Skip to main content

Advertisement

SpringerLink
Log in

Role of novel and GWAS originated PLCE1 genetic variants in susceptibility and prognosis of esophageal cancer patients in northern Indian population

  • Research Article
  • Published:
Tumor Biology

Abstract

Recent genome-wide association studies (GWAS) have identified variants in phospholipase C epsilon1 (PLCE1) as novel susceptibility markers for esophageal squamous cell carcinoma (ESCC) in Chinese population. Although few studies have replicated this findings in other populations, but results are contradictory. So, we aimed to replicate association of two previously reported non-synonymous polymorphisms (rs2274223A>G and rs3765524C>T) from haplotype block 10 and evaluated a novel variant (rs7922612C>T) from haplotype block 2 of PLCE1 with susceptibility and prognosis of ESCC in northern Indian population. The genotyping of PLCE1 variants were performed in 293 histopathologically confirmed incident ESCC cases (including 177 follow-up cases) and 314 age-, gender-, and ethnicity-matched controls using PCR RFLP. All statistical analyses were performed through SPSS version 15.0. Modeling and functional prediction of two non-synonymous variants were carried out using bioinformatics tools. PLCE1 polymorphisms were not associated with susceptibility to ESCC or its clinical phenotypes (tumor location/lymph node metastasis). No interaction with environmental risk factors was found. In silico analysis suggested negligible effect on structure of PLCE1 protein due to PLCE1 rs2274223 (H1927R) and rs3765524 (T1777I) polymorphisms. Survival analysis showed PLCE1 rs7922612CT + TT genotype conferred adverse outcome to ESCC patients. Our study for the first time suggests that GWAS originated PLCE1 variants do not have independent role in susceptibility of ESCC in northern Indian population; however, a novel haplo-tagging SNP rs7922612 may modify survival outcome of ESCC patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Takiar R, Nadayil D, Nandakumar A. Projections of number of cancer cases in India (2010–2020) by cancer groups. Asian Pac J Cancer Prev. 2010;11:1045–9.

    PubMed  Google Scholar 

  2. McCabe ML, Dlamini Z. The molecular mechanisms of oesophageal cancer. Int Immunopharmacol. 2005;5:1113–30.

    Article  CAS  PubMed  Google Scholar 

  3. Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med. 2003;349:2241–52.

    Article  CAS  PubMed  Google Scholar 

  4. Hiyama T, Yoshihara M, Tanaka S, Chayama K. Genetic polymorphisms and esophageal cancer risk. Int J Cancer. 2007;121:1643–58.

    Article  CAS  PubMed  Google Scholar 

  5. Chung CC, Magalhaes WC, Gonzalez-Bosquet J, Chanock SJ. Genome-wide association studies in cancer—current and future directions. Carcinogenesis. 2010;31:111–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Wang LD, Zhou FY, Li XM, Sun LD, Song X, Jin Y, et al. Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54. Nat Genet. 2010;42:759–63.

    Article  CAS  PubMed  Google Scholar 

  7. Abnet CC, Freedman ND, Hu N, Wang Z, Yu K, Shu XO, et al. A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma. Nat Genet. 2010;42:764–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Wu C, Hu Z, He Z, Jia W, Wang F, Zhou Y, et al. Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations. Nat Genet. 2011;43:679–84.

    Article  CAS  PubMed  Google Scholar 

  9. Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, et al. Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet. 2006;38:1397–405.

    Article  CAS  PubMed  Google Scholar 

  10. Rhee SG. Regulation of phosphoinositide-specific phospholipase c. Annu Rev Biochem. 2001;70:281–312.

    Article  CAS  PubMed  Google Scholar 

  11. Bourguignon LY, Gilad E, Brightman A, Diedrich F, Singleton P. Hyaluronan-CD44 interaction with leukemia-associated RhoGEF and epidermal growth factor receptor promotes Rho/Ras co-activation, phospholipase C epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells. J Biol Chem. 2006;281:14026–40.

    Article  CAS  PubMed  Google Scholar 

  12. Gbadegesin R, Hinkes BG, Hoskins BE, Vlangos CN, Heeringa SF, Liu J, et al. Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS). Nephrol Dial Transplant. 2008;23:1291–7.

