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Tumor Biology

, Volume 37, Issue 6, pp 7785–7796 | Cite as

PTEN polymorphisms contribute to clinical outcomes of advanced lung adenocarcinoma patients treated with platinum-based chemotherapy

  • Yang Yang
  • Wen Xu
  • Di Liu
  • Xi Ding
  • Bo Su
  • Yifeng Sun
  • Wen Gao
Original Article

Abstract

This study aimed to elucidate the impact of PTEN single nucleotide polymorphism (SNP) on clinical outcomes for advanced lung adenocarcinoma (LAC) patients treated with platinum-based chemotherapy. Three functional SNPs (rs11202607 G>A, rs701848 A>G, and rs11202592 G>C) of PTEN gene were genotyped by using DNA from blood samples of 618 advanced LAC patients, and their relationships with clinical outcomes were analyzed. The carriers of homozygous mutant of rs701848 and rs11202592 polymorphisms revealed significantly worse overall survival (OS) than those with heterozygote or wild-type homozygote (18.83 vs. 21.47 vs. 24.37 months, P = 0.034 and 13.40 vs. 19.03 vs. 21.90 months, P = 0.025, respectively). Subgroup analysis revealed that this association was particularly significant in tumor-lymph-node metastasis (TNM) stage III patients. The objective response rates (ORR) and disease control rates (DCR) of patients with genotype AA, AG, and GG in PTEN rs701848 polymorphism were statistically different (24.1 vs 16.6 vs 12.2 %, P = 0.017 and 82.7 vs 76.0 vs 70.2 %, P = 0.029, respectively). Haplotype analysis revealed a protective effect of the haplotype G-A-A (in the order of rs11202592, rs701848, and rs11202607) on chemotherapy efficacy and survival. Taken together, PTEN polymorphisms may contribute to survival and chemotherapy efficacy of advanced LAC patients treated with platinum-based agents.

Keywords

Chemotherapy Lung adenocarcinoma PTEN Platinum Single nucleotide polymorphisms 

Notes

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81572269) and the Science and Technology Commission of Shanghai Municipality (No. 14411950800 and No. 134119a3400).

Compliance with ethical standards

All the subjects signed a consent form, and the study was approved by the ethics committee of Shanghai Pulmonary Hospital.

Conflicts of interest

None

Supplementary material

13277_2015_4651_MOESM1_ESM.docx (18 kb)
Suppl. Table S1 Distribution of PTEN genotypes according to clinical factors (DOCX 17 kb)
13277_2015_4651_MOESM2_ESM.docx (13 kb)
Suppl. Table S2 Linkage disequilibrium (D’ and r2) between SNPs in PTEN (DOCX 12 kb)

References

  1. 1.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  2. 2.
    Pilkington G, Boland A, Brown T, Oyee J, Bagust A, Dickson R. A systematic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer. Thorax. 2015;70:359–67.CrossRefPubMedGoogle Scholar
  3. 3.
    Shi Y, Sun Y. Medical management of lung cancer: experience in China. Thorac Cancer. 2015;6:10–6.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Lee Y, Yoon KA, Joo J, Lee D, Bae K, Han JY, et al. Prognostic implications of genetic variants in advanced non-small cell lung cancer: a genome-wide association study. Carcinogenesis. 2013;34:307–13.CrossRefPubMedGoogle Scholar
  5. 5.
    Giovannetti E, Toffalorio F, De Pas T, Peters GJ. Pharmacogenetics of conventional chemotherapy in non-small-cell lung cancer: a changing landscape? Pharmacogenomics. 2012;13:1073–86.CrossRefPubMedGoogle Scholar
  6. 6.
    Loktionov A. Common gene polymorphisms, cancer progression and prognosis. Cancer Lett. 2004;208:1–33.CrossRefPubMedGoogle Scholar
  7. 7.
    Yin Y, Shen WH. PTEN: a new guardian of the genome. Oncogene. 2008;27:5443–53.CrossRefPubMedGoogle Scholar
  8. 8.
    Cao Q, Ju X, Li P, Meng X, Shao P, Cai H, et al. A functional variant in the MTOR promoter modulates its expression and is associated with renal cell cancer risk. PLoS One. 2012;7:e50302.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Xu X, Chen G, Wu L, Liu L. Association of genetic polymorphisms in PTEN and additional gene-gene interaction with risk of esophageal squamous cell carcinoma in Chinese Han population. Dis Esophagus. 2015. doi: 10.1111/dote.12428.Google Scholar
  10. 10.
    Wang X, Lin Y, Lan F, Yu Y, Ouyang X, Wang X, et al. A GG allele of 3′-side AKT1 SNP is associated with decreased AKT1 activation and better prognosis of gastric cancer. J Cancer Res Clin Oncol. 2014;140:1399–411.CrossRefPubMedGoogle Scholar
  11. 11.
    Zhang X, Chen X, Zhai Y, Cui Y, Cao P, Zhang H, et al. Combined effects of genetic variants of the PTEN, AKT1, MDM2 and p53 genes on the risk of nasopharyngeal carcinoma. PLoS One. 2014;9:e92135.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Jing F, Mao Y, Zhang Z, Li Y, Cai S, Li Q, et al. The association of phosphatase and tensin homolog deleted on chromosome 10 polymorphisms and lifestyle habits with colorectal cancer risk in a Chinese population. Tumor Biol. 2014;35:9233–40.CrossRefGoogle Scholar
  13. 13.
    Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55.CrossRefPubMedGoogle Scholar
  14. 14.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.CrossRefPubMedGoogle Scholar
  15. 15.
    Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–65.CrossRefPubMedGoogle Scholar
  16. 16.
    Stephens M, Smith MJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68:978–89.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Milella M, Falcone I, Conciatori F, Cesta Incani U, Del Curatolo A, Inzerilli N, et al. PTEN: multiple functions in human malignant tumors. Fron Oncol. 2015;5:24.Google Scholar
  18. 18.
    Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997;275:1943–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Soria JC, Lee HY, Lee JI, Wang L, Issa JP, Kemp BL, et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res. 2002;8:1178–84.PubMedGoogle Scholar
  20. 20.
    Lee S, Choi EJ, Jin C, Kim DH. Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol. 2005;97:26–34.CrossRefPubMedGoogle Scholar
  21. 21.
    Forgacs E, Biesterveld EJ, Sekido Y, Fong K, Muneer S, Wistuba II, et al. Mutation analysis of the PTEN/MMAC1 gene in lung cancer. Oncogene. 1998;17:1557–65.CrossRefPubMedGoogle Scholar
  22. 22.
    Marsit CJ, Zheng S, Aldape K, Hinds PW, Nelson HH, Wiencke JK, et al. PTEN expression in non-small-cell lung cancer: evaluating its relation to tumor characteristics, allelic loss, and epigenetic alteration. Hum Pathol. 2005;36:768–76.CrossRefPubMedGoogle Scholar
  23. 23.
    Mignone F, Gissi C, Liuni S, Pesole G. Untranslated regions of mRNAs. Genome Biol. 2002;3:REVIEWS0004.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Conne B, Stutz A, Vassalli JD. The 3 untranslated region of messenger RNA: a molecular ‘hotspot’ for pathology? Nat Med. 2000;6:637–41.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of Thoracic Surgery, Shanghai Chest Hospital, School of MedicineShanghai Jiao-tong UniversityShanghaiChina
  2. 2.Central Laboratory, Shanghai Pulmonary Hospital, School of MedicineTongji UniversityShanghaiChina

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