DNA Damage Repair and Telomere Length in Normal Breast, Preneoplastic Lesions, and Invasive Cancer

Raynaud, Christophe M.; Hernandez, J.; Llorca, F. Penault; Nuciforo, Paolo; Mathieu, Marie Christine; Commo, Frédéric; Delaloge, Suzette; Sabatier, Laure; André, Fabrice; Soria, Jean Charles

doi:10.1097/coc.0b013e3181b0c4c2

Cited by 42 publications

(29 citation statements)

References 16 publications

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“…Indeed, DDRs already observed herein in normal bronchial and bronchioloalveolar cells, exhibiting a p-ATM, p-H2AX, and p-CHK2 expression, were not described during colon or breast carcinogenesis, in which normal epithelial cells adjacent to tumors were almost negative (21,35); this indicates that within the respiratory tract, tobacco carcinogens are yet able to generate DNA damages in normal epithelium. In agreement with the literature, we observed an increased p-H2AX, p-CHK2, and p-ATM expression along with the severity of bronchial preneoplasia.…”

Section: Discussionmentioning

confidence: 49%

Telomere Maintenance and DNA Damage Responses during Lung Carcinogenesis

Lantuéjoul

Raynaud

Salameire

et al. 2010

Clinical Cancer Research

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Purpose: Telomere shortening is an early event in bronchial carcinogenesis, preceding P53/Rb pathway inactivation and telomerase reactivation, and leading to DNA damage responses (DDR). As their inactivation in cancer increases genetic instability, our objective was to identify the chronology of telomere machinery critical events for malignant progression.Experimental Design: We have evaluated telomere length by fluorescence in situ hybridization and analyzed DDR proteins p-CHK2, p-ATM, and p-H2AX, and telomeric maintenance proteins TRF1 and TRF2 expression by immunohistochemistry in normal bronchial/bronchiolar epithelium, and in 109 bronchial preneoplastic lesions, in comparison with 32 squamous invasive carcinoma (SCC), and in 27 atypical alveolar hyperplasia (AAH) in comparison with 6 adenocarcinoma in situ (AIS; formerly bronchiolo-alveolar carcinoma) and 24 invasive adenocarcinoma (ADC).Results: Telomere length critically shortened at bronchial metaplasia stage to increase gradually from dysplasia to invasive SCC; in bronchiolo-alveolar lesions, telomere length decreased from normal to AIS and increased from stage I to II to stage III to IV ADC. Expression of TRF1 and TRF2 increased progressively from dysplasia to SCC and from AAH to invasive ADC. The expression of concomitant DDR proteins increased significantly from low-to high-grade dysplasia and from AAH to AIS and stage I to II ADC. P-CHK2 and p-H2AX expressions were highly correlated and both decreased, along with p-ATM, in SCC and advanced ADC.Conclusion: Telomere attrition occurs at the earliest stage of lung carcinogenesis as an initiating event, preceding TRF1 and TRF2 overexpression for telomere stabilization. In contrast, dismiss of DDR, through p-H2AX and p-CHK2 downregulation, represents a late progressing event associated with SCC and ADC progression. Clin Cancer Res; 16(11); 2979-88. ©2010 AACR.Lung cancer remains the leading cause of cancer-related death worldwide; its poor survival being mainly due to unresectable advanced diseases at the time of diagnosis. Eighty percent to 90% of lung cancers are related to tobacco consumption and lung carcinogenesis is a multifocal ("field cancerization") and a multistep process, resulting from the sequential accumulation of molecular and genetic/epigenetic abnormalities, mostly caused by tobacco carcinogens. These abnormalities lead to the activation of growthpromoting oncogenes and the inactivation of tumorsuppressor genes, favoring proliferation and resistance to apoptosis. Survival improvement will require the understanding of carcinogenesis events to identify the genetic markers of tumor initiation and progression, and to develop novel targeted therapeutic or prophylactic/preventive strategies.The main histologic types of lung cancer are small cell lung carcinoma (15%), adenocarcinoma (ADC), which increases in frequency worldwide (50%), and squamous cell carcinoma (SCC; 30%). The histologic transformation of bronchial and bronchiolo-alveolar epithelium parallels the accumulation of genetic...

