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

Paolo Giovanni Nuciforo, Chiara Luise, Maria Capra, Giuseppe Pelosi, Fabrizio D'Adda di Fagagna

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

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 (γ-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and γ-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 γ-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 γ-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.

Original languageEnglish
Pages (from-to)2082-2088
Number of pages7
JournalCarcinogenesis
Volume28
Issue number10
DOIs
Publication statusPublished - Oct 2007

Fingerprint

DNA Damage
Lung Neoplasms
Neoplasms
Lung
Phosphorylation
Histones
Carcinogenesis
Inflammation
Carcinoma
Recurrence
Survival

ASJC Scopus subject areas

  • Cancer Research

Cite this

Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression. / Nuciforo, Paolo Giovanni; Luise, Chiara; Capra, Maria; Pelosi, Giuseppe; D'Adda di Fagagna, Fabrizio.

In: Carcinogenesis, Vol. 28, No. 10, 10.2007, p. 2082-2088.

Research output: Contribution to journalArticle

Nuciforo, Paolo Giovanni ; Luise, Chiara ; Capra, Maria ; Pelosi, Giuseppe ; D'Adda di Fagagna, Fabrizio. / Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression. In: Carcinogenesis. 2007 ; Vol. 28, No. 10. pp. 2082-2088.
@article{e0c2629f09144d2cad390f1f786a4e4c,
title = "Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression",
abstract = "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 (γ-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and γ-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 γ-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 γ-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.",
author = "Nuciforo, {Paolo Giovanni} and Chiara Luise and Maria Capra and Giuseppe Pelosi and {D'Adda di Fagagna}, Fabrizio",
year = "2007",
month = "10",
doi = "10.1093/carcin/bgm108",
language = "English",
volume = "28",
pages = "2082--2088",
journal = "Carcinogenesis",
issn = "0143-3334",
publisher = "Oxford University Press",
number = "10",

}

TY - JOUR

T1 - Complex engagement of DNA damage response pathways in human cancer and in lung tumor progression

AU - Nuciforo, Paolo Giovanni

AU - Luise, Chiara

AU - Capra, Maria

AU - Pelosi, Giuseppe

AU - D'Adda di Fagagna, Fabrizio

PY - 2007/10

Y1 - 2007/10

N2 - 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 (γ-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and γ-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 γ-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 γ-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.

AB - 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 (γ-H2AX). The systematic study of DDR in human tumors and normal tissues by high-throughput tissue microarrays revealed that ATM and γ-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 γ-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 γ-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.

UR - http://www.scopus.com/inward/record.url?scp=35148812601&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=35148812601&partnerID=8YFLogxK

U2 - 10.1093/carcin/bgm108

DO - 10.1093/carcin/bgm108

M3 - Article

VL - 28

SP - 2082

EP - 2088

JO - Carcinogenesis

JF - Carcinogenesis

SN - 0143-3334

IS - 10

ER -