Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: A molecular subclass of rectal cancer

Lisa A. Boardman, Ruth A. Johnson, Kimberly B. Viker, Kari A. Hafner, Robert B. Jenkins, Douglas L. Riegert-Johnson, Thomas C. Smyrk, Kristin Litzelman, Songwon Seo, Ronald E. Gangnon, Corinne D. Engelman, David N. Rider, Russell J. Vanderboom, Stephen N. Thibodeau, Gloria M. Petersen, Halcyon G. Skinner

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32 Scopus citations

Abstract

Introduction: Colorectal cancer (CRC) tumor DNA is characterized by chromosomal damage termed chromosomal instability (CIN) and excessively shortened telomeres. Up to 80% of CRC is microsatellite stable (MSS) and is historically considered to be chromosomally unstable (CIN+). However, tumor phenotyping depicts some MSS CRC with little or no genetic changes, thus being chromosomally stable (CIN-). MSS CIN- tumors have not been assessed for telomere attrition. Experimental Design: MSS rectal cancers from patients ≤50 years old with Stage II (B2 or higher) or Stage III disease were assessed for CIN, telomere length and telomere maintenance mechanism (telomerase activation [TA]; alternative lengthening of telomeres [ALT]). Relative telomere length was measured by qPCR in somatic epithelial and cancer DNA. TA was measured with the TRAPeze assay, and tumors were evaluated for the presence of C-circles indicative of ALT. p53 mutation status was assessed in all available samples. DNA copy number changes were evaluated with Spectral Genomics aCGH. Results: Tumors were classified as chromosomally stable (CIN-) and chromosomally instable (CIN+) by degree of DNA copy number changes. CIN- tumors (35%; n=6) had fewer copy number changes (<17% of their clones with DNA copy number changes) than CIN+ tumors (65%; n=13) which had high levels of copy number changes in 20% to 49% of clones. Telomere lengths were longer in CIN- compared to CIN+ tumors (p=0.0066) and in those in which telomerase was not activated (p=0.004). Tumors exhibiting activation of telomerase had shorter tumor telomeres (p=0.0040); and tended to be CIN+ (p=0.0949). Conclusions: MSS rectal cancer appears to represent a heterogeneous group of tumors that may be categorized both on the basis of CIN status and telomere maintenance mechanism. MSS CIN- rectal cancers appear to have longer telomeres than those of MSS CIN+ rectal cancers and to utilize ALT rather than activation of telomerase.

Original languageEnglish (US)
Article numbere80015
JournalPloS one
Volume8
Issue number11
DOIs
StatePublished - Nov 21 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Boardman, L. A., Johnson, R. A., Viker, K. B., Hafner, K. A., Jenkins, R. B., Riegert-Johnson, D. L., Smyrk, T. C., Litzelman, K., Seo, S., Gangnon, R. E., Engelman, C. D., Rider, D. N., Vanderboom, R. J., Thibodeau, S. N., Petersen, G. M., & Skinner, H. G. (2013). Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: A molecular subclass of rectal cancer. PloS one, 8(11), [e80015]. https://doi.org/10.1371/journal.pone.0080015