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Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

ABSTRACT: While mutations in the KRAS oncogene are among 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 the 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 and 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.

SUBMITTER: Schabath MB

PROVIDER: S-EPMC4837098 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

Schabath M B MB Welsh E A EA Fulp W J WJ Chen L L Teer J K JK Thompson Z J ZJ Engel B E BE Xie M M Berglund A E AE Creelan B C BC Antonia S J SJ Gray J E JE Eschrich S A SA Chen D-T DT Cress W D WD Haura E B EB Beg A A AA

Oncogene 20151019 24

While mutations in the KRAS oncogene are among 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 the 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 t ...[more]

PMID: 26477306

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Project description:BackgroundAlthough TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported.MethodsAn integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway.FindingsThe TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy.InterpretationOur study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs.FundingThe study was supported by Key Lab System Project of Guangdong Science and Technology Department - Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU).

Dataset Information

Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

Publications

Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

Similar Datasets

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