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Annals of Oncology Advance Access originally published online on July 17, 2008
Annals of Oncology 2008 19(11):1875-1881; doi:10.1093/annonc/mdn405
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© The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

gastrointestinal tumors

Telomere shortening is correlated with the DNA damage response and telomeric protein down-regulation in colorectal preneoplastic lesions

C. M. Raynaud1, S. J. Jang2, P. Nuciforo3, S. Lantuejoul4, E. Brambilla4, N. Mounier5, K. A. Olaussen6, F. André6, L. Morat1, L. Sabatier1 and J.-C. Soria1,6,*

1 Laboratoire de radiobiologie et oncologie, CEA, Fontenay-aux-Roses, France
2 Department of Pathology, Assan Medical Center, Uslan University Medical College, Seoul, South Korea
3 FIRC Institute of Molecular Oncology Foundation, Milan, Italy
4 Department of Pathology CHU A Michallon and INSERM U 823 A Bonniot Institut Grenoble, France
5 Department of Onco-Hematology, Hospital l'Archet, CHU de Nice, Nice, France
6 Division of Cancer Medicine, IGR, Villejuif, France

* Correspondence to: Dr J.-C. Soria, Department of Medecine, Institut Gustave Roussy, 39 Rue Camille Desmoulins, 94805 Villejuif, France. Tel: +33-1-42-11-42-91; Fax: +33-1-42-11-52-17; E-mail: soria{at}igr.fr

Background: A relation between telomere attrition in early carcinogenesis and activation of DNA damage response (DDR) has been proposed. We explored telomere length and its link with DDR in colorectal multistep carcinogenesis.

Patients and methods: We studied normal mucosa, low-grade dysplasia (LGD) and high-grade dysplasia (HGD) and invasive carcinoma (IC) in matched human colon specimens by evaluating p-ataxia telangiectasia mutated (ATM), p-checkpoint kinase 2 (Chk2), c-H2AX, TRF1 and TRF2 expressions by immunohistochemistry. FISH was used to assess telomere length.

Results: Telomeres shortened significantly from normal (N) to LGD and HGD (P < 0.0001; P = 0.012), then increased in length in IC (P = 0.006). TRF1 and TRF2 expressions were diminished from N to LGD and HGD (P = 0.004, P < 0.0001, ns) and were reexpressed at the invasive stage (P = 0.053 and P = 0.046). Phosphorylated ATM, Chk2 and H2AX appeared already in LGD (respectively, P = 0.001, P = 0.002 and P = 0.02). Their expression decreased from HGD to IC (respectively, P = 0.03, P = 0.02 and P = 0.37). These activating phosphorylations were inversely correlated with telomere length and TRF1/2 expression.

Conclusion: In a model of colon multistep carcinogenesis, our data indicate that telomeric length and protein expression levels are inversely correlated with the activation of the DDR pathway.

Key words: Carcinogenesis, DNA damage repair, telomeres, telomeric proteins

Received for publication February 26, 2008. Revision received May 26, 2008. Accepted for publication May 28, 2008.


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