    Article  CAS  PubMed  Google Scholar 

  13. Wang X, Zhou C, Qiu G, Yang Y, Yan D, Xing T, et al. Phospholipase C epsilon plays a suppressive role in incidence of colorectal cancer. Med Oncol. 2012;29:1051–8.

    Article  CAS  PubMed  Google Scholar 

  14. Bai Y, Edamatsu H, Maeda S, Saito H, Suzuki N, Satoh T, et al. Crucial role of phospholipase Cε in chemical carcinogen-induced skin tumor development. Cancer Res. 2004;64:8808–10.

    Article  CAS  PubMed  Google Scholar 

  15. Li M, Edamatsu H, Kitazawa R, Kitazawa S, Kataoka T. Phospholipase Cε promotes intestinal tumorigenesis of Apc Min/+ mice through augmentation of inflammation and angiogenesis. Carcinogenesis. 2009;30:1424–32.

    Article  CAS  PubMed  Google Scholar 

  16. Ou L, Guo Y, Luo C, Wu X, Zhao Y, Cai X. RNA interference suppressing PLCE1 gene expression decreases invasive power of human bladder cancer T24 cell line. Cancer Genet Cytogenet. 2010;200:110–9.

    Article  CAS  PubMed  Google Scholar 

  17. Luo D, Gao Y, Wang S, Wang M, Wu D, Wang W, et al. Genetic variation in PLCE1 is associated with gastric cancer survival in a Chinese population. J Gastroenterol. 2011;46:1260–6.

    Article  PubMed  Google Scholar 

  18. Jain M, Kumar S, Lal P, Tiwari A, Ghoshal UC, Mittal B. Association of genetic polymorphisms of N-acetyltransferase 2 and susceptibility to esophageal cancer in north Indian population. Cancer Invest. 2007;25:340–6.

    Article  CAS  PubMed  Google Scholar 

  19. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Gauderman WJ, Morrison JM: Quanto 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies. http://hydra.usc.edu/gxe 2006.

  21. Dupont WD, Plummer Jr WD. Power and sample size calculations. A review and computer program. Control Clin Trials. 1990;11:116–28.

    Article  CAS  PubMed  Google Scholar 

  22. Yoo J, Seo B, Kim Y. SNPAnalyzer: a web-based integrated workbench for single-nucleotide polymorphism analysis. Nucleic Acids Res. 2005;33:W483–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Upadhyay R, Jain M, Kumar S, Ghoshal UC, Mittal B. Functional polymorphisms of cyclooxygenase-2 (COX-2) gene and risk for esophageal squmaous cell carcinoma. Mutat Res. 2009;663:52–9.

    Article  CAS  PubMed  Google Scholar 

  24. Carlson JM, Heckerman D, Shani G: Estimating false discovery rates for contingency tables. Microsoft Res. 2009.

  25. Sali A, Potterton L, Yuan F, van Vlijmen H, Karplus M. Evaluation of comparative protein modeling by MODELLER. Proteins. 1995;23:318–26.

    Article  CAS  PubMed  Google Scholar 

  26. Kelley LA, MacCallum RM, Sternberg MJ. Enhanced genome annotation using structural profiles in the program 3D-PSSM. J Mol Biol. 2000;299:499–520.

    Article  CAS  PubMed  Google Scholar 

  27. Morris AL, MacArthur MW, Hutchinson EG, Thornton JM. Stereochemical quality of protein structure coordinates. Proteins. 1992;12:345–64.

    Article  CAS  PubMed  Google Scholar 

  28. Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Jain M, Kumar S, Upadhyay R, Lal P, Tiwari A, Ghoshal UC, et al. Influence of apoptosis (BCL2, FAS), cell cycle (CCND1) and growth factor (EGF, EGFR) genetic polymorphisms on survival outcome: an exploratory study in squamous cell esophageal cancer. Cancer Biol Ther. 2007;6:1553–8.

    Article  CAS  PubMed  Google Scholar 

  31. Bunney TD, Harris R, Gandarillas NL, Josephs MB, Roe SM, Sorli SC, et al. Structural and mechanistic insights into RAS association domains of phospholipase C epsilon. Mol Cell. 2006;21:495–507.

    Article  CAS  PubMed  Google Scholar 

  32. Hu H, Yang J, Sun Y, Yang Y, Qian J, Jin L, et al. Putatively functional PLCE1 variants and susceptibility to esophageal squamous cell carcinoma (ESCC): a case–control study in eastern Chinese populations. Ann Surg Oncol. 2012;19:2403–10.