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Section: Discussionmentioning

confidence: 49%

Telomere Maintenance and DNA Damage Responses during Lung Carcinogenesis

Lantuéjoul

Raynaud

Salameire

et al. 2010

Clinical Cancer Research

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“…Telomere shortening has been reported to occur in highly proliferative normal and cancer cells (Raynaud et al, 2010;Wentzensen et al, 2011;Xu and Blackburn, 2007). To compare the average telomere DNA length in tumor relative to normal cerebellar tissue, we compared the mean average fluorescence intensity of telomere DNA FISH signals.…”

Section: Terfs Form In Cells With Shortened Telomeresmentioning

confidence: 99%

Formation of telomeric repeat-containing RNA (TERRA) foci in highly proliferating mouse cerebellar neuronal progenitors and medulloblastoma

Deng

Wang

Xiang

et al. 2012

Journal of Cell Science

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SummaryTelomeres play crucial roles in the maintenance of genome integrity and control of cellular senescence. Most eukaryotic telomeres can be transcribed to generate a telomeric repeat-containing RNA (TERRA) that persists as a heterogeneous nuclear RNA and can be developmentally regulated. However, the precise function and regulation of TERRA in normal and cancer cell development remains poorly understood. Here, we show that TERRA accumulates in highly proliferating normal and cancer cells, and forms large nuclear foci, which are distinct from previously characterized markers of DNA damage or replication stress. Using a mouse model for medulloblastoma driven by chronic Sonic hedgehog (SHH) signaling, TERRA RNA was detected in tumor, but not adjacent normal cells using both RNA fluorescence in situ hybridization (FISH) and northern blotting. RNA FISH revealed the formation of TERRA foci (TERFs) in the nuclear regions of rapidly proliferating tumor cells. In the normal developing cerebellum, TERRA aggregates could also be detected in highly proliferating zones of progenitor neurons. SHH could enhance TERRA expression in purified granule progenitor cells in vitro, suggesting that proliferation signals contribute to TERRA expression in responsive tissue. TERRA foci did not colocalize with cH2AX foci, promyelocytic leukemia (PML) or Cajal bodies in mouse tumor tissue. We also provide evidence that TERRA is elevated in a variety of human cancers. These findings suggest that elevated TERRA levels reflect a novel early form of telomere regulation during replication stress and cancer cell evolution, and the TERRA RNA aggregates may form a novel nuclear body in highly proliferating mammalian cells.

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“…Telomeres are considered a biomarker for ageing and age-related diseases such as cancer [Plentz et al, 2004;Raynaud et al, 2010], heart disease [Samani et al, 2001;Salpea et al, 2008], osteoporosis [Valdes et al, 2007], and Alzheimer's disease [Panossian et al, 2003], which have been linked to telomere loss. Accelerated telomere shortening is caused by different physiological and pathological environmental factors, including oxidative stress [von Zglinicki et al, 1995;Epel et al, 2004].…”

Section: Discussionmentioning

confidence: 99%

Telomeres in Trisomy 21 Amniocytes

Sukenik-Halevy¹,

Biron‐Shental²,

Sharony³

et al. 2011

Cytogenet Genome Res

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Individuals with trisomy 21 have an increased risk of developing leukemia and premature dementia. They also have a higher rate of telomere loss. The aim of the study was to compare telomere length and the hTERC gene copy number, which encodes the telomerase RNA subunit, in amniocytes of trisomy 21 conceptions and normal pregnancies. A quantitative fluorescence-in-situ protocol (Q-FISH) was used to compare telomere length in amniocytes cultured from 11 trisomy 21 conceptions and from 14 normal pregnancies. Quantification was conducted using novel computer software. Fluorescence in situ hybridization (FISH) was used to assess the percentage of cells with additional copies of hTERC. We found that the immunofluorescence intensity, which represents telomere length, was significantly lower in amniocytes from trisomy 21 conceptions compared to the control group. The trisomy 21 group had a higher number of cells with additional copies of hTERC. This observation could be one of the cytogenetic parameters that represent a state of genetic instability and might play a role in the pathomechanism of typical features of Down syndrome, such as dementia and malignancy.

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DNA Damage Repair and Telomere Length in Normal Breast, Preneoplastic Lesions, and Invasive Cancer

Abstract: This study suggests that a major defect in DNA repair occurs between preneoplasia and breast cancer. This defect is associated with changes in telomere length between the preneoplastic and the cancer stage.

Cited by 42 publications

References 16 publications

Telomere Maintenance and DNA Damage Responses during Lung Carcinogenesis

Telomere Maintenance and DNA Damage Responses during Lung Carcinogenesis

Formation of telomeric repeat-containing RNA (TERRA) foci in highly proliferating mouse cerebellar neuronal progenitors and medulloblastoma

Telomeres in Trisomy 21 Amniocytes

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