Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer

A molecular subclass of rectal cancer

Lisa Allyn Boardman, Ruth A. Johnson, Kimberly B. Viker, Kari A. Hafner, Robert Brian Jenkins, Douglas L. Riegert-Johnson, Thomas Christopher 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

Research output: Contribution to journalArticle

29 Citations (Scopus)

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

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Telomere Homeostasis
Chromosomal Instability
telomeres
Telomere
Rectal Neoplasms
colorectal neoplasms
Microsatellite Repeats
microsatellite repeats
Tumors
neoplasms
telomerase
Telomerase
Neoplasms
DNA Copy Number Variations
Colorectal Neoplasms
DNA
Chemical activation
clones
Clone Cells
Telomere Shortening

ASJC Scopus subject areas

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

Cite this

Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer : A molecular subclass of rectal cancer. / Boardman, Lisa Allyn; Johnson, Ruth A.; Viker, Kimberly B.; Hafner, Kari A.; Jenkins, Robert Brian; Riegert-Johnson, Douglas L.; Smyrk, Thomas Christopher; Litzelman, Kristin; Seo, Songwon; Gangnon, Ronald E.; Engelman, Corinne D.; Rider, David N.; Vanderboom, Russell J.; Thibodeau, Stephen N; Petersen, Gloria M; Skinner, Halcyon G.

In: PLoS One, Vol. 8, No. 11, e80015, 21.11.2013.

Research output: Contribution to journalArticle

Boardman, LA, Johnson, RA, Viker, KB, Hafner, KA, Jenkins, RB, Riegert-Johnson, DL, Smyrk, TC, Litzelman, K, Seo, S, Gangnon, RE, Engelman, CD, Rider, DN, Vanderboom, RJ, Thibodeau, SN, Petersen, GM & Skinner, HG 2013, 'Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: A molecular subclass of rectal cancer', PLoS One, vol. 8, no. 11, e80015. https://doi.org/10.1371/journal.pone.0080015
Boardman, Lisa Allyn ; Johnson, Ruth A. ; Viker, Kimberly B. ; Hafner, Kari A. ; Jenkins, Robert Brian ; Riegert-Johnson, Douglas L. ; Smyrk, Thomas Christopher ; Litzelman, Kristin ; Seo, Songwon ; Gangnon, Ronald E. ; Engelman, Corinne D. ; Rider, David N. ; Vanderboom, Russell J. ; Thibodeau, Stephen N ; Petersen, Gloria M ; Skinner, Halcyon G. / Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer : A molecular subclass of rectal cancer. In: PLoS One. 2013 ; Vol. 8, No. 11.
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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.",
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T1 - Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer

T2 - A molecular subclass of rectal cancer

AU - Boardman, Lisa Allyn

AU - Johnson, Ruth A.

AU - Viker, Kimberly B.

AU - Hafner, Kari A.

AU - Jenkins, Robert Brian

AU - Riegert-Johnson, Douglas L.

AU - Smyrk, Thomas Christopher

AU - Litzelman, Kristin

AU - Seo, Songwon

AU - Gangnon, Ronald E.

AU - Engelman, Corinne D.

AU - Rider, David N.

AU - Vanderboom, Russell J.

AU - Thibodeau, Stephen N

AU - Petersen, Gloria M

AU - Skinner, Halcyon G.

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N2 - 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.

AB - 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.

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