Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers.
Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers.
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DOI：
10.1158/2159-8290.cd-13-0103
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发表时间：
2013-07
期刊：
影响因子：
28.2
通讯作者：
Grandis JR
中科院分区：
文献类型：
--
作者：
Lui VW;Hedberg ML;Li H;Vangara BS;Pendleton K;Zeng Y;Lu Y;Zhang Q;Du Y;Gilbert BR;Freilino M;Sauerwein S;Peyser ND;Xiao D;Diergaarde B;Wang L;Chiosea S;Seethala R;Johnson JT;Kim S;Duvvuri U;Ferris RL;Romkes M;Nukui T;Kwok-Shing Ng P;Garraway LA;Hammerman PS;Mills GB;Grandis JR
基因组研究结果强调了头颈部鳞状细胞癌（HNSCC）的异质性。鉴定预测治疗反应的突变将是一个重大进展。我们在一个大型的HNSCC队列中确定了突变改变的、可靶向的促有丝分裂途径。来自151个肿瘤的全外显子组测序数据的分析显示PI 3 K途径是最常突变的致癌途径（30.5%）。PI 3 K通路突变的HNSCC肿瘤在已知的癌症基因中具有显著更高的突变率。在HPV阳性肿瘤的子集中，PIK 3CA或PIK 3R 1是唯一突变的癌症基因。引人注目的是，所有具有多个PI 3 K通路基因的并发突变的肿瘤都是晚期的（IV期），这暗示了HNSCC进展中协调的PI 3 K通路畸变。与PIK 3CA野生型肿瘤移植物相比，具有典型和非典型PIK 3CA突变的患者来源的肿瘤移植物对m-TOR/PI 3 K抑制剂（BEZ-235）敏感。这些结果表明，PI 3 K通路突变可作为治疗选择的预测性生物标志物。
Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the PI3K pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway-mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of HPV-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and non-canonical PIK3CA mutations were sensitive to an m-TOR/PI3K inhibitor (BEZ-235) in contrast to PIK3CA wildtype tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.