Prognostic value of KRAS/TP53/PIK3CA in non‑small cell lung cancer

Zhao,Jiayi; Han,Yiping; Li,Jiamei; Chai,Rong; Bai,Chong

doi:10.3892/ol.2019.10012

Prognostic value of KRAS/TP53/PIK3CA in non‑small cell lung cancer

Authors:
- Jiayi Zhao
- Yiping Han
- Jiamei Li
- Rong Chai
- Chong Bai
View Affiliations

Affiliations: Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R. China, Department of Psychology, Second Military Medical University, Shanghai 200433, P.R. China
Published online on: February 4, 2019 https://doi.org/10.3892/ol.2019.10012
Pages: 3233-3240
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study explored the association between KRAS proto‑oncogene GTPase (KRAS), phosphatidylinositol-4,5-bisphosphate 3‑kinase catalytic subunit α (PIK3CA) and tumor protein p53 (TP53) mutations, and the clinical features and survival prognosis in 50 patients with non‑small cell lung cancer (NSCLC). The most common concurrent single gene mutation was TP53, followed by KRAS and PIK3CA. Co‑existing mutations were found in 17 patients. KRAS, PIK3CA and TP53 mutations were associated with carbohydrate antigen 19‑9 expression, invasive growth, vacuolar signs and margin lobulation on chest CT. The incidence of distant metastasis (bone and adrenal) with KRAS and TP53 mutations was greater than that of local metastasis (pleura). Patients with the wild‑type genes experienced longer progression‑free survival (PFS) times than those with KRAS, TP53, KRAS/TP53 or PIK3CA/TP53 mutations. Patients with KRAS/TP53 or PIK3CA/TP53 mutations experienced shorter PFS times than those with a single KRAS or TP53 mutation. KRAS, PIK3CA and TP53 mutations were associated with distant metastases and a poor prognosis. Patients with NSCLC should receive routine KRAS, PIK3CA and TP53 gene sequencing to determine mutations for the analysis of clinical characteristics and prognosis.

