Oncotarget

Research Papers:

Relative telomere lengths in tumor and normal mucosa are related to disease progression and chromosome instability profiles in colorectal cancer

Nirosha Suraweera _, Dmitri Mouradov, Shan Li, Robert N. Jorissen, Debbie Hampson, Anil Ghosh, Neel Sengupta, Mohamed Thaha, Shafi Ahmed, Michael Kirwan, Floor Aleva, David Propper, Roger M. Feakins, Tom Vulliamy, Ngaire J. Elwood, Pei Tian, Robyn L. Ward, Nicholas J. Hawkins, Zheng-Zhou Xu, Peter L. Molloy, Ian T. Jones, Matthew Croxford, Peter Gibbs, Andrew Silver and Oliver M. Sieber

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Oncotarget. 2016; 7:36474-36488. https://doi.org/10.18632/oncotarget.9015

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Abstract

Nirosha Suraweera1,*, Dmitri Mouradov2,3,*, Shan Li2,*, Robert N. Jorissen2,3, Debbie Hampson1, Anil Ghosh1, Neel Sengupta1, Mohamed Thaha1,4, Shafi Ahmed4, Michael Kirwan5, Floor Aleva6, David Propper6, Roger M. Feakins7, Tom Vulliamy8, Ngaire J. Elwood9,10, Pei Tian9,10, Robyn L. Ward11, Nicholas J. Hawkins12, Zheng-Zhou Xu13, Peter L. Molloy13, Ian T. Jones14,15, Matthew Croxford16, Peter Gibbs2,3,17, Andrew Silver1, Oliver M. Sieber2,3,15,18

1Centre for Digestive Diseases, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK

2Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medial Research, Parkville, Victoria, Australia

3Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia

4Academic Surgical Unit, The Royal London Hospital, Whitechapel, London, UK

5Centre for Paediatrics, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK

6Department of Medical Oncology, St Bartholomew's Hospital, Little Britain, London, UK

7Department of Pathology, The Royal London Hospital, Whitechapel, London, UK

8Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Whitechapel, London, UK

9Cord Blood Research, Murdoch Children’s Research Institute, Melbourne, Australia

10Department of Paediatrics, University of Melbourne, Melbourne, Australia

11The University of Queensland, Brisbane, Queensland, Australia

12School of Medicine, The University of Queensland, Brisbane, Queensland, Australia

13CSIRO Preventative Health Flagship, North Ryde, NSW, Australia

14Department of Colorectal Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia

15Department of Surgery, The University of Melbourne, Parkville, Victoria, Australia

16Department of Colorectal Surgery, Western Hospital, Footscray, Victoria, Australia

17Department of Medical Oncology, Royal Melbourne Hospital, Parkville, Victoria, Australia

18School of Biomedical Sciences, Monash University, Victoria, Australia

*These authors have contributed equally to this work

Correspondence to:

Andrew Silver, e-mail: [email protected]

Oliver M. Sieber, e-mail: [email protected]

Keywords: telomere length, colorectal cancer, chromosome instability, prognosis

Received: February 16, 2016     Accepted: April 10, 2016     Published: April 26, 2016

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.


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