title: Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: a molecular subclass of rectal cancer.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Boardman
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Johnson
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Viker
authors.forename: Kari A
authors.initials: KA
authors.lastname: Hafner
authors.forename: Robert B
authors.initials: RB
authors.lastname: Jenkins
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Riegert-Johnson
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.forename: Kristin
authors.initials: K
authors.lastname: Litzelman
authors.forename: Songwon
authors.initials: S
authors.lastname: Seo
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gangnon
authors.forename: Corinne D
authors.initials: CD
authors.lastname: Engelman
authors.forename: David N
authors.initials: DN
authors.lastname: Rider
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Vanderboom
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Halcyon G
authors.initials: HG
authors.lastname: Skinner
mesh_terms: D001483:Base Sequence; D043171:Chromosomal Instability; D055028:Comparative Genomic Hybridization; D017931:DNA Primers; D004789:Enzyme Activation; D016158:Genes, p53; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D017354:Point Mutation; D060888:Real-Time Polymerase Chain Reaction; D012004:Rectal Neoplasms / Q000201:enzymology / Q000235:genetics*; D019098:Telomerase / Q000378:metabolism; D016615:Telomere
chemical_list: D017931:DNA Primers; D019098:Telomerase