Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.
Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.
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DOI：
10.1038/onc.2015.375
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发表时间：
2016-06-16
期刊：
影响因子：
8
通讯作者：
Beg AA
中科院分区：
文献类型：
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作者：
Schabath MB;Welsh EA;Fulp WJ;Chen L;Teer JK;Thompson ZJ;Engel BE;Xie M;Berglund AE;Creelan BC;Antonia SJ;Gray JE;Eschrich SA;Chen DT;Cress WD;Haura EB;Beg AA
虽然KRAS癌基因突变在人类癌症中最为普遍，但针对这些肿瘤的成功治疗方法却很少。kras突变肿瘤生物学的异质性也可能显著影响对治疗的反应。我们假设，STK11和TP53肿瘤抑制因子中共同发生的突变可能是kras突变肿瘤异质性的重要来源。为了解决这个问题，我们利用了来自442名肺腺癌患者的切除肿瘤的大队列数据，包括普遍驱动突变（KRAS， EGFR）和肿瘤抑制突变（STK11和TP53）的注解，基于微阵列的基因表达和临床协变量，包括总生存期（OS）。具体而言，我们确定了STK11和TP53突变对新的KRAS突变相关基因表达特征以及先前定义的肿瘤细胞增殖和免疫监视反应特征的影响。有趣的是，STK11突变，而不是TP53突变，与KRAS突变相关基因的高表达相关。无论KRAS状态如何，TP53和STK11突变也会影响肿瘤生物学，其中TP53与增殖增强密切相关，STK11与免疫监视抑制密切相关。这些发现说明了肿瘤抑制基因突变可能导致kras突变肿瘤生物学异质性的显著不同途径。此外，这些研究指出了基因突变和免疫监视之间的新联系，这可能会影响对免疫治疗的反应。
While mutations in the KRAS oncogene are amongst the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS, EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.