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Carcinogenesis Advance Access originally published online on May 22, 2007
Carcinogenesis 2007 28(10):2082-2088; doi:10.1093/carcin/bgm108
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression

Paolo Giovanni Nuciforo{dagger}, Chiara Luise{dagger}, Maria Capra, Giuseppe Pelosi1 and Fabrizio d'Adda di Fagagna*

FIRC Institute of Molecular Oncology Foundation, via Adamello 16, 20139 Milan, Italy
1 Department of Pathology, European Institute of Oncology, 20139 Milan, Italy

* To whom correspondence should be addressed. Tel. +39 02 574303.227; Fax +39 02 574303.231 Email: fabrizio.dadda{at}ifom-ieo-campus.it

Tumor initiation and progression provide a multitude of occasions for the generation of DNA damage and the consequent activation of the DNA damage response (DDR) pathway. DDR signaling involves the engagement of key factors such as ATM, CHK2, 53BP1 and the phosphorylation of histone H2AX ({gamma}-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and {gamma}-H2AX were engaged in cancer but the extent of their activation was strongly affected by the organ and cell type involved, whereas 53BP1 loss was the most consistent feature among the tumor studied. Unexpectedly, we also observed activated DDR markers in morphologically normal tissues, also in association with inflammation. Analysis of the dynamic engagement of DDR along the different stages of lung tumorigenesis showed that 53BP1 loss occurs early at the transition from normal to dysplastic change whereas the activated forms of ATM and CHK2, but not {gamma}-H2AX, initially accumulate in pre-invasive lesions and are then lost during tumor progression. In individual lung tumors, the activation of ATM, CHK2 and the presence of 53BP1 were consistently correlated, whereas {gamma}-H2AX did not correlate with activated ATM. Finally, the study of associations between critical clinicopathological parameters and activated DDR factors highlighted a statistically meaningful correlation between reduced local tumor extension and the phosphorylation of ATM, CHK2 and the presence of 53BP1, whereas no significant correlations with parameters such as survival or relapse of early-stage lung carcinomas were found.

Abbreviations: DDR, DNA damage response; DSB, double-strand break; HGD, high-grade dysplasia; IHC, immunohistochemistry; LGD, low-grade dysplasia; SCC, squamous cell carcinoma; TMA, tissue microarray

{dagger} These authors contributed equally to this work.

Received December 29, 2006; revised April 27, 2007; accepted April 30, 2007.


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