View Figures

View References

1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Zeng H, Zheng R, Guo Y, Zhang S, Zou X, Wang N, Zhang L, Tang J, Chen J, Wei K, et al: Cancer survival in China, 2003–2005: A population-based study. Int J Cancer. 136:1921–1930. 2015. View Article : Google Scholar : PubMed/NCBI
3	Moreira AL and Thornton RH: Personalized medicine for non-small-cell lung cancer: Implications of recent advances in tissue acquisition for molecular and histologic testing. Clin Lung Cancer. 13:334–339. 2012. View Article : Google Scholar : PubMed/NCBI
4	Martin P, Leighl NB, Tsao MS and Shepherd FA: KRAS mutations as prognostic and predictive markers in non-small cell lung cancer. J Thorac Oncol. 8:530–542. 2013. View Article : Google Scholar : PubMed/NCBI
5	Papadimitrakopoulou V: Development of PI3K/AKT/mTOR pathway inhibitors and their application in personalized therapy for non-small-cell lung cancer. J Thorac Oncol. 7:1315–1326. 2012. View Article : Google Scholar : PubMed/NCBI
6	Shepherd FA, Lacas B, Le Teuff G, Hainaut P, Jänne PA, Pignon JP, Le Chevalier T, Seymour L, Douillard JY, Graziano S, et al: Pooled analysis of the prognostic and predictive effects of TP53 comutation status combined with KRAS or EGFR mutation in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy. J Clin Oncol. 35:2018–2027. 2017. View Article : Google Scholar : PubMed/NCBI
7	Detterbeck FC, Boffa DJ, Kim AW and Tanoue LT: The eighth edition lung cancer stage classification. Chest. 151:193–203. 2017. View Article : Google Scholar : PubMed/NCBI
8	Lv W, Wei X, Guo R, Liu Q, Zheng Y, Chang J, Bai T, Li H, Zhang J, Song Z, et al: Noninvasive prenatal testing for Wilson disease by use of circulating single-molecule amplification and resequencing technology (cSMART). Clin Chem. 61:172–181. 2015. View Article : Google Scholar : PubMed/NCBI
9	Watanabe H, Okada M, Kaji Y, Satouchi M, Sato Y, Yamabe Y, Onaya H, Endo M, Sone M and Arai Y: New response evaluation criteria in solid tumours-revised RECIST guideline (version 1.1). Gan To Kagaku Ryoho. 36:2495–2501. 2009.(In Japanese). PubMed/NCBI
10	Tsim S, O'Dowd CA, Milroy R and Davidson S: Staging of non-small cell lung cancer (NSCLC): A review. Respir Med. 104:1767–1774. 2010. View Article : Google Scholar : PubMed/NCBI
11	Cooper WA, O'Toole S, Boyer M, Horvath L and Mahar A: What's new in non-small cell lung cancer for pathologists: The importance of accurate subtyping, EGFR mutations and ALK rearrangements. Pathology. 43:103–115. 2011. View Article : Google Scholar : PubMed/NCBI
12	Mao C, Qiu LX, Liao RY, Du FB, Ding H, Yang WC, Li J and Chen Q: KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: A meta-analysis of 22 studies. Lung Cancer. 69:272–278. 2010. View Article : Google Scholar : PubMed/NCBI
13	Luo W, Wang H, Xu WJ, et al: Analysis of KRAS mutation in patients with non- small cell lung cancer. Guangdong Med J. 35:2025–2028. 2014.(In Chinese).
14	Yi SQ, Zhuang Y, Zhu WD, et al: Analysis of KRAS gene mutations in non-small cell lung cancer. Zhonghua Lin Chuan Yi Shi Za Zhi (Electronic Edition). 7:9111–9115. 2013.(In Chinese).
15	Scheffler M, Bos M, Gardizi M, König K, Michels S, Fassunke J, Heydt C, Künstlinger H, Ihle M, Ueckeroth F, et al: PIK3CA mutations in non-small cell lung cancer (NSCLC): Genetic heterogeneity, prognostic impact and incidence of prior malignancies. Oncotarget. 6:1315–1326. 2015. View Article : Google Scholar : PubMed/NCBI
16	Liang NX, Liu YX, Liu L and Li SQ: Co-mutation of PIK3CA and other oncogenes in patients with non-small cell lung cancer. Med J PUMCH. 6:186–190. 2015.(In Chinese).
17	Huang CL, Taki T, Adachi M, Konishi T, Higashiyama M, Kinoshita M, Hadama T and Miyake M: Mutations of p53 and K-ras genes as prognostic factors for non-small cell lung cancer. Int J Oncol. 12:553–569. 1998.PubMed/NCBI
18	Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R and Ishioka C: Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci USA. 100:8424–8429. 2003. View Article : Google Scholar : PubMed/NCBI
19	Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, Varella-Garcia M, Franklin WA, Aronson SL, Su PF, et al: Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. Jama. 311:1998–2006. 2014. View Article : Google Scholar : PubMed/NCBI
20	Cancer Genome Atlas Research Network: Comprehensive molecular profiling of lung adenocarcinoma. Nature. 511:543–550. 2014. View Article : Google Scholar : PubMed/NCBI
21	Gao J, Chen JQ, Zhang L and Liang ZY: Relationship between EGFR and KRAS mutations and prognosis in Chinese patients with non-small cell lung cancer: A mutation analysis with real-time polymerase chain reaction using scorpion amplification refractory mutation system. Zhonghua Bing Li Xue Za Zhi. 41:652–656. 2012.(In Chinese). PubMed/NCBI