    Article  PubMed  Google Scholar 

  33. Gu H, Ding G, Zhang W, Liu C, Chen Y, Chen S, et al. Replication study of PLCE1 and C20orf54 polymorphism and risk of esophageal cancer in a Chinese population. Mol Biol Rep. 2012;39:9105–11.

    Article  CAS  PubMed  Google Scholar 

  34. Zhou RM, Li Y, Wang N, Liu BC, Chen ZF, Zuo LF. PLC-ε1 gene polymorphisms significantly enhance the risk of esophageal squamous cell carcinoma in individuals with a family history of upper gastrointestinal cancers. Arch Med Res. 2012;43:578–84.

    Article  CAS  PubMed  Google Scholar 

  35. Palmer AJ, Lochhead P, Hold GL, Rabkin CS, Chow WH, Lissowska J, et al. Genetic variation in C20orf54, PLCE1 and MUC1 and the risk of upper gastrointestinal cancers in Caucasian populations. Eur J Cancer Prev. 2012;21:541–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Bye H, Prescott NJ, Lewis CM, Matejcic M, Moodley L, Robertson B, et al. Distinct genetic association at the PLCE1 locus with oesophageal squamous cell carcinoma in the South African population. Carcinogenesis. 2012;33:2155–61.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Umar M, Upadhyay R, Khurana R, Kumar S, Ghoshal UC, Mittal B. Evaluation of MTHFR677C > T polymorphism in prediction and prognosis of esophageal squamous cell carcinoma: a case-control study in a northern Indian population. Nutr Cancer. 2010;62:743–9.

    Article  CAS  PubMed  Google Scholar 

  38. Upadhyay R, Khurana R, Kumar S, Ghoshal UC, Mittal B. Role of survivin gene promoter polymorphism (−31G>C) in susceptibility and survival of esophageal cancer in northern India. Ann Surg Oncol. 2011;18:880–7.

    Article  PubMed  Google Scholar 

  39. Umar M, Upadhyay R, Kumar S, Ghoshal UC, Mittal B. CASP8–652 6N del and CASP8 IVS12–19G>A gene polymorphisms and susceptibility/prognosis of ESCC: a case control study in northern Indian population. J Surg Oncol. 2011;103:716–23.

    Article  CAS  PubMed  Google Scholar 

  40. van Leeuwen DM, van Agen E, Gottschalk RW, Vlietinck R, Gielen M, van Herwijnen MH, et al. Cigarette smoke-induced differential gene expression in blood cells from monozygotic twin pairs. Carcinogenesis. 2007;28:691–7.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Fellowship grant support from Indian Council of Medical Research (ICMR), New Delhi, is acknowledged. Funders had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in decision to submit the article for publication. The authors also want to acknowledge scholars from School of Telemedicine and Biomedical Informatics, SGPGIMS, for their help in in silico analysis.

Conflicts of interest

None

Author information

Author notes

  1. Meenakshi Umar

    Present address: Division of Endocrinology, Gerontology and Metabolism, Stanford University, Stanford, CA, 94305, USA

  2. Rohit Upadhyay

    Present address: Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha, Qatar

Authors and Affiliations

  1. Department of Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareilly Road, Lucknow, 226014, India

    Meenakshi Umar, Rohit Upadhyay & Balraj Mittal

  2. Department of Radiotherapy, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareilly Road, Lucknow, 226014, India

    Shaleen Kumar

  3. Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareilly Road, Lucknow, 226014, India

    Uday Chand Ghoshal

Authors
  1. Meenakshi Umar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rohit Upadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shaleen Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Uday Chand Ghoshal
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Balraj Mittal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Balraj Mittal.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(GIF 149 kb)

High resolution image (TIFF 1737 kb)

ESM 2

(GIF 138 kb)

High resolution image (TIFF 528 kb)

ESM 3

(DOC 44 kb)

ESM 4

(GIF 70 kb)

High resolution image (TIFF 841 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Umar, M., Upadhyay, R., Kumar, S. et al. Role of novel and GWAS originated PLCE1 genetic variants in susceptibility and prognosis of esophageal cancer patients in northern Indian population. Tumor Biol. 35, 11667–11676 (2014). https://doi.org/10.1007/s13277-014-2458-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-014-2458-z

Keywords

Search

Navigation