title: Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer.
abstract: Telomeric dysfunction is linked to colorectal cancer (CRC) initiation. However, the relationship of normal tissue and tumor telomere lengths with CRC progression, molecular features and prognosis is unclear. Here, we measured relative telomere length (RTL) by real-time quantitative PCR in 90 adenomas (aRTL), 419 stage I-IV CRCs (cRTL) and adjacent normal mucosa (nRTL). Age-adjusted RTL was analyzed against germline variants in telomere biology genes, chromosome instability (CIN), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), TP53, KRAS, BRAF mutations and clinical outcomes. In 509 adenoma or CRC patients, nRTL decreased with advancing age. Female gender, proximal location and the TERT rs2736100 G allele were independently associated with longer age-adjusted nRTL. Adenomas and carcinomas exhibited telomere shortening in 79% and 67% and lengthening in 7% and 15% of cases. Age-adjusted nRTL and cRTL were independently associated with tumor stage, decreasing from adenoma to stage III and leveling out or increasing from stage III to IV, respectively. Cancer MSI, CIMP, TP53, KRAS and BRAF status were not related to nRTL or cRTL. Near-tetraploid CRCs exhibited significantly longer cRTLs than CIN- and aneuploidy CRCs, while cRTL was significantly shorter in CRCs with larger numbers of chromosome breaks. Age-adjusted nRTL, cRTL or cRTL:nRTL ratios were not associated with disease-free or overall survival in stage II/III CRC. Taken together, our data show that both normal mucosa and tumor RTL are independently associated with CRC progression, and highlight divergent associations of CRC telomere length with tumor CIN profiles.
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK.
authors.forename: Nirosha
authors.initials: N
authors.lastname: Suraweera
authors.affiliation: Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Mouradov
authors.affiliation: Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia.
authors.forename: Shan
authors.initials: S
authors.lastname: Li
authors.affiliation: Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Jorissen
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK.
authors.forename: Debbie
authors.initials: D
authors.lastname: Hampson
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK.
authors.forename: Anil
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK.
authors.forename: Neel
authors.initials: N
authors.lastname: Sengupta
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK.|Academic Surgical Unit, The Royal London Hospital, Whitechapel, London, UK.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Thaha
authors.affiliation: Academic Surgical Unit, The Royal London Hospital, Whitechapel, London, UK.
authors.forename: Shafi
authors.initials: S
authors.lastname: Ahmed
authors.affiliation: Centre for Paediatrics, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Kirwan
authors.affiliation: Department of Medical Oncology, St Bartholomew's Hospital, Little Britain, London, UK.
authors.forename: Floor
authors.initials: F
authors.lastname: Aleva
authors.affiliation: Department of Medical Oncology, St Bartholomew's Hospital, Little Britain, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Propper
authors.affiliation: Department of Pathology, The Royal London Hospital, Whitechapel, London, UK.
authors.forename: Roger M
authors.initials: RM
authors.lastname: Feakins
authors.affiliation: Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.affiliation: Cord Blood Research, Murdoch Children's Research Institute, Melbourne, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Australia.
authors.forename: Ngaire J
authors.initials: NJ
authors.lastname: Elwood
authors.affiliation: Cord Blood Research, Murdoch Children's Research Institute, Melbourne, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Australia.
authors.forename: Pei
authors.initials: P
authors.lastname: Tian
authors.affiliation: The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Ward
authors.affiliation: School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Hawkins
authors.affiliation: CSIRO Preventative Health Flagship, North Ryde, NSW, Australia.
authors.forename: Zheng-Zhou
authors.initials: ZZ
authors.lastname: Xu
authors.affiliation: CSIRO Preventative Health Flagship, North Ryde, NSW, Australia.
authors.forename: Peter L
authors.initials: PL
authors.lastname: Molloy
authors.affiliation: Department of Colorectal Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia.|Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Ian T
authors.initials: IT
authors.lastname: Jones
authors.affiliation: Department of Colorectal Surgery, Western Hospital, Footscray, Victoria, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Croxford
authors.affiliation: Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.|Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Gibbs
authors.affiliation: Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Silver
authors.affiliation: Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia.|Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.|Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia.|School of Biomedical Sciences, Monash University, Victoria, Australia.
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Sieber
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D043171:Chromosomal Instability / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism*; D015999:Multivariate Analysis; D009154:Mutation / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D016615:Telomere / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D016159:Tumor Suppressor Protein p53; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: chromosome instability; colorectal cancer; prognosis; telomere length