Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer.
<h4>Introduction</h4>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+). Howe...
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oai:doaj.org-article:0cbf7004f69043d4a6e8c2961198119c2021-11-18T08:45:16ZCorrelation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer.1932-620310.1371/journal.pone.0080015https://doaj.org/article/0cbf7004f69043d4a6e8c2961198119c2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24278232/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Introduction</h4>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.<h4>Experimental design</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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.Lisa A BoardmanRuth A JohnsonKimberly B VikerKari A HafnerRobert B JenkinsDouglas L Riegert-JohnsonThomas C SmyrkKristin LitzelmanSongwon SeoRonald E GangnonCorinne D EngelmanDavid N RiderRussell J VanderboomStephen N ThibodeauGloria M PetersenHalcyon G SkinnerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 11, p e80015 (2013) |
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Medicine R Science Q 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 Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer. |
| description |
<h4>Introduction</h4>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.<h4>Experimental design</h4>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.<h4>Results</h4>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).<h4>Conclusions</h4>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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Lisa A Boardman |
| title |
Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer. |
| title_short |
Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer. |
| title_full |
Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer. |
| title_fullStr |
Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer. |
| title_full_unstemmed |
Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer. |
| title_sort |
correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2013 |
| url |
https://doaj.org/article/0cbf7004f69043d4a6e8c2961198119c |
| work_keys_str_mv |
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