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Genomic Instability Measured by Inter-(Simple Sequence Repeat) PCR and High-Resolution Microsatellite Instability are Prognostic of Colorectal Carcinoma Survival After Surgical Resection

  • Translational Research and Biomarkers
  • Published:
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Abstract

Background

During the multiyear progression to colorectal cancer, numerous genomic alterations arise in events ranging from single base mutations to gains or losses of entire chromosomes. A single genetic change might not stand out as an independent predictor of outcome. The goal of this study was to determine if more comprehensive measurements of genomic instability provide clinically relevant prognostic information.

Methods

Our study included 65 sporadic colorectal cancer patients diagnosed from 1987 to 1991 with last follow-up ascertained in 2006. We estimated an overall tally of alterations using the genome-wide sampling technique of inter-(simple sequence repeat [SSR]) polymerase chain reaction (PCR), and evaluated its relationship with all-cause survival. We also extended and sensitized the Bethesda criteria for microsatellite instability (MSI), by analyzing 348 microsatellite markers instead of the normal five. We expanded the MSI categories into four levels: MSI stable (MSS), very low-level MSI, moderately low-level MSI, and classical high-level MSI.

Results

Tumors with genomic instability above the median value of 2.6% as measured by inter-SSR PCR, were associated with far greater risk of death compared to tumors with lower levels of genomic instability. Adverse outcome was most pronounced for patients presenting with stage 3 disease. A gradient of increased survival was observed across increasing MSI levels but did not reach statistical significance.

Conclusion

Our findings suggest genomic instabilities quantified by inter-SSR PCR and increased precision in MSI values may be clinically useful tools for estimating prognosis in colorectal cancer.

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References

  1. Beerenwinkel N, Antal T, Dingli D, et al. Genetic progression and the waiting time to cancer. PLoS Comp Biol. 2007;3:2239–46.

    Article  CAS  Google Scholar 

  2. Sjöblom T, Jones S, Wood LD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314:268–74.

    Article  PubMed  Google Scholar 

  3. Stoler DL, Chen N, Basik M, et al. The onset and extent of genomic instability in sporadic colorectal tumor progression. Proc Natl Acad Sci USA. 1999;96:15121–6.

    Article  PubMed  CAS  Google Scholar 

  4. Stephens PJ, McBride DJ, Lin ML, et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature. 2009;462:1005–10.

    Article  PubMed  CAS  Google Scholar 

  5. Greenman C, Stephens P, Smith R, et al. Patterns of somatic mutation in human cancer genomes. Nature. 2007;446:153–8.

    Article  PubMed  CAS  Google Scholar 

  6. Sugarbaker DJ, Richards WG, Gordon GJ, et al. Transcriptome sequencing of malignant pleural mesothelioma tumors. Proc Natl Acad Sci USA. 2008;105:3521–6.

    Article  PubMed  CAS  Google Scholar 

  7. Benatti P, Gafà R, Barana D, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332–40.

    Article  PubMed  CAS  Google Scholar 

  8. Sinicrope FA, Rego RL, Halling KC, et al. Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology. 2006;131:729–37.

    Article  PubMed  CAS  Google Scholar 

  9. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261–8.

    Article  PubMed  CAS  Google Scholar 

  10. Poulogiannis G, Ichimura K, Hamoudi RA, et al. Prognostic relevance of DNA copy number changes in colorectal cancer. J Pathol. 2009;220:338–47.

    Article  Google Scholar 

  11. Zhang Y, Martens JWM, Yu JX, et al. Copy number alterations that predict metastatic capability of human breast cancer. Cancer Res. 2009;69:3795–801.

    Article  PubMed  CAS  Google Scholar 

  12. Pretorius ME, Waehre H, Abeler VM, et al. Large scale genomic instability as an additive prognostic marker in early prostate cancer. Cell Oncol. 2009;31:251–9.

