Homozygous deletion of p16<sup>INK4a</sup>and tobacco carcinogen exposure in nonsmall cell lung cancer

Kraunz, Kim S.; Nelson, Heather H.; Lemos, Miriam; Godleski, John J.; Wiencke, John K.; Kelsey, Karl T.

doi:10.1002/ijc.21522

Cited by 32 publications

(37 citation statements)

References 24 publications

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“…The results indicate that causative factors for p16 HD were different from those for p16 methylation, although both alterations result in the inactivation of the same gene. Previously, Kraunz and colleagues reported that p16 HD occurred at a higher frequency in neversmokers as compared with former and current smokers (6). Although such an association was not observed in this study, both studies indicated the absence of a positive association between p16 HD and smoking history, and the possible association of p16 HD with other causative factors for lung adenocarcinoma.…”

Section: Resultscontrasting

confidence: 76%

“…However, it is still unknown whether p16 HD also occurs preferentially in the KRAS type or not. In addition, the involvement of tobacco smoking in the occurrence of p16 HD is also unclear because both positive and negative associations between tobacco smoking and HD have been reported (5,6). Indeed, p16 HDs have been reported to occur with a highly variable frequency in primary lung adenocarcinomas (0 -40%; refs.…”

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confidence: 99%

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Association of p16 Homozygous Deletions with Clinicopathologic Characteristics and EGFR/KRAS/p53 Mutations in Lung Adenocarcinoma

Iwakawa

Anami

Noguchi

et al. 2008

Clinical Cancer Research

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Purpose:Thep16 geneis frequentlyinactivatedinlungadenocarcinoma.Inparticular,homozygous deletions (HD)havebeenfrequentlydetectedincelllines; however, their frequencyandspecificityis not well-established in primary tumors.The purpose of this study was to elucidate the prevalence and the timing for the occurrence of p16 HDs inlung adenocarcinoma progression in vivo. Experimental Design: Multiple ligation-dependent probe amplification was used for the detection of p16 HDs in 28 primary small-sized lung adenocarcinomas and 22 metastatic lung adenocarcinomas to the brain. Cancer cells were isolated from primary adenocarcinoma specimens by laser capture microdissection. HDs were confirmed by quantitative real-time genomic PCR analysis. Results: HDs were detected in 8 of 28 (29%) primary tumors, including 2 of 8 (25%) noninvasive bronchioloalveolar carcinomas, and 5 of 22 (26%) brain metastases, respectively. No significant associations were observed between p16 HDs and gender, age, smoking history, stage, and prognosis. HDs were detected with similar frequencies (17^29%) among adenocarcinomas with epidermal growth factor receptor (EGFR) mutations, with KRAS mutations, and without EGFR/KRAS mutations, and with similar frequencies (22^28%) between adenocarcinomas with and without p53 mutations. Conclusions: p16 HDs occur early in the development of lung adenocarcinomas and with similar frequencies among EGFR type, KRAS type, and non-EGFR/KRAS type lung adenocarcinomas. Tobacco carcinogens would not be a major factor inducing p16 HDs in lung adenocarcinoma progression.

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Section: Resultscontrasting

confidence: 76%

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confidence: 99%

Association of p16 Homozygous Deletions with Clinicopathologic Characteristics and EGFR/KRAS/p53 Mutations in Lung Adenocarcinoma

Iwakawa

Anami

Noguchi

et al. 2008

Clinical Cancer Research

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“…The lack of prognostic influence of p16 methylation found in our study was previously reported (30,34), with the IALT group confirming that p16 immunohistochemistery did not influence prognosis in early-stage NSCLC (35). The p16 promoter is not the sole mechanism in the inactivation of the CDKN2A locus, which also includes chromosome 9p21 deletion (36). In a previous work involving the same series of patients, we reported that 9p21 AI tended to be a predictor of worse prognosis in a multivariate model with Hochberg correction (HR ¼ 1.61, 95% CI: 0.90-2.90, P ¼ 0.13; ref.…”

Section: Discussionsupporting

confidence: 71%

An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial

Fraipont

Levallet

Créveuil

et al. 2012

Clinical Cancer Research

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Purpose: To evaluate prognostic and predictive molecular biomarkers in early-stage non-small cell lung carcinoma (NSCLC) receiving neoadjuvant chemotherapy.Experimental Design: The IFCT-0002 trial compared two neoadjuvant regimens in 528 stages I to II NSCLC patients. DNA extraction of snap-frozen surgical samples taken from 208 patients receiving gemcitabine-cisplatin or paclitaxel-carboplatin regimens allowed for the identification of 3p allelic imbalance, Ras association domain family 1A (RASSF1A) and death-associated protein kinase 1 (DAPK1) promoter methylation, and epidermal growth factor receptor, K-ras, and TP53 mutations. Multivariate analysis identified prognostic and predictive effects of molecular alterations. A Bootstrapping approach was used to assess stability of the prognostic models generating optimism corrected indexes.Results: RASSF1A methylation correlated significantly with shorter disease-free survival (DFS; adjusted HR ¼ 1.88, 95% CI: 1.25-2.82, P ¼ 0.0048) and shorter median overall survival (OS; adjusted HR ¼ 2.01, 95% CI: 1.26-3.20, P ¼ 0.020). A computed bootstrap resampling strategy led to a prognostic model, including RASSF1A, DAPK1, and tumor stage, dividing patients into three prognostic groups, with median OS ranging from 34 months for high-risk patients (HR for death ¼ 3.85, 95% CI: 1.79-6.40) to more than 84 months for moderate (HR ¼ 1.85, 95% CI: 0.97-3.52) and low-risk patients (reference group; P ¼ 0.00044). In addition, RASSF1A methylation predicted longer DFS in patients treated with paclitaxel-carboplatin compared with gemcitabine-cisplatin (adjusted HR ¼ 0.47, 95% CI: 0.23-0.97, P interaction ¼ 0.042).Conclusions: Following neoadjuvant chemotherapy, RASSF1A methylation negatively impacted prognosis of early-stage NSCLC. Along with DAPK1 methylation and tumor stage, RASSF1A methylation allowed definition of three subgroups with strikingly different prognosis. Conversely, significantly longer DFS following paclitaxel-based neoadjuvant chemotherapy for patients whose tumors showed RASSF1A methylation suggