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Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes

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Abstract

Purpose

The phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT/mTOR and Ras/Raf/MEK/ERK pathways have been implicated in endometrial tumorigenesis. In this candidate pathway analysis, we investigated associations between genetic variations in these two pathways and both risk and clinical outcomes of endometrial cancer.

Methods

We genotyped a total of 48 potentially functional SNPs in 11 key genes (AKT1, AKT2, AKT3, BRAF, FRAP1, KRAS, PDPK1, PIK3CA, PIK3CB, PIK3R1, and PTEN) with the Sequenom genotyping platform in 115 endometrial cancer patients and 230 cancer-free women to evaluate their associations with risk, survival, and recurrence of endometrial cancer.

Results

We found the following: (1) PIK3CA rs6443624 and rs9838411 variants either borderline or significantly decreased risk of endometrial cancer in a dominant model (adjusted odds ratio [OR], 0.62; 95% CI, 0.39–1.00 and 0.59; 95% CI, 0.36–0.95, respectively). Furthermore, there was a statistically significant multiplicative interaction (P int = 0.036) between these two loci in risk of endometrial cancer. In contrast, the AKT1 rs2498801 genotype significantly increased risk of endometrial cancer (adjusted OR, 1.94; 95% CI, 1.02–3.67 in a recessive model). (2) In Cox regression analyses, three SNPs (PIK3R1 rs1862162, AKT2 rs892119, and PIK3CA rs2699887) showed significant associations with survival of endometrial cancer patients. (3) KRAS rs7312175 and PIK3CA rs6443624 had significant effects on recurrence of endometrial cancer individually and combined in a locus–dosage manner (adjusted P trend = 0.003).

Conclusion

These results suggest that common genetic variations in these pathways may modulate risk and clinical outcomes of endometrial cancer. Further replication and functional studies are needed to confirm these findings.

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References

  • Abal M, Planaguma J, Gil-Moreno A, Monge M, Gonzalez M, Baro T, Garcia A, Castellvi J, Ramon YCS, Xercavins J, Alameda F, Reventos J (2006) Molecular pathology of endometrial carcinoma: transcriptional signature in endometrioid tumors. Histol Histopathol 21(2):197–204

    PubMed  CAS  Google Scholar 

  • Abrams SL, Steelman LS, Shelton JG, Wong EW, Chappell WH, Basecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA (2010) The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle 9(9):1781–1791

    Article  PubMed  CAS  Google Scholar 

  • Akhmedkhanov A, Zeleniuch-Jacquotte A, Toniolo P (2001) Role of exogenous and endogenous hormones in endometrial cancer: review of the evidence and research perspectives. Ann N Y Acad Sci 943:296–315

    Google Scholar 

  • Almind K, Delahaye L, Hansen T, Van Obberghen E, Pedersen O, Kahn CR (2002) Characterization of the Met326Ile variant of phosphatidylinositol 3-kinase p85alpha. Proc Natl Acad Sci USA 99(4):2124–2128

    Article  PubMed  CAS  Google Scholar 

  • Antico-Arciuch VG, Dima M, Liao XH, Refetoff S, Di Cristofano A (2010) Cross-talk between PI3K and estrogen in the mouse thyroid predisposes to the development of follicular carcinomas with a higher incidence in females. Oncogene

  • Arcaro A, Guerreiro AS (2007) The phosphoinositide 3-kinase pathway in human cancer: genetic alterations and therapeutic implications. Curr Genomics 8(5):271–306

    Article  PubMed  CAS  Google Scholar 

  • Bellacosa A, Kumar CC, Di Cristofano A, Testa JR (2005) Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 94:29–86

    Google Scholar 

  • Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai MH, Blanchard KL, Thomas JE (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448(7152):439–444

    Article  PubMed  CAS  Google Scholar 

  • Catasus L, Gallardo A, Cuatrecasas M, Prat J (2008) PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters. Mod Pathol 21(2):131–139

    PubMed  CAS  Google Scholar 

  • Catasus L, Gallardo A, Cuatrecasas M, Prat J (2009) Concomitant PI3K-AKT and p53 alterations in endometrial carcinomas are associated with poor prognosis. Mod Pathol 22(4):522–529

    Article  PubMed  CAS  Google Scholar 

  • Chen JS, Wang Q, Fu XH, Huang XH, Chen XL, Cao LQ, Chen LZ, Tan HX, Li W, Bi J, Zhang LJ (2009) Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9. Hepatol Res 39(2):177–186

    Article  PubMed  CAS  Google Scholar 

  • Hayes MP, Wang H, Espinal-Witter R, Douglas W, Solomon GJ, Baker SJ, Ellenson LH (2006) PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clin Cancer Res 12(20 Pt 1):5932–5935

    Google Scholar 

  • Hildebrandt MA, Yang H, Hung MC, Izzo JG, Huang M, Lin J, Ajani JA, Wu X (2009) Genetic variations in the PI3K/PTEN/AKT/mTOR pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy. J Clin Oncol 27(6):857–871

