresponding metastases.Experimental Design: Tumor tissues, macrodissected from tumor centers, invasion fronts (n = 100), lymph nodes (n = 55), and distant metastases (n = 20), respectively, were subjected to DNA extraction and mutation analysis of KRAS, BRAF, and PIK3CA.Results: Activating mutations were detected in 41% (KRAS), 7% (BRAF), and 21% (PIK3CA) of the primary tumors. By comparing tumor centers and invasion fronts, the intratumoral heterogeneity of KRAS, BRAF, and PIK3CA mutations was observed in 8%, 1%, and 5% of primary tumors, respectively. Heterogeneity between primary tumors and lymph node metastases was found in 31% (KRAS), 4% (BRAF), and 13% (PIK3CA) of the cases. Heterogeneity between primary tumors and distant metastases was present in two patients (10%) for KRAS and one patient for PIK3CA (5%), but not for BRAF. Discordant results between primary tumors and metastases could markedly be reduced by testing the additional tumor samples.Conclusions: Failure of EGFR antibody therapy in patients with wild-type KRAS colorectal cancer may result from activating BRAF or PIK3CA mutations and false-negative sequencing results caused by intratumoral heterogeneity. Due to the particularly high rates of heterogeneity between primary tumors and lymph node metastases, the latter are least suitable for diagnostic mutation analysis. Clin Cancer Res; 16(3); 790-9. (C) 2010 AACR.