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A let-7 microRNA binding site polymorphism in the KRAS 3′UTR is associated with increased risk and reduced survival for gallbladder cancer in North Indian population

  • Original Article – Clinical Oncology
  • Published:
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Abstract

Purpose

Gallbladder cancer is a lethal malignancy of hepato-biliary system with high incidence in North India, especially along gangetic plain. The let-7 microRNAs play a key role in regulating KRAS expression and a polymorphism in 3′ untranslated region (rs61764370, T/G) of KRAS leads to its higher expression. This polymorphism is known to be associated with increased risk and prognosis of various cancers but its association with gallbladder cancer has not been evaluated. To address this research question, we evaluated whether rs61764370 variant is associated with gallbladder cancer susceptibility and clinical outcomes.

Methods

In present case–control study, we enrolled 541 patients with gallbladder malignancy and 307 controls. Genomic DNA was obtained from peripheral blood and genotyping was performed using Taqman allelic discrimination assay.

Results

Heterozygous (TG) individuals are at a significant higher risk for GBC as compared with wild genotype (TT) (p = 0.007, odds ratio = 2.56, 95 % CI 1.27–5.18). At allelic level, allele G has significant higher risk for GBC as compared with T allele (p = 0.008, odds ratio = 2.5, 95 % CI 1.25–5.01). Survival analysis reveals decrease in overall survival for heterozygous genotype (p < 0.0001, hazard ratio = 3.42, 95 % CI 1.21–4.20). Also, significant decrease in overall survival was observed for patient carrying allele G (p < 0.0001, HR = 2.89, 95 % CI 1.21–4.20) as compared with allele C.

Conclusions

We conclude that KRAS rs61764370 polymorphism is significantly associated with risk and prognosis of gallbladder malignancy in this endemic belt.

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References

  • Caiola E, Rulli E, Fruscio R, Buda A, Broggini M, Marabese M (2012) KRas-LCS6 polymorphism does not impact on outcomes in ovarian cancer. Am J Cancer Res 2(3):298–308

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cerne JZ, Stegel V, Gersak K, Novakovic S (2012) KRAS rs61764370 is associated with HER2-overexpressed and poorly-differentiated breast cancer in hormone replacement therapy users: a case control study. BMC Cancer 12:105. doi:10.1186/1471-2407-12-105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, Muller RU, Straka E, Su L, Burki EA, Crowell RE, Patel R, Kulkarni T, Homer R, Zelterman D, Kidd KK, Zhu Y, Christiani DC, Belinsky SA, Slack FJ, Weidhaas JB (2008) A SNP in a let-7 microRNA complementary site in the KRAS 3′ untranslated region increases non-small cell lung cancer risk. Cancer Res 68(20):8535–8540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Christensen BC, Moyer BJ, Avissar M, Ouellet LG, Plaza SL, McClean MD, Marsit CJ, Kelsey KT (2009) A let-7 microRNA-binding site polymorphism in the KRAS 3′ UTR is associated with reduced survival in oral cancers. Carcinogenesis 30(6):1003–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cipollini M, Landi S, Gemignani F (2014) MicroRNA binding site polymorphisms as biomarkers in cancer management and research. Pharmgenomics Personal Med 7:173–191

    Google Scholar 

  • Dai Q, Wei HL, Huang J, Zhou TJ, Chai L, Yang ZH (2015) KRAS polymorphisms are associated with survival of CRC in Chinese population. Tumour Biol 37(4):4727–4734

    Article  PubMed  Google Scholar 

  • Dhir V, Mohandas KM (1999) Epidemiology of digestive tract cancers in India IV. Gall bladder and pancreas. Indian J Gastroenterol 18(1):24–28

    CAS  PubMed  Google Scholar 

  • Dutta U (2012) Gallbladder cancer: can newer insights improve the outcome? J Gastroenterol Hepatol 27(4):642–653

    Article  PubMed  Google Scholar 

  • Ganzinelli M, Rulli E, Caiola E, Chiara Garassino M, Broggini M, Copreni E, Piva S, Longo F, Labianca R, Bareggi C, Agnese Fabbri M, Martelli O, Fagnani D, Cristina Locatelli M, Bertolini A, Valmadre G, Pavese Calcagno A, Giuseppa Sarobba M, Marabese M (2015) Role of KRAS-LCS6 polymorphism in advanced NSCLC patients treated with erlotinib or docetaxel in second line treatment (TAILOR). Sci Rep 5:16331. doi:10.1038/srep16331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta S, Kori C, Kumar V, Misra S, Akhtar N (2016) Epidemiological study of gallbladder cancer patients from North Indian Gangetic Planes—a high-volume centre’s experience. J Gastrointest Cancer 47(1):27–35

    Article  PubMed  Google Scholar 

  • Hollestelle A, Pelletier C, Hooning M, Crepin E, Schutte M, Look M, Collee JM, Nieuwlaat A, Dorssers LC, Seynaeve C, Aulchenko YS, Martens JW, van den Ouweland AM, Weidhaas JB (2011) Prevalence of the variant allele rs61764370 T>G in the 3′UTR of KRAS among Dutch BRCA1, BRCA2 and non-BRCA1/BRCA2 breast cancer families. Breast Cancer Res Treat 128(1):79–84

    Article  PubMed  Google Scholar 

  • Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ (2005) RAS is regulated by the let-7 microRNA family. Cell 120(5):635–647