    Article  PubMed  CAS  Google Scholar 

  • Kirkegaard T, Witton CJ, McGlynn LM, Tovey SM, Dunne B, Lyon A, Bartlett JM (2005) AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 207(2):139–146

    Article  PubMed  CAS  Google Scholar 

  • Konstantinova D, Kaneva R, Dimitrov R, Savov A, Ivanov S, Dyankova T, Kremensky I, Mitev V (2010) Rare mutations in the PIK3CA gene contribute to aggressive endometrial cancer. DNA Cell Biol 29(2):65–70

    Article  PubMed  CAS  Google Scholar 

  • Lacey JV Jr, Yang H, Gaudet MM, Dunning A, Lissowska J, Sherman ME, Peplonska B, Brinton LA, Healey CS, Ahmed S, Pharoah P, Easton D, Chanock S, Garcia-Closas M (2011) Endometrial cancer and genetic variation in PTEN, PIK3CA, AKT1, MLH1, and MSH2 within a population-based case-control study. Gynecol Oncol 120(2):167–173

    Article  PubMed  CAS  Google Scholar 

  • Lax SF (2007) Molecular genetic changes in epithelial, stromal and mixed neoplasms of the endometrium. Pathology 39(1):46–54

    Article  PubMed  CAS  Google Scholar 

  • Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275(5308):1943–1947

    Article  PubMed  CAS  Google Scholar 

  • Li L, Plummer SJ, Thompson CL, Tucker TC, Casey G (2008) Association between phosphatidylinositol 3-kinase regulatory subunit p85alpha Met326Ile genetic polymorphism and colon cancer risk. Clin Cancer Res 14(3):633–637

    Article  PubMed  CAS  Google Scholar 

  • Luo J, Cantley LC (2005) The negative regulation of phosphoinositide 3-kinase signaling by p85 and it’s implication in cancer. Cell Cycle 4(10):1309–1312

    Article  PubMed  CAS  Google Scholar 

  • Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, Harris PL, Haserlat SM, Supko JG, Haluska FG, Louis DN, Christiani DC, Settleman J, Haber DA (2004) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350(21):2129–2139

    Article  PubMed  CAS  Google Scholar 

  • Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274

    Article  PubMed  CAS  Google Scholar 

  • McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, Navolanic PM, Terrian DM, Franklin RA, D’Assoro AB, Salisbury JL, Mazzarino MC, Stivala F, Libra M (2006) Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 46:249–279

    Google Scholar 

  • Minaguchi T, Yoshikawa H, Oda K, Ishino T, Yasugi T, Onda T, Nakagawa S, Matsumoto K, Kawana K, Taketani Y (2001) PTEN mutation located only outside exons 5, 6, and 7 is an independent predictor of favorable survival in endometrial carcinomas. Clin Cancer Res 7(9):2636–2642

    PubMed  CAS  Google Scholar 

  • Mizuuchi H, Nasim S, Kudo R, Silverberg SG, Greenhouse S, Garrett CT (1992) Clinical implications of K-ras mutations in malignant epithelial tumors of the endometrium. Cancer Res 52(10):2777–2781

    PubMed  CAS  Google Scholar 

  • Mori N, Kyo S, Sakaguchi J, Mizumoto Y, Ohno S, Maida Y, Hashimoto M, Takakura M, Inoue M (2007) Concomitant activation of AKT with extracellular-regulated kinase 1/2 occurs independently of PTEN or PIK3CA mutations in endometrial cancer and may be associated with favorable prognosiss. Cancer Sci 98(12):1881–1888

    Article  PubMed  CAS  Google Scholar 

  • Murayama-Hosokawa S, Oda K, Nakagawa S, Ishikawa S, Yamamoto S, Shoji K, Ikeda Y, Uehara Y, Fukayama M, McCormick F, Yano T, Taketani Y, Aburatani H (2010) Genome-wide single-nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil frequent chromosomal imbalances involved in the PI3-kinase pathway. Oncogene 29(13):1897–1908

    Article  PubMed  CAS  Google Scholar 

  • Nicholson KM, Anderson NG (2002) The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 14(5):381–395

    Article  PubMed  CAS  Google Scholar 

  • Ninomiya Y, Kato K, Takahashi A, Ueoka Y, Kamikihara T, Arima T, Matsuda T, Kato H, Nishida J, Wake N (2004) K-Ras and H-Ras activation promote distinct consequences on endometrial cell survival. Cancer Res 64(8):2759–2765

    Article  PubMed  CAS  Google Scholar 

  • Oehler MK, Brand A, Wain GV (2003) Molecular genetics and endometrial cancer. J Br Menopause Soc 9(1):27–31

    Article  PubMed  Google Scholar 

  • Paynter RA, Hankinson SE, Colditz GA, Kraft P, Hunter DJ, De Vivo I (2005) CYP19 (aromatase) haplotypes and endometrial cancer risk. Int J Cancer 116(2):267–274

    Article  PubMed  CAS  Google Scholar 

  • Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH, Thomas RJ, Phillips WA (2001) The phosphatidylinositol 3′-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 61(20):7426–7429

