Analysis of radon-associated squamous cell carcinomas of the lung for a p53 gene hotspot mutation

Yang, Qin; Wesch, H.; Km, Mueller; Bartsch, Helmut; Wegener, Kurt; Hollstein, Monica

doi:10.1054/bjoc.1999.0995

Cited by 18 publications

(11 citation statements)

References 12 publications

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“…However, no such mutations were found in this sample set implicating tumor histology as one determinant for the specific mutation [McDonald et al, 1995]. In following studies in lung cancers among uranium miners from Germany [Bartsch et al, 1995;Hollstein et al, 1997;Yang et al, 2000] the specific mutation was described in 2 out of 79 lung cancers, both of them in SCC. This was, however, not significantly different from the frequency of codon 249 mutations in lung cancer in the IARC-based p53 mutation database [Yang et al, 2000].…”

Section: Radonmentioning

confidence: 88%

TP53 mutations in workers exposed to occupational carcinogens

Vähäkangas¹

2003

Hum. Mutat.

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For the p53 Special IssueIn some cases, evidence exists that exogenous carcinogenic exposures contribute to the mutation spectrum of the TP53 gene (p53) in human cancers. Although the clearest examples come from dietary and environmental sources, only a restricted number of papers have concentrated specifically on TP53 mutations in tumors from workers exposed to occupational carcinogens. In populations exposed to dietary aflatoxin B1 with liver cancer (AFB1) and ultraviolet (UV)-radiation with skin cancer, a single specific-looking TP53 mutation has been described in some of the tumors. Whether these fingerprints in the TP53 gene can be used to reveal an occupational etiology remains to be shown. In other cases, although differences in the TP53 mutation spectrum exist, they are more diffuse and difficult to interpret at this point. For instance, cigarette smoking seems to induce long-lasting molecular footprints in TP53. However, their use to rule out other occupational exposures as etiological factors in occupational cancers is still very questionable, especially due to the putative synergistic effects of cigarette smoke with other carcinogens. Although interesting implications of possible typical mutation spectra among cancers with other occupational etiologies exist, the data are scanty and await further development of TP53 mutation databases. Hum Mutat 21:240-251,

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Section: Radonmentioning

confidence: 88%

TP53 mutations in workers exposed to occupational carcinogens

Vähäkangas¹

2003

Hum. Mutat.

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“…Genomic DNA was prepared from the tumor samples as previously described (Yang et al , 2000). PCR amplification was performed with primers previously described for exons 9 and 20 of PIK3CA (Samuels et al , 2004).…”

Section: Methodsmentioning

confidence: 99%

Targeting the Akt/mTOR pathway in Brca1-deficient cancers

et al. 2011

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The breast cancer susceptibility gene 1 (Brca1) has a key role in both hereditary and sporadic mammary tumorigenesis. However, the reasons why Brca1-deficiency leads to the development of cancer are not clearly understood. Activation of Akt kinase is one of the most common molecular alterations associated with human malignancy. Increased Akt kinase activity has been reported in most breast cancers. We previously found that downregulation of Brca1 expression or mutations of the Brca1 gene activate the Akt oncogenic pathway. To further investigate the role of Brca1/Akt in tumorigenesis, we analyzed Brca1/Akt expression in human breast cancer samples and found that reduced expression of Brca1 was highly correlated with increased phosphorylation of Akt. Consistent with the clinical data, knockdown of Akt1 by short-hairpin RNA inhibited cellular proliferation of Brca1 mutant cells. Importantly, depletion of Akt1 significantly reduced tumor formation induced by Brca1-deficiency in mice. The third generation inhibitor of mammalian target of rapamycin (mTOR), Palomid 529, significantly suppressed Brca1-deficient tumor growth in mice through inhibition of both Akt and mTOR signaling. Our results indicate that activation of Akt is involved in Brca1-deficiency mediated tumorigenesis and that the mTOR pathway can be used as a novel target for treatment of Brca1-deficient cancers.

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“…Among the 52 studied lung cancers, 16 contained an AGG – ATG transversion leading to an amino acid change (arg to met), distinct from the aflatoxin-related mutation in liver cancers at the same locus (AGG - AGT, arg to ser, (126, 127)). However, other studies of uranium miners with radon exposure (128–132), or of other environmentally exposed populations (43, 133, 134) have found very few or no codon 249 AGG-ATG mutations in lung cancers. The predominant type of mutations induced by ionizing radiation in mammalian cells are large deletions or translocations (127).…”

Section: Biomarkers Of Exposurementioning

confidence: 96%

Lung Cancer in Never Smokers: Molecular Profiles and Therapeutic Implications

Rudin

Ávila-Tang

Harris

et al. 2009

Clinical Cancer Research

137

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The majority of lung cancers are caused by long term exposure to the several classes of carcinogens present in tobacco smoke. Although a significant fraction of lung cancers in never smokers may also be attributable to tobacco, many such cancers arise in the absence of detectable tobacco exposure, and may follow a very different cellular and molecular pathway of malignant transformation. Recent studies summarized here suggest that lung cancers arising in never smokers have a distinct natural history, profile of oncogenic mutations, and response to targeted therapy. The majority of molecular analyses of lung cancer have focused on genetic profiling of pathways responsible for metabolism of primary tobacco carcinogens. Limited research has been conducted evaluating familial aggregation and genetic linkage of lung cancer, particularly among never smokers in whom such associations might be expected to be strongest. Data emerging over the past several years show that lung cancers in never smokers are much more likely to carry activating mutations of the epidermal growth factor receptor (EGFR), a key oncogenic factor and direct therapeutic target of several newer anticancer drugs. EGFR mutant lung cancers may represent a distinct class of lung cancers, enriched in the never-smoking population, and less clearly linked to direct tobacco carcinogenesis. These insights followed initial testing and demonstration of efficacy of EGFR-targeted drugs. Focused analysis of molecular carcinogenesis in lung cancers in never smokers is needed, and may provide additional biologic insight with therapeutic implications for lung cancers in both ever smokers and never smokers. Natural History and PrognosisThe preceding articles in this issue of CCR Focus present an overview, and a description of clinical epidemiology and risk factors associated with lung cancer in never smokers (1, 2). This article is intended to summarize the current status of molecular profiling of lung cancer in never smokers, to indicate how profiles differ between lung cancer in ever smokers and never smokers, and to review the therapeutic implications of these molecular characteristics. To place the therapeutic implications in context, this section will first summarize recent studies of differential clinical outcomes in lung cancer patients by ever smoker versus never smoker status, irrespective of therapies targeting particular molecular determinants.Four recent retrospective analyses have compared the characteristics and treatment outcomes of never smokers and smokers with lung cancer across stages of disease and regardless of modality of treatment (3-6). All of these series report on data obtained prior to widespread use of epidermal growth factor receptor (EGFR) inhibitors or other targeted therapies. Together these studies suggest that lung cancer in never smokers has peak incidence at a younger age than in smokers, is more likely to arise in women, and is more likely to be of adenocarcinoma histology. Furthermore, these studies show a survival adva...

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Analysis of radon-associated squamous cell carcinomas of the lung for a p53 gene hotspot mutation

Cited by 18 publications

References 12 publications

TP53 mutations in workers exposed to occupational carcinogens

TP53 mutations in workers exposed to occupational carcinogens

Targeting the Akt/mTOR pathway in Brca1-deficient cancers

Lung Cancer in Never Smokers: Molecular Profiles and Therapeutic Implications

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