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

Christophe M. Raynaud, S. J. Jang, P. Nuciforo, S. Lantuejoul, E. Brambilla, N. Mounier, K. A. Olaussen, F. André, L. Morat, L. Sabatier, J. C. Soria

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1875-1881
Number of pages7
JournalAnnals of Oncology
Volume19
Issue number11
DOIs
Publication statusPublished - 3 Nov 2008
Externally publishedYes

Fingerprint

Telomere Shortening
Telomere
DNA Damage
Checkpoint Kinase 2
Down-Regulation
Ataxia Telangiectasia
Carcinogenesis
Carcinoma
Colon
Proteins
Mucous Membrane
Immunohistochemistry
Phosphorylation

Keywords

  • Carcinogenesis
  • DNA damage repair
  • Telomeres
  • Telomeric proteins

ASJC Scopus subject areas

  • Oncology
  • Hematology

Cite this

Telomere shortening is correlated with the DNA damage response and telomeric protein down-regulation in colorectal preneoplastic lesions. / Raynaud, Christophe M.; Jang, S. J.; Nuciforo, P.; Lantuejoul, S.; Brambilla, E.; Mounier, N.; Olaussen, K. A.; André, F.; Morat, L.; Sabatier, L.; Soria, J. C.

In: Annals of Oncology, Vol. 19, No. 11, 03.11.2008, p. 1875-1881.

Research output: Contribution to journalArticle

Raynaud, CM, Jang, SJ, Nuciforo, P, Lantuejoul, S, Brambilla, E, Mounier, N, Olaussen, KA, André, F, Morat, L, Sabatier, L & Soria, JC 2008, 'Telomere shortening is correlated with the DNA damage response and telomeric protein down-regulation in colorectal preneoplastic lesions', Annals of Oncology, vol. 19, no. 11, pp. 1875-1881. https://doi.org/10.1093/annonc/mdn405
Raynaud, Christophe M. ; Jang, S. J. ; Nuciforo, P. ; Lantuejoul, S. ; Brambilla, E. ; Mounier, N. ; Olaussen, K. A. ; André, F. ; Morat, L. ; Sabatier, L. ; Soria, J. C. / Telomere shortening is correlated with the DNA damage response and telomeric protein down-regulation in colorectal preneoplastic lesions. In: Annals of Oncology. 2008 ; Vol. 19, No. 11. pp. 1875-1881.
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abstract = "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.",
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AU - Raynaud, Christophe M.

AU - Jang, S. J.

AU - Nuciforo, P.

AU - Lantuejoul, S.

AU - Brambilla, E.

AU - Mounier, N.

AU - Olaussen, K. A.

AU - André, F.

AU - Morat, L.

AU - Sabatier, L.

AU - Soria, J. C.

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N2 - 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.

AB - 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.

KW - Carcinogenesis

KW - DNA damage repair

KW - Telomeres

KW - Telomeric proteins

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