22	Kim HR, Ahn JR, Lee JG, Bang DH, Ha SJ, Hong YK, Kim SM, Nam KC, Rha SY, Soo RA, et al: The impact of cigarette smoking on the frequency of and qualitative differences in KRAS mutations in Korean patients with lung adenocarcinoma. Yonsei Med J. 54:865–874. 2013. View Article : Google Scholar : PubMed/NCBI
23	Li Y, Li Y, Yang T, Wei S, Wang J, Wang M, Wang Y, Zhou Q, Liu H and Chen J: Clinical significance of EML4-ALK fusion gene and association with EGFR and KRAS gene mutations in 208 Chinese patients with non-small cell lung cancer. PLoS One. 8:e520932013. View Article : Google Scholar : PubMed/NCBI
24	Zhang Q, Wang J, Li X, Zhang H, Nong J, Qin N, Zhang X, Wu Y, Yang X, Lv J and Zhang S: Clinical Analysis of 107 NSCLC Patients Harboring KRAS Mutation. Zhongguo Fei Ai Za Zhi. 19:257–262. 2016.(In Chinese). PubMed/NCBI
25	Hu W, Liu Y and Chen J: Concurrent gene alterations with EGFR mutation and treatment efficacy of EGFR-TKIs in Chinese patients with non-small cell lung cancer. Oncotarget. 8:250462017.PubMed/NCBI
26	Korpanty GJ, Graham DM, Vincent MD and Leighl NB: Biomarkers that currently affect clinical practice in lung cancer: EGFR, ALK, MET, ROS-1, and KRAS. Front Oncol. 4:2042014. View Article : Google Scholar : PubMed/NCBI
27	Deben C, Van den Bossche J, Van Der Steen N, Lardon F, Wouters A, de Beeck KO, Hermans C, Jacobs J, Peeters M, Van Camp G, et al: Deep sequencing of the TP53 gene reveals a potential risk allele for non-small cell lung cancer and supports the negative prognostic value of TP53 variants. Tumour Biol. 39:10104283176943272017. View Article : Google Scholar : PubMed/NCBI
28	Vanderlaan PA, Rangachari D, Mockus SM, Spotlow V, Reddi HV, Malcolm J, Huberman MS, Joseph LJ, Kobayashi SS and Costa DB: Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes. Lung Cancer. 106:17–21. 2017. View Article : Google Scholar : PubMed/NCBI
29	Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, Haller A, Lothaire P, Meert AP, Noel S, et al: The role of RAS oncogene in survival of patients with lung cancer: A systematic review of the literature with meta-analysis. Br J Cancer. 92:131–139. 2005. View Article : Google Scholar : PubMed/NCBI
30	Lin EY, Rupani R and Gitlitz BJ: Markers in lung cancer. Springer. (New York, NY). 2013. View Article : Google Scholar
31	Scoccianti C, Vesin A, Martel G, Olivier M, Brambilla E, Timsit JF, Tavecchio L, Brambilla C, Field JK and Hainaut P;: European Early Lung Cancer Consortium: Prognostic value of TP53, KRAS and EGFR mutations in nonsmall cell lung cancer: The EUELC cohort. Eur Respir J. 40:177–184. 2012. View Article : Google Scholar : PubMed/NCBI
32	Ma X, Rousseau V, Sun H, Lantuejoul S, Filipits M, Pirker R, Popper H, Mendiboure J, Vataire AL, Le Chevalier T, et al: Significance of TP53 mutations as predictive markers of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer. Mol Oncol. 8:555–564. 2014. View Article : Google Scholar : PubMed/NCBI
33	Lee SY, Jeon HS, Hwangbo Y, Jeong JY, Park JY, Lee EJ, Jin G, Shin KM, Yoo SS, Lee J, et al: The influence of TP53 mutations on the prognosis of patients with early stage non-small cell lung cancer may depend on the intratumor heterogeneity of the mutations. Mol Carcinog. 54:93–101. 2015. View Article : Google Scholar : PubMed/NCBI
34	Mcgowan M, Hoven AS, Lund-Iversen M, Solberg S, Helland Å, Hirsch FR and Brustugun OT: PIK3CA mutations as prognostic factor in squamous cell lung carcinoma. Lung Cancer. 103:52–57. 2017. View Article : Google Scholar : PubMed/NCBI
35	Kang S, Bader AG and Vogt PK: Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA. 102:802–807. 2005. View Article : Google Scholar : PubMed/NCBI
36	Molina-Vila MA, Bertran-Alamillo J, Gascó A, Mayo-de-las-Casas C, Sánchez-Ronco M, Pujantell-Pastor L, Bonanno L, Favaretto AG, Cardona AF, Vergnenègre A, et al: Nondisruptive p53 mutations are associated with shorter survival in patients with advanced non-small cell lung cancer. Clin Cancer Res. 20:4647–4659. 2014. View Article : Google Scholar : PubMed/NCBI
37	Meng D, Yuan M, Li X, Chen L, Yang J, Zhao X, Ma W and Xin J: Prognostic value of K-RAS mutations in patients with non-small cell lung cancer: A systematic review with meta-analysis. Lung Cancer. 81:1–10. 2013. View Article : Google Scholar : PubMed/NCBI
38	Jao K, Tomasini P, Kamel-Reid S and Tsao MS: Prognostic effect of single versus multiple somatic mutations in non-small cell lung cancer (NSCLC). J Clin Oncol. 33:75212015.