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The hTERT-VNTR2-2nd alleles are involved in genomic stability in gastrointestinal cancer

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Abstract

Background

hTERT contains a high density of minisatellites, of which rare alleles of hTERT-VNTR2-2nd have been reported to be associated with prostate cancer. This shows an association between VNTR and cancer, but this repeat sequence is likely to be associated with genomic instability. Therefore, we investigated the effects of hTERT-VNTR2-2nd on gastrointestinal cancer and the relationship between repeated sequence and chromosome instability.

Methods

A case–control study was performed using DNA from 818 cancer-free controls, 539 cases with gastric cancer, 275 cases with colon cancer and 274 cases with rectal cancer. To determine whether minisatellites affect gene expression, expression levels were examined using TERT-reporter vectors in cell lines. In addition, the length of the hTERT-VNTR2-2nd alleles were determined in blood and cancer tissues from 107 gastric cancers, 112 colon cancers and 76 rectal cancers patients to determine whether the repeat sequence was associated with genomic instability during cancer development.

Results

No statistically significant association between hTERT-VNTR2-2nd and risk of gastrointestinal cancer was detected. However, it has been shown that VNTRs inserted into the enhancer region can regulate the expression of TERT in gastrointestinal cancer cells. Moreover, hTERT-VNTR2-2nd was analyzed in matched blood and cancer tissue from patients with gastrointestinal cancer and in seven among 294 subjects, and hTERT-VNTR2-2nd was found to be rearranged.

Conclusions

We suggest that minisatellites are associated with genomic instability in cancer and that the hTERT-VNTRs region may increase hTERT expression in gastrointestinal cancer cells.

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References

  • Ahn EK, Kim WJ, Kwon JA, Choi PJ, Kim WJ, Sunwoo Y, Heo J, Leem SH (2009) Variants of MUC5B minisatellites and the susceptibility of bladder cancer. DNA Cell Biol 28:169–176

    Article  CAS  Google Scholar 

  • Blackburn EH (2000) The end of the (DNA) line. Nat Struct Biol 7:847–850

    Article  CAS  Google Scholar 

  • Blackburn EH (2001) Switching and signaling at the telomere. Cell 106:661–673

    Article  CAS  Google Scholar 

  • Carpentier C, Lejeune J, Gros F, Everhard S, Marie Y, Kaloshi G, Laigle-Donadey F, Hoang-Xuan K, Delattre JY, Sanson M (2007) Association of telomerase gene hTERT polymorphism and malignant gliomas. J Neurooncol 84:249–253

    Article  CAS  Google Scholar 

  • Feng J, Funk W, Wang S, Weinrich S, Avilion A, Chiu C, Adams R, Chang E, Allsopp R, Yu J et al (1995) The RNA component of human telomerase. Science 269:1236–1241

    Article  CAS  Google Scholar 

  • He XL, Qiao Q, Ge NJ, Nan J, Shen SQ, Wang ZZ, Yang YF, Bao GQ (2010) Irradiation-induced telomerase activity and gastric cancer risk: a case-control analysis in a Chinese Han population. BMC Cancer 10:9

    Article  Google Scholar 

  • Ito H, Kyo S, Kanaya T, Takakura M, Inoue M, Namiki M (1998) Expression of human telomerase subunits and correlation with telomerase activity in urothelial cancer. Clin Cancer Res 4:1603–1608

    CAS  PubMed  Google Scholar 

  • Jeong YH, Kim MC, Ahn EK, Seol SY, Do EJ, Choi HJ, Chu IS, Kim WJ, Kim WJ, Sunwoo Y et al (2007) Rare exonic minisatellite alleles in muc2 influence susceptibility to gastric carcinoma. PLoS One 2:10

    Article  Google Scholar 

  • Jiang X-R, Jimenez G, Chang E, Frolkis M, Kusler B, Sage M, Beeche M, Bodnar AG, Wahl GM, Tlsty TD et al (1999) Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype. Nat Genet 21:111–114

