Oncogenic PIK3CA mutations in colorectal cancers and polyps
Oncogenic PIK3CA mutations in colorectal cancers and polyps
复制标题
DOI：
10.1002/ijc.26440
复制
发表时间：
2012-08-15
影响因子：
6.4
通讯作者：
Leggett, Barbara A.
中科院分区：
文献类型：
--
作者：
Whitehall, Vicki L. J.;Rickman, Celestine;Leggett, Barbara A.
致癌性PIK 3CA突变通过激活AKT信号传导以减少细胞凋亡和增加肿瘤侵袭而促成结直肠肿瘤发生。PIK 3CA突变与KRAS突变的协同关联已被认为可增加晚期结直肠癌的AKT信号传导和对抗表皮生长因子受体抑制剂治疗的耐药性，尽管研究一直存在冲突。我们试图通过检查PIK 3CA突变频率与确定的肿瘤发生途径的其他关键分子特征的关系来澄清这一点。通过高分辨率熔解分析在829个结直肠癌样品和426个结直肠息肉中评估PIK 3CA突变。突变与包括患者年龄、性别和肿瘤位置的临床病理学特征以及包括微卫星不稳定性、KRAS和BRAF突变、MGMT甲基化和CpG岛甲基化表型（CIMP）的分子特征独立相关。螺旋（外显子9）和催化（外显子20）结构域突变热点的突变也进行了独立检查。总体而言，PIK 3CA突变与KRAS突变（p < 0.001）、MGMT甲基化（p = 0.007）和CIMP（p < 0.001）正相关。新的外显子特异性关联将外显子9突变与以KRAS突变、MGMT甲基化和CIMP-Low为特征的癌症亚组联系起来，而外显子20突变与锯齿状通路肿瘤的特征（包括BRAF突变、微卫星不稳定性和CIMP-High或Low）联系更紧密。PIK 3CA突变不常见，但仅见于管状绒毛状腺瘤（4/124，3.2%）和1/4（25.0%）伴癌灶的管状绒毛状腺瘤。这些数据提供了深入了解驱动传统与锯齿状途径肿瘤发生的分子事件。
Oncogenic PIK3CA mutations contribute to colorectal tumorigenesis by activating AKT signaling to decrease apoptosis and increase tumor invasion. A synergistic association of PIK3CA mutation with KRAS mutation has been suggested to increase AKT signaling and resistance to antiepidermal growth factor receptor inhibitor therapy for advanced colorectal cancer, although studies have been conflicting. We sought to clarify this by examining PIK3CA mutation frequency in relation to other key molecular features of defined pathways of tumorigenesis. PIK3CA mutation was assessed by high resolution melt analysis in 829 colorectal cancer samples and 426 colorectal polyps. Mutations were independently correlated with clinicopathological features including patient age, sex and tumor location as well as molecular features including microsatellite instability, KRAS and BRAF mutation, MGMT methylation and the CpG Island Methylator Phenotype (CIMP). Mutation of the helical (Exon 9) and catalytic (Exon 20) domain mutation hotspots were also examined independently. Overall, PIK3CA mutation was positively correlated with KRAS mutation (p < 0.001), MGMT methylation (p = 0.007) and CIMP (p < 0.001). Novel, exon-specific associations linked Exon 9 mutations to a subgroup of cancers characterized by KRAS mutation, MGMT methylation and CIMP-Low, whilst Exon 20 mutations were more closely linked to features of serrated pathway tumors including BRAF mutation, microsatellite instability and CIMP-High or Low. PIK3CA mutations were uncommonly, but exclusively, seen in tubulovillous adenomas (4/124, 3.2%) and 1/4 (25.0%) tubulovillous adenomas with a focus of cancer. These data provide insight into the molecular events driving traditional versus serrated pathway tumorigenesis.