Comparative Genomic Analysis of Primary Versus Metastatic Colorectal Carcinomas
Comparative Genomic Analysis of Primary Versus Metastatic Colorectal Carcinomas
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DOI：
10.1200/jco.2011.38.2994
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发表时间：
2012-08-20
影响因子：
45.3
通讯作者：
Solit, David B.
中科院分区：
文献类型：
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作者：
Vakiani, Efsevia;Janakiraman, Manickam;Solit, David B.
目的利用来自原发灶和转移灶的未配对和配对标本，比较原发结直肠癌和转移性结直肠癌的突变和拷贝数分布。队列包括84名患者，其中84名患者既有原发部位的肿瘤组织，也有转移部位的肿瘤组织，31名患者有两对转移瘤。分析了肿瘤中KRAS、NRAS、BRAF、PIK3CA和TP53基因的突变，通过分析福尔马林固定的石蜡包埋组织和/或454测序，进一步研究了配对样本之间的不一致结果。结果转移性肿瘤中TP53基因突变的发生率显著高于原发灶(分别为53.1%和30.3%；P<0.01)，而BRAF基因突变的发生率显著低于原发灶(分别为1.9%和7.7%；P=0.01)。配对的突变状态高度一致(所有五个基因的>；90%一致)。对阵列CGH数据的克隆性分析表明，多个原发结直肠癌或治疗相关效应可能是原发肿瘤和转移瘤之间突变和/或拷贝数分布差异的原因。结论对于大多数患者来说，对于确定RAS、BRAF和PIK3CA突变状态，原发结直肠癌的基因分型就足够了。有多原发癌病史的患者应考虑对转移部位进行活检，对于接受过放射或细胞毒性化疗的间歇性治疗的患者，应考虑对TP53患者进行转移部位活检。
PurposeTo compare the mutational and copy number profiles of primary and metastatic colorectal carcinomas (CRCs) using both unpaired and paired samples derived from primary and metastatic disease sites.Patients and MethodsWe performed a multiplatform genomic analysis of 736 fresh frozen CRC tumors from 613 patients. The cohort included 84 patients in whom tumor tissue from both primary and metastatic sites was available and 31 patients with pairs of metastases. Tumors were analyzed for mutations in the KRAS, NRAS, BRAF, PIK3CA, and TP53 genes, with discordant results between paired samples further investigated by analyzing formalin-fixed, paraffin-embedded tissue and/or by 454 sequencing. Copy number aberrations in primary tumors and matched metastases were analyzed by comparative genomic hybridization (CGH).ResultsTP53 mutations were more frequent in metastatic versus primary tumors (53.1% v 30.3%, respectively; P < .001), whereas BRAF mutations were significantly less frequent (1.9% v 7.7%, respectively; P = .01). The mutational status of the matched pairs was highly concordant (> 90% concordance for all five genes). Clonality analysis of array CGH data suggested that multiple CRC primary tumors or treatment-associated effects were likely etiologies for mutational and/or copy number profile differences between primary tumors and metastases.ConclusionFor determining RAS, BRAF, and PIK3CA mutational status, genotyping of the primary CRC is sufficient for most patients. Biopsy of a metastatic site should be considered in patients with a history of multiple primary carcinomas and in the case of TP53 for patients who have undergone interval treatment with radiation or cytotoxic chemotherapies.