    Article  CAS  Google Scholar 

  • Kanaya T, Kyo S, Takakura M, Ito H, Namiki M, Inoue M (1998) hTERT is a critical determinant of telomerase activity in renal-cell carcinoma. Int J Cancer 78:539–543

    Article  CAS  Google Scholar 

  • Kilian A, Bowtell DDL, Abud HE, Hime GR, Venter DJ, Keese PK, Duncan EL, Reddel RR, Jefferson RA (1997) Isolation of a candidate human telomerase catalytic subunit gene, which reveals complex splicing patterns in different cell types. Hum Mol Genet 6:2011–2019

    Article  CAS  Google Scholar 

  • Kim JH, Leem SH, Sunwoo Y, Kouprina N (2003) Separation of long-range human TERT gene haplotypes by transformation-associated recombination cloning in yeast. Oncogene 22:2452–2456

    Article  CAS  Google Scholar 

  • Krontiris TG, DiMartino NA, Colb M, Parkinson DR (1985) Unique allelic restriction fragments of the human Ha-ras locus in leukocyte and tumour DNAs of cancer patients. Nature 313:369–374

    Article  CAS  Google Scholar 

  • Kwon JA, Lee SY, Ahn EK, Seol SY, Kim MC, Kim SJ, Kim SI, Chu IS, Leem SH (2010) Short Rare MUC6 minisatellites-5 alleles influence susceptibility to gastric carcinoma by regulating gene expression. Hum Mutat 31:942–949

    Article  CAS  Google Scholar 

  • Kyo S, Takakura M, Tanaka M, Kanaya T, Inoue M (1998) Telomerase activity in cervical cancer is quantitatively distinct from that in its precursor lesions. Int J Cancer 79:66–70

    Article  CAS  Google Scholar 

  • Kyo S, Kanaya T, Takakura M, Tanaka M, Yamashita A, Inoue H, Inoue M (1999) Expression of human telomerase subunits in ovarian malignant borderline and benign tumors. Int J Cancer 80:804–809

    Article  CAS  Google Scholar 

  • Leem SH, Londono-Vallejo JA, Kim JH, Bui H, Tubacher E, Solomon G, Park JE, Horikawa I, Kouprina N, Barrett JC et al (2002) The human telomerase gene: complete genomic sequence and analysis of tandem repeat polymorphisms in intronic regions. Oncogene 21:769–777

    Article  CAS  Google Scholar 

  • Lengauer C, Kinzler KW, Vogelstein B (1998) Genetic instabilities in human cancers. Nature 396:643–649

    Article  CAS  Google Scholar 

  • Messa C, Russo F, Pricci M, Di Leo A (2000) Epidermal growth factor and 17 beta-estradiol effects on proliferation of a human gastric cancer cell line (AGS). Scand J Gastroenterol 35:753–758

    Article  CAS  Google Scholar 

  • Meyerson M, Counter CM, Eaton EN, Ellisen LW, Steiner P, Caddle SD, Ziaugra L, Beijersbergen RL, Davidoff MJ, Liu Q et al (1997) <em > hEST2 </em > the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90:785–795

    Article  CAS  Google Scholar 

  • Morales CP, Holt SE, Ouellette M, Kaur KJ, Yan Y, Wilson KS, White MA, Wright WE, Shay JW (1999) Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat Genet 21:115–118

    Article  CAS  Google Scholar 

  • Nakamura TM, Morin GB, Chapman KB, Weinrich SL, Andrews WH, Lingner J, Harley CB, Cech TR (1997) Telomerase catalytic subunit homologs from fission yeast and human. Science 277:955–959

    Article  CAS  Google Scholar 

  • Sasaki N, Morisaki T, Hashizume K, Yao T, Tsuneyoshi M, Noshiro H, Nakamura K, Yamanaka T, Uchiyama A, Tanaka M et al (2001) Nuclear factor-kappa B p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res 7:4136–4142

