Molecular variants of the ATM gene in Hodgkin's disease in children

Liberzon, Ella; Avigad, Smadar; Yaniv, Isaac; Stark, Batia; Avrahami, Gali; Goshen, Y.; Zaizov, Rina

doi:10.1038/sj.bjc.6601522

Cited by 18 publications

(17 citation statements)

References 37 publications

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“…The presence of inactivating point mutations in p53 in both tumors without large T antigen expression and in only 1 of 58 specimens that expressed large T antigen is highly signifi cant (Fisher's exact P = 0.0017). A fourth tumor specimen (UPI 38) contained a point substitution in ATM P604S (31). Notably, none of the other tumor specimens nor the 4 MCC cell lines showed the presence of any additional point mutations or polymorphisms tested in this panel.…”

Section: Resultsmentioning

confidence: 99%

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Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus

Rodig¹,

Cheng²,

Wardzala³

et al. 2012

J. Clin. Invest.

195

176

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Section: Resultsmentioning

confidence: 99%

“…This may rep resent a normal polymorphism, although normal tissue was not available from this patient to exclude this possibility (31). Two recent reports have identified point substitution mutations in the PIK3CA gene in MCC specimens (25,26).…”

Section: Discussionmentioning

confidence: 99%

Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus

Rodig¹,

Cheng²,

Wardzala³

et al. 2012

J. Clin. Invest.

195

176

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“…Two recent studies have addressed the role of potentially pathogenic heterozygous ATM germline variants 21, 22 in paediatric cHL. However, in neither of these was the ATM gene status addressed in a comprehensive manner in the tumour cell population.…”

Section: Introductionmentioning

confidence: 99%

Down‐regulation of ATM protein in HRS cells of nodular sclerosis Hodgkin's lymphoma in children occurs in the absence of ATM gene inactivation

Bose¹,

Starczynski

Chukwuma³

et al. 2007

The Journal of Pathology

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The tumour component of classical Hodgkin's lymphoma (cHL), Hodgkin Reed-Sternberg (HRS) cells, are believed to be derived from germinal centre (GC) B cells but intriguingly display a characteristic loss of B cell receptor (BCR) expression. The precise mechanisms by which BCR-negative HRS cell progenitors survive negative selection during the GC reaction remain obscure. Individuals with ataxia telangiectasia, caused by biallelic inactivation of the DNA damage response gene, ataxia telangiectasia mutated (ATM), have a higher risk of cHL development. Here we show that, in contrast to normal GC B cells that expressed low but detectable ATM protein, ATM protein was not detected in HRS cells of 17/18 cases of paediatric cHL, all but one with nodular sclerosis (NS) subtype. A comprehensive analysis of the ATM gene in microdissected HRS cells of nine representative tumours showed no evidence of either loss of heterozygosity or consistent pathogenic mutations. Furthermore, bisulphite sequencing of the ATM promoter from HRS cells of five tumours also revealed the absence of hypermethylation. Since our microarray data suggested significantly reduced ATM transcription in HRS cells compared to GC B cells, we conclude that loss of ATM expression could be the result of alterations in upstream regulators of ATM transcription. Importantly, ATM loss in paediatric cHLs has clinical implications and could be potentially exploited to guide future, less toxic, tumour-specific treatments.

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“…6,7 Individuals with inherited mutations or polymorphisms in the ATM gene (ATM) are more susceptible to various cancers, including lung cancer, breast cancer, leukemia, and lymphoma. [8][9][10][11] In addition, altered ATM expression levels have been identified in colon and pancreatic tumor tissues. 12,13 Accordingly, the prognostic value of ATM expression in colorectal and breast cancer has been investigated.…”

mentioning

confidence: 99%

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Xing

Vaporciyan

et al. 2008

Cancer

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BACKGROUND.The double‐strand break (DSB) repair capacity has been implicated in the survival of patients in several cancer types. However, little is known about the prognostic importance of the key DSB repair genes—ataxia‐telangiectasia mutated (ATM), DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs), and the Ku heterodimeric regulatory complex 86‐kD subunit (Ku80)—in nonsmall cell lung cancer (NSCLC). To address this issue, the authors determined the messenger RNA (mRNA) expression of these genes in patients NSCLC and assessed their prognostic relevance.METHODS.mRNA expression levels of ATM, DNA‐PKcs, and Ku80 were measured in tumor and adjacent normal tissues from 140 patients with NSCLC by using quantitative real‐time polymerase chain reaction analysis. Then, a Cox proportional hazards regression model and Kaplan‐Meier plots were used to evaluate the association between the tumor:normal (T/N) expression ratios of the 3 genes and the overall survival rate and duration in patients with NSCLC.RESULTS.mRNA expression of ATM and DNA‐PKcs, but not of Ku80, was significantly higher in tumor tissues than in adjacent normal tissues (P = .003 and P < .001, respectively). The high T/N expression ratios of ATM and DNA‐PKcs were associated significantly with a 1.82‐fold increased risk of death (95% confidence interval, 1.05–2.70) and a 2.13‐fold increased risk of death (95% confidence interval, 1.21–3.76), respectively. However, no significant association with risk was observed for Ku80. Kaplan‐Meier analyses revealed that patients with high T/N expression ratios of ATM or DNA‐PKcs had notably shorter median survival than patients with low ratios.CONCLUSIONS.The current findings suggested that the T/N expression ratios of ATM and DNA‐PKcs may be useful for identifying NSCLC patients with a poor prognosis who may benefit from more aggressive therapy. Cancer 2008. ©2008 American Cancer Society.

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Molecular variants of the ATM gene in Hodgkin's disease in children

Cited by 18 publications

References 37 publications

Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus

Improved detection suggests all Merkel cell carcinomas harbor Merkel polyomavirus

Down‐regulation of ATM protein in HRS cells of nodular sclerosis Hodgkin's lymphoma in children occurs in the absence of ATM gene inactivation

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

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