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Association of the KRAS genotype and clinicopathologic findings of resected non‐small‐cell lung cancer: A pooled analysis of 179 patients

Published:September 16, 2022DOI:https://doi.org/10.1016/j.cancergen.2022.09.004

      Highlights

      • 1.The KRAS p.G12V genotype and solid predominant adenocarcinoma phenotype may be independent predictive factors of a poor clinical course in resected early-stage non-small-cell lung cancers.
      • 2. The most common KRAS genotype was p.G12C, followed by p.G12D, p.G12V and p.G12A.
      • 3. In G12V tumors, the stress response, Rhogtpase activity, and amino acid metabolism were increased, and M phase and cell cycle checkpoint and TCF activation by WNT cascade were observed.
      • 4. G12V tumor showed an increase in the expression of SLC28A2 and an increase in the expression of HLA-A, which is a characteristic of the tumor environment. tumor environment.

      Abstract

      Background

      This study assessed the clinicopathological background of early-stage KRAS-mutated non-small-cell lung cancer and analyzed the biological process of KRAS-mutated tumor using an RNA sequencing procedure.

      Patients and methods

      We used a cohort of consecutive series of 179 surgically resected early-stage non-small-cell lung cancers harboring KRAS mutations and analyzed the clinicopathological features, including the KRAS genotypes, affecting the recurrence-free survival and prognosis. Consequently, we performed RNA sequencing to determine the gene expression profiles of nineteen KRAS-mutated non-small-cell cancers.

      Results

      The most common KRAS genotype was p.G12C (57; 31.8%). A high p-stage (hazard ratio [HR], 4.181; P < 0.0001) and solid predominant adenocarcinoma histology (HR, 2.343; P = 0.0076) were significant independent prognostic factors for the recurrence-free survival. A high p-stage (HR, 3.793; P < 0.0001), solid predominant adenocarcinoma histology (HR, 2.373; P = 0.0147), and KRAS p.G12V genotype (HR, 1.975; P = 0.0407) were significant independent prognostic factors for the overall survival. A gene expression analysis of the two factors revealed the p.G12V genotype to be closer to those of stem cells, and the traits of e an enhanced fatty acid and amino acid metabolism. as well as And a solid predominant phenotype were shown to an acquired a trait that can withstand hypoxia and the effect of prostaglandin-endoperoxide synthase.

      Conclusion

      : The KRAS p.G12V genotype and solid predominant adenocarcinoma phenotype may be independent predictive factors of a poor clinical course in resected early-stage non-small-cell lung cancers, possibly due to the differentiation tendency observed in stem cells, the trait of an enhanced fatty acid and amino acid metabolism, and the effect of prostaglandin-endoperoxide synthase.

      Keywords

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      References

        • Wang M.
        • Herbst R.S.
        • Boshoff C.
        Toward personalized treatment approaches for non-small-cell lung cancer.
        Nat Med. 2021; 27: 1345-1356
        • Prior I.A.
        • Lewis P.D.
        • Mattos C.
        A comprehensive survey of Ras mutations in cancer.
        Cancer Res. 2012; 72: 2457-2467
        • Prior I.A.
        • Hood F.E.
        • Hartley J.L.
        The frequency of ras mutations in cancer.
        Cancer Res. 2020; 80: 2969-2974
        • Reck M.
        • Carbone D.P.
        • Garassino M.
        • Barlesi F.
        Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches.
        Annal Oncol. 2021; 32: 1101-1110
        • Skoulidis F.
        • Li B.T.
        • Dy G.K.
        • et al.
        Sotorasib for lung cancers with KRAS p.G12C mutation.
        N Engl J Med. 2021; 384: 2371-2381
        • Hallin J.
        • Engstrom L.D.
        • Hargis L.
        • et al.
        The KRAS(G12C) Inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-Mutant cancers in mouse models and patients.
        Cancer Discov. 2020; 10: 54-71
        • Awad M.M.
        • Liu S.
        • Rybkin II,
        • et al.
        Acquired resistance to KRAS(G12C) inhibition in cancer.
        N Engl J Med. 2021; 384: 2382-2393
        • Kosaka T.
        • Yatabe Y.
        • Onozato R.
        • Kuwano H.
        • Mitsudomi T.
        Prognostic implication of EGFR, KRAS, and TP53 gene mutations in a large cohort of Japanese patients with surgically treated lung adenocarcinoma.
        J Thorac Oncol. 2009; 4: 22-29
        • Dumenil C.
        • Vieira T.
        • Rouleau E.
        • et al.
        Is there a specific phenotype associated with the different subtypes of KRAS mutations in patients with advanced non-small-cell lung cancers?.
        Lung Cancer. 2015; 90: 561-567
        • Dang A.H.
        • Tran V.U.
        • Tran T.T.
        • et al.
        Actionable mutation profiles of non-small cell lung cancer patients from vietnamese population.
        Sci Rep. 2020; 102707
        • Cai D.
        • Hu C.
        • Li L.
        • et al.
        The prevalence and prognostic value of KRAS co-mutation subtypes in Chinese advanced non-small cell lung cancer patients.
        Cancer Med. 2020; 9: 84-93
        • Ujiie H.
        • Kadota K.
        • Chaft J.E.
        • et al.
        Solid predominant histologic subtype in resected stage I lung adenocarcinoma is an independent predictor of early, extrathoracic, multisite recurrence and of poor postrecurrence survival.
        J Clin Oncol. 2015; 33: 2877-2884
        • Hunter J.C.
        • Manandhar A.
        • Carrasco M.A.
        • Gurbani D.
        • Gondi S.
        • Westover K.D.
        Biochemical and structural analysis of common cancer-associated KRAS mutations.
        Mol Cancer Res. 2015; 13: 1325-1335
        • Skoulidis F.
        • Byers L.A.
        • Diao L.
        • et al.
        Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
        Cancer Discov. 2015; 5: 860-877
        • Galan-Cobo A.
        • Sitthideatphaiboon P.
        • Qu X.
        • et al.
        LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence in KRAS-Mutant lung adenocarcinoma.
        Cancer Res. 2019; 79: 3251-3267
        • Peng Y.F.
        • Mandai K.
        • Nakanishi H.
        • et al.
        Restoration of E-cadherin-based cell-cell adhesion by overexpression of Nectin in HSC-39 cells, a human signet ring cell gastric cancer cell line.
        Oncogene. 2002; 21: 4108-4119
        • Hida T.
        • Yatabe Y.
        • Achiwa H.
        • et al.
        Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas.
        Cancer Res. 1998; 58: 3761-3764
        • Liu J.
        • Yang X.
        • Zhang L.
        • et al.
        Microarray analysis of the expression profile of immune-related gene in rapid recurrence early-stage lung adenocarcinoma.
        J Cancer Res Clin Oncol. 2020; 146: 2299-2310
        • Yuan T.L.
        • Amzallag A.
        • Bagni R.
        • et al.
        Differential effector engagement by oncogenic KRAS.
        Cell Rep. 2018; 22: 1889-1902