    PubMed  CAS  Google Scholar 

  13. Anderson GR, Brenner BM, Swede H, et al. Intrachromosomal genomic instability in human sporadic colorectal cancer measured by genome-wide allelotyping and inter-(simple sequence repeat) PCR. Cancer Res. 2001;61:8274–83.

    PubMed  CAS  Google Scholar 

  14. Jones BA, Christensen AR, Wise Sr, JP, Yu H. Glutathione S-transferase polymorphisms and survival in African-American and white colorectal cancer patients. Cancer Epidemiol. 2009;33:249–56.

    Article  PubMed  CAS  Google Scholar 

  15. Basik M, Stoler DL, Kontzoglou KC, Rodriguez-Bigas MA, Petrelli NJ, Anderson GR. Genomic instability in sporadic colorectal cancer quantitated by inter-(simple sequence repeat) PCR analysis. Genes Chromosomes Cancer. 1997;18:19–29.

    Article  PubMed  CAS  Google Scholar 

  16. Laiho P, Launonen V, Lahermo P, et al. Low-level microsatellite instability in most colorectal carcinomas. Cancer Res. 2002;62:1166–70.

    PubMed  CAS  Google Scholar 

  17. Markowitz S, Wang J, Myeroff L, et al. Inactivation of the type II TGF-β receptor in colon cancer cells with microsatellite instability. Science. 1995;268:1276–7.

    Article  Google Scholar 

  18. Vikki S, Launonen V, Karhu A, Sistonen P, Vastrik I, Aaltonen LA. Screening for microsatellite instability target genes in colorectal cancers. J Med Genet. 2002;39:785–9.

    Article  Google Scholar 

  19. Valeri N, Gasparini P, Fabbri M, et al. Modulation of mismatch repair and genomic stability by miR-155. Proc Natl Acad Sci USA. 2010;107:6982–7.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by NCI grants R01CA74127 to GRA and P30-CA16056 to the Roswell Park Cancer Institute; by the NCI SEER program contract (N01-PC-35133) and Rapid Response Surveillance Study amendment (HS, 2003) with the Connecticut Tumor Registry in the Connecticut Department of Public Health (DPH); and by the Patrick and Catherine Weldon Donaghue Medial Research Foundation (DF#01-025) and the NCI Program Project Grant (5-P01-CA42101) to BAJ. Certain data used in this publication were obtained from the Connecticut DPH, and the authors assume full responsibility for analyses and interpretation of these data. We thank Nicholas Petrelli for valuable conversations and his role in supplying the specimens, Janet Winston for the pathological examinations, and Roy Heinaman for expert technical assistance. We thank Daniel Rosenberg and staff for microdissection and DNA extraction of the Connecticut subset of tissues.

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Authors and Affiliations

  1. Division of Surgery, University of Connecticut Health Center, Farmington, CT, USA

    Bruce M. Brenner MD

  2. Department of Community Medicine and Health Care and Neag Cancer Center, University of Connecticut Health Center, Farmington, CT, USA

    Helen Swede PhD

  3. Department of Epidemiology and Public Health, Yale University, New Haven, CT, USA

    Beth A. Jones PhD

  4. Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY, USA

    Garth R. Anderson PhD

  5. Department of Head and Neck Surgery, Roswell Park Cancer Institute, Buffalo, NY, USA

    Daniel L. Stoler PhD

Authors
  1. Bruce M. Brenner MD
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  2. Helen Swede PhD
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  3. Beth A. Jones PhD
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  4. Garth R. Anderson PhD
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  5. Daniel L. Stoler PhD
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Corresponding author

Correspondence to Daniel L. Stoler PhD.

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Brenner, B.M., Swede, H., Jones, B.A. et al. Genomic Instability Measured by Inter-(Simple Sequence Repeat) PCR and High-Resolution Microsatellite Instability are Prognostic of Colorectal Carcinoma Survival After Surgical Resection. Ann Surg Oncol 19, 344–350 (2012). https://doi.org/10.1245/s10434-011-1708-1

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  • DOI: https://doi.org/10.1245/s10434-011-1708-1

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