    PubMed  CAS  Google Scholar 

  • Pu X, Hildebrandt MA, Lu C, Lin J, Stewart DJ, Ye Y, Gu J, Spitz MR, Wu X (2010) PI3K/PTEN/AKT/mTOR pathway genetic variation predicts toxicity and distant progression in lung cancer patients receiving platinum-based chemotherapy. Lung Cancer

  • Quaye L, Song H, Ramus SJ, Gentry-Maharaj A, Hogdall E, DiCioccio RA, McGuire V, Wu AH, Van Den Berg DJ, Pike MC, Wozniak E, Doherty JA, Rossing MA, Ness RB, Moysich KB, Hogdall C, Blaakaer J, Easton DF, Ponder BA, Jacobs IJ, Menon U, Whittemore AS, Kruger-Kjaer S, Pearce CL, Pharoah PD, Gayther SA (2009) Tagging single-nucleotide polymorphisms in candidate oncogenes and susceptibility to ovarian cancer. Br J Cancer 100(6):993–1001

    Article  PubMed  CAS  Google Scholar 

  • Rudd ML, Price JC, Fogoros S, Godwin AK, Sgroi DC, Merino MJ, Bell DW (2011) A unique spectrum of somatic PIK3CA (p110{alpha}) mutations within primary endometrial carcinomas. Clin Cancer Res 17(6):1331–1340

    Article  PubMed  CAS  Google Scholar 

  • Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670):554

    Article  PubMed  CAS  Google Scholar 

  • Siegel R, Ward E, Brawley O, Jemal A (2011) Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 61(4):212–236

    Article  PubMed  Google Scholar 

  • Steelman LS, Stadelman KM, Chappell WH, Horn S, Basecke J, Cervello M, Nicoletti F, Libra M, Stivala F, Martelli AM, McCubrey JA (2008) Akt as a therapeutic target in cancer. Expert Opin Ther Targets 12(9):1139–1165

    Article  PubMed  CAS  Google Scholar 

  • Steelman LS, Abrams SL, Shelton JG, Chappell WH, Basecke J, Stivala F, Donia M, Nicoletti F, Libra M, Martelli AM, McCubrey JA (2010) Dominant roles of the Raf/MEK/ERK pathway in cell cycle progression, prevention of apoptosis and sensitivity to chemotherapeutic drugs. Cell Cycle 9:8

    Google Scholar 

  • Testa JR, Bellacosa A (2001) AKT plays a central role in tumorigenesis. Proc Natl Acad Sci USA 98(20):10983–10985

    Article  PubMed  CAS  Google Scholar 

  • Treloar SA, Zhao ZZ, Le L, Zondervan KT, Martin NG, Kennedy S, Nyholt DR, Montgomery GW (2007) Variants in EMX2 and PTEN do not contribute to risk of endometriosis. Mol Hum Reprod 13(8):587–594

    Article  PubMed  CAS  Google Scholar 

  • Urick ME, Rudd ML, Godwin AK, Sgroi DC, Merino M, Bell DW (2011) PIK3R1 (p85-alpha/p85{alpha}) is somatically mutated at high frequency in primary endometrial cancer. Cancer Res

  • Wang T, Ho G, Ye K, Strickler H, Elston RC (2009) A partial least-square approach for modeling gene–gene and gene-environment interactions when multiple markers are genotyped. Genet Epidemiol 33(1):6–15

    Article  PubMed  CAS  Google Scholar 

  • Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27(41):5497–5510

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported in part by National Institute of Health (NIH) grants ES11740 and CA131274 (Q. Wei), Stand Up to Cancer/American Association for Cancer Research Dream Team Translational Cancer Research Grant SU2C-AACR—DT0209, the Uterine SPORE CA098258 and the Kleberg Center For Molecular Markers (G. B. Mills), CA127219 (M. R. Spitz), and a Cancer Center Core grant from the National Cancer Institute to M. D. Anderson (CA016672). We would like to thank Joseph Celestino, Yang Li, Min Zhao, and Kejing Xu for preparing the DNA samples.

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Authors and Affiliations

  1. Department of Epidemiology, Unit 1365, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA

    Li-E Wang, Hongxia Ma, Ming Yin, Hongliang Liu, Margaret R. Spitz & Qingyi Wei

  2. Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Katherine S. Hale, Jie Li, Xuesong Li & Gordon B. Mills

  3. Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Larissa A. Meyer, Karen H. Lu & Bryan T. Hennessy

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  1. Li-E Wang
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  2. Hongxia Ma
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Correspondence to Li-E Wang.

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Wang, LE., Ma, H., Hale, K.S. et al. Roles of genetic variants in the PI3K and RAS/RAF pathways in susceptibility to endometrial cancer and clinical outcomes. J Cancer Res Clin Oncol 138, 377–385 (2012). https://doi.org/10.1007/s00432-011-1103-0

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  • DOI: https://doi.org/10.1007/s00432-011-1103-0

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