    Article  CAS  PubMed  Google Scholar 

  • Kazmi HR, Chandra A, Baghel K, Singh A, Nigam J, Parmar D, Mahdi AA, Goel SK, Kumar S (2014) Differential expression of cholecystokinin A receptor in gallbladder cancer in the young and elderly suggests two subsets of the same disease? Biomed Res Int 2014:625695

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim M, Slack FJ (2014) MicroRNA-mediated regulation of KRAS in cancer. J Hematol Oncol 7:84. doi:10.1186/s13045-014-0084-2

    Article  PubMed  PubMed Central  Google Scholar 

  • Manoharan N, Tyagi BB, Raina V (2010) Cancer incidences in rural Delhi—2004-05. Asian Pac J Cancer Prev 11(1):73–77

    CAS  PubMed  Google Scholar 

  • Nelson HH, Christensen BC, Plaza SL, Wiencke JK, Marsit CJ, Kelsey KT (2010) KRAS mutation, KRAS-LCS6 polymorphism, and non-small cell lung cancer. Lung Cancer 69(1):51–53

    Article  CAS  PubMed  Google Scholar 

  • Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Consortium of Modifiers of BRCA1 and BRCA2, Hollestelle A, van der Baan FH, Berchuck A, Johnatty SE, Aben KK, Agnarsson BA et al (2016) No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer. Gynecol Oncol 141(2):386–401

    Article  Google Scholar 

  • Paranjape T, Heneghan H, Lindner R, Keane FK, Hoffman A, Hollestelle A, Dorairaj J, Geyda K, Pelletier C, Nallur S, Martens JW, Hooning MJ, Kerin M, Zelterman D, Zhu Y, Tuck D, Harris L, Miller N, Slack F, Weidhaas J (2011) A 3′-untranslated region KRAS variant and triple-negative breast cancer: a case-control and genetic analysis. Lancet Oncol 12(4):377–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pelletier C, Weidhaas JB (2010) MicroRNA binding site polymorphisms as biomarkers of cancer risk. Expert Rev Mol Diagn 10(6):817–829

    Article  CAS  PubMed  Google Scholar 

  • Pilarski R, Patel DA, Weitzel J, McVeigh T, Dorairaj JJ, Heneghan HM, Miller N, Weidhaas JB, Kerin MJ, McKenna M, Wu X, Hildebrandt M, Zelterman D, Sand S, Shulman LP (2012) The KRAS-variant is associated with risk of developing double primary breast and ovarian cancer. PLoS ONE 7(5):e37891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ratner E, Lu L, Boeke M, Barnett R, Nallur S, Chin LJ, Pelletier C, Blitzblau R, Tassi R, Paranjape T, Hui P, Godwin AK, Yu H, Risch H, Rutherford T, Schwartz P, Santin A, Matloff E, Zelterman D, Slack FJ, Weidhaas JB (2010) A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk. Cancer Res 70(16):6509–6515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sebio A, Paré L, Páez D, Salazar J, González A, Sala N, del Río E, Martín-Richard M, Tobeña M, Barnadas A, Baiget M (2013) The LCS6 polymorphism in the binding site of let-7 microRNA to the KRAS 3′-untranslated region: its role in the efficacy of anti-EGFR-based therapy in metastatic colorectal cancer patients. Pharmacogenet Genom 23(3):142–147

    Article  CAS  Google Scholar 

  • Shaffer EA (2008) Gallbladder cancer: the basics. Gastroenterol Hepatol (NY) 4(10):737–741

    Google Scholar 

  • Yadav A, Gupta A, Yadav S, Rastogi N, Agrawal S, Kumar A, Kumar V, Misra S, Mittal B (2015) Association of Wnt signaling pathway genetic variants in gallbladder cancer susceptibility and survival. Tumour Biol 37(6):8083–8095

    Article  PubMed  Google Scholar 

  • Zhu AX, Hong TS, Hezel AF, Kooby DA (2010) Current management of gallbladder carcinoma. Oncologist 15(2):168–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors are thankful to the Council of Science and Technology, Government of Uttar Pradesh, Lucknow, India for financially supporting the study (Grant No. CST/SERPD/D-3429). Hasan Raza Kazmi is thankful to Indian Council of Medical Research, Government of India, New Delhi, India for providing fellowship (Grant No. 3/2/2/60/2011/NCDIII).

Funding

The study was funded by Council of Science and Technology, Government of Uttar Pradesh, India (Grant No. CST/SERPD/D-3429) and Indian Council of Medical Research, Government of India, India (Grant No. 3/2/2/60/2011/NCDIII).

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Author notes

  1. Hasan Raza Kazmi

    Present address: Department of Molecular and Human Genetics, Banaras Hindu University, Varanasi, 221005, India

Authors and Affiliations

  1. Department of Surgical Gastroenterology, King George’s Medical University, Lucknow, 226003, India

    Hasan Raza Kazmi, Abhijit Chandra, Saket Kumar, Jaya Nigam & Meenu Srivastava

  2. Cell and Molecular Biology Department, Aurigene Discovery Technologies Limited, Bangalore, 560095, India

    Leena Khare Satyam

  3. Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, 226003, India

    Annapurna Gupta & Balraj Mittal

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  1. Hasan Raza Kazmi
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Correspondence to Abhijit Chandra.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Kazmi, H.R., Chandra, A., Kumar, S. et al. A let-7 microRNA binding site polymorphism in the KRAS 3′UTR is associated with increased risk and reduced survival for gallbladder cancer in North Indian population. J Cancer Res Clin Oncol 142, 2577–2583 (2016). https://doi.org/10.1007/s00432-016-2254-9

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  • DOI: https://doi.org/10.1007/s00432-016-2254-9

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