    CAS  PubMed  Google Scholar 

  • Seol SY, Lee SY, Kim YD, Do EJ, Kwon JA, Kim SI, Chu IS, Leem SH (2008) Minisatellite polymorphisms of the SLC6A19: susceptibility in hypertension. Biochem Biophys Res Commun 374:714–719

    Article  CAS  Google Scholar 

  • Shay JW, Bacchetti S (1997) A survey of telomerase activity in human cancer. Eur J Cancer 33:787–791

    Article  CAS  Google Scholar 

  • Singh S, Poulsom R, Wright NA, Sheppard MC, Langman MJ (1997) Differential expression of oestrogen receptor and oestrogen inducible genes in gastric mucosa and cancer. Gut 40:516–520

    Article  CAS  Google Scholar 

  • Takakura M, Kyo S, Kanaya T, Tanaka M, Inoue M (1998) Expression of human telomerase subunits and correlation with telomerase activity in cervical cancer. Cancer Res 58:1558–1561

    CAS  PubMed  Google Scholar 

  • Takano N, Iizuka N, Hazama S, Yoshino S, Tangoku A, Oka M (2002) Expression of estrogen receptor-alpha and -beta mRNAs in human gastric cancer. Cancer Lett 176:129–135

    Article  CAS  Google Scholar 

  • Xu CY, Guo JL, Jiang ZN, Xie SD, Shen JG, Shen JY, Wang LB (2010) Prognostic role of estrogen receptor a and estrogen receptor beta in gastric cancer. Ann Surg Oncol 17:2503–2509

    Article  CAS  Google Scholar 

  • Yoon YH, Seol SY, Heo J, Chung CN, Park IH, Leem SH (2008) Analysis of VNTRs in the solute carrier family 6, member 18 (SLC6A18) and lack of association with hypertension. DNA Cell Biol 27:559–567

    Article  CAS  Google Scholar 

  • Yoon SL, Jung SI, Do EJ, Lee SR, Lee SY, Chu IS, Kim WJ, Jung J, Kim CS, Cheon SH et al (2010a) Short rare hTERT-VNTR2-2(nd) alleles are associated with prostate cancer susceptibility and influence gene expression. BMC Cancer 10:10

    Article  Google Scholar 

  • Yoon SL, Kim DC, Cho SH, Lee SY, Chu IS, Heo J, Leem SH (2010b) Susceptibility for breast cancer in young patients with short rare minisatellite alleles of BORIS. BMB Rep 43:698–703

    Article  CAS  Google Scholar 

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Acknowledgements

We gratefully acknowledge patients and their caregivers for their willing participation in this project and for consenting to the use of information obtained from the study.

Funding

This work was supported by the Dong-A University research fund.

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Correspondence to Sun-Hee Leem.

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Conflict of interest

Jeong-Ah Kwon, Mi-So Jeong, Se-Lyun Yoon, Jeong-Yeon Mun, Min-Hye Kim, Gi-Eun Yang, Seong-Hwan Park, Jin-Woong Chung, Yung Hyun Choi, Hee-Jae Cha and Sun-Hee Leem declare that they have no competing interests.

Ethical approval

This study was conducted with informed written consent from participants and after approval by the bioethics committees of Dong-A University Hospital (#IRB-07-10-7; Busan, Korea), Inje University Paik Hospital (#IRB11-011) and the Chungbuk National University Hospital (#IRB-2006-1; Cheongju, Korea).

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Kwon, JA., Jeong, MS., Yoon, SL. et al. The hTERT-VNTR2-2nd alleles are involved in genomic stability in gastrointestinal cancer. Genes Genom 41, 1517–1525 (2019). https://doi.org/10.1007/s13258-019-00882-y

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  • DOI: https://doi.org/10.1007/s13258-019-00882-y

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