Skip to main content

Advertisement

SpringerLink
Log in

Appearance of epithelial and stromal genomic instability in background colorectal mucosa of sporadic colorectal cancer patients: relation to age and gender

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

We have previously demonstrated that not only epithelial but also stromal genetic instability possibly contributes to colorectal tumorigenesis. To assess the increasing risk of carcinogenesis in the colorectum with aging, we examined genomic instability in both epithelia and stroma in the background noncancerous mucosa of patients with colorectal carcinomas.

Methods

In 213 noncancerous colorectal mucosa samples from colorectal cancer cases and 51 normal mucosa specimens of diverticulosis cases, epithelial and stromal genomic instability was analyzed with National Cancer Institute standard microsatellite markers, chromosome 17 (Chr.17) markers and tumor suppressor gene-related markers, using a combination of laser-capture microdissection and GeneScan approaches. Results were compared with immunohistochemically demonstrated expression of FHIT, Rb, WT1, hMLH1 and hMSH2.

Results

Genomic instability (MSI and LOH) in both epithelia and stroma appeared after around 40 years of age and remained relatively constant thereafter at relatively low frequencies (4.8–30.4%). The Epithelial LOH tended to show a stepwise increase in people in their 40s and 50s along with aging, especially in males. Overall frequencies of both epithelial MSI and LOH in left-side colon and LOH in right-side colon were significantly higher in males than in females. Epithelial hMLH1 expression in MSI (−) cases tended to be reduced with aging.

Conclusions

Genomic instability of both MSI and LOH in noncancerous colonic mucosa, and more particularly epithelial and stromal LOH, appears relatively early in adults, suggesting age-related changes which increase the risk of cancer development, particularly in males.

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
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319:525–32.

    PubMed  CAS  Google Scholar 

  2. Kuramoto S, Oohara T. Minute cancers arising de novo in the human large intestine. Cancer. 1988;61:829–34.

    Article  PubMed  CAS  Google Scholar 

  3. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993;260:816–9.

    Article  PubMed  CAS  Google Scholar 

  4. Jass JR, Do KA, Simms LA, Iino H, Wynter C, Pillary Sp, et al. Morphology of sporadic colorectal cancer with DNA replication errors. Gut. 1998;42:673–9.

    Article  PubMed  CAS  Google Scholar 

  5. Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature. 1997;386:623–7.

    Article  PubMed  CAS  Google Scholar 

  6. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998;396:643–9.

    Article  PubMed  CAS  Google Scholar 

  7. Michael-Robinson JM, Biemer-Huttmann A, Purdie DM, Walsh MD, Simms LA, Biden KG, et al. Tumour infiltrating lymphocytes and apoptosis are independent features in colorectal cancer stratified according to microsatellite instability status. Gut. 2001;48:360–6.

    Article  PubMed  CAS  Google Scholar 

  8. Goel A, Arnold CN, Niedzwiecki D, Chang DK, Ricciardiello L, Carethers JM, et al. Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res. 2003;63:1608–14.

    PubMed  CAS  Google Scholar 

  9. Matsumoto N, Yoshida T, Yamashita K, Numata Y, Okayasu I. Possible alternative carcinogenesis pathway featuring microsatellite instability in colorectal cancer stroma. Br J Cancer. 2003;89:707–12.

    Article  PubMed  CAS  Google Scholar 

  10. Ishiguro K, Yoshida T, Yagishita H, Numata Y, Okayasu I. Epithelial and stromal genetic instability contributes to genesis of colorectal adenomas. Gut. 2006;55:695–702.

    Article  PubMed  CAS  Google Scholar 

  11. Matsumoto N, Yoshida T, Okayasu I. High epithelial and stromal genetic instability of chromosome 17 in ulcerative colitis-associated carcinogenesis. Cancer Res. 2003;63:6158–61.

    PubMed  CAS  Google Scholar 

  12. Yagishita H, Yoshida T, Ishiguro K, Numata Y, Okayasu I. Epithelial and stromal genetic instability linked to tumor suppressor genes in ulcerative colitis-associated tumorigenesis. Scand J Gastroenterol. 2008;43:559–66.

    Article  PubMed  CAS  Google Scholar 

  13. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248–57.

    PubMed  CAS  Google Scholar 

  14. Anderson LA, Friedman L, Osborne-Lawrence S, Lynch E, Wessenbach J, Bowcock A, et al. High-density genetic map of the BRCA1 region of chromosome 17q12–q21. Genomics. 1993;17:618–23.

    Article  PubMed  CAS  Google Scholar 

  15. Gyapay G, Morissette J, Vignal A, Dib C, Fizames C, Millasseau P, et al. The 1993–94 Genethon human genetic linkage map. Nat Genet. 1994;7:246–339.

    Article  PubMed  CAS  Google Scholar 

  16. Wang S, Mori Y, Sato F, Yin J, Xu Y, Zou TT, et al. An LOH and mutational investigation of the ST7 gene locus in human esophageal carcinoma. Oncogene. 2003;22:467–70.

    Article  PubMed  CAS  Google Scholar 

  17. Ogawa T, Yoshida T, Tsuruta T, Saigenji K, Okayasu I. Genetic instability on chromosome 17 in the epithelium of non-polypoid colorectal carcinomas compared to polypoid lesions. Cancer Sci. 2006;97:1335–42.

    Article  PubMed  CAS  Google Scholar 

  18. Japanese Ministry of Health and Welfare. Fifth report of statistics of malignant neoplasm in Japan (Supervised ed. Masuzoe K). Tokyo: Sogouigakusha; 1990. p. 19–43.

    Google Scholar 

  19. Japanese Society for Cancer of the Colon, Rectum. Multi-Institutional Registry of Large Bowel Cancer in Japan, vol. 24. Utsunomiya: Matsui PTO; 2003. p. 9–21.

    Google Scholar 

  20. Miyakura Y, Sugano K, Konishi F, Ichikawa A, Maekawa M, Saitoh K, et al. Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability. Gastroenterology. 2001;121:1300–9.

    Article  PubMed  CAS  Google Scholar 

  21. Tou SIH, Drye ER, Boulos PB, Hollingsworth SJ. Activity (transcription) of the genes for MLH1, MSH2 and p53 in sporadic colorectal tumours with micro-satellite instability. Br J Cancer. 2004;90:2006–12.

    Article  PubMed  CAS  Google Scholar 

  22. Okayasu I, Hana K, Tsuruta T, Okamura N, Ogawa T, Tokuyama W. Significant increase of colonic mutated crypts correlates with age in sporadic cancer and diverticulosis cases, with higher frequency in the left- than right-side colorectum. Cancer Sci. 2006;97:362–7.

    Article  PubMed  CAS  Google Scholar 

  23. Okayasu I, Hana K, Yoshida T, Mikami T, Kanno J, Fuiwara M. Significant increase of colonic mutated crypts in ulcerative colitis correlatively with duration of illness. Cancer Res. 2002;62:2236–8.

    PubMed  CAS  Google Scholar 

  24. Kwabi-Addo B, Chung W, Shen L, Ittmann M, Wheeler T, Jelinek J, et al. Age-related DNA methylation changes in normal human prostate tissues. Clin Cancer Res. 2007;13:3796–802.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, the Kanagawa Nanbyo Foundation, and the Kitasato University Graduate School of Medical Sciences.

Conflict of interest statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Author information

Authors and Affiliations

  1. Department of Cellular and Histo-pathology, Kitasato University Postgraduate School of Medical Sciences, Sagamihara, Japan

    Harue Umeto, Tsutomu Yoshida, Kayo Araki, Hiroko Yagishita, Tetuo Mikami & Isao Okayasu

  2. Department of Pathology, Kitasato University School of Medicine, 1-15-1, Kitasato, Sagamihara, Kanagawa, 228-8555, Japan

    Tsutomu Yoshida, Tetuo Mikami & Isao Okayasu

Authors
  1. Harue Umeto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tsutomu Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kayo Araki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroko Yagishita
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tetuo Mikami
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Isao Okayasu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Isao Okayasu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Umeto, H., Yoshida, T., Araki, K. et al. Appearance of epithelial and stromal genomic instability in background colorectal mucosa of sporadic colorectal cancer patients: relation to age and gender. J Gastroenterol 44, 1036–1045 (2009). https://doi.org/10.1007/s00535-009-0103-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-009-0103-1

Keywords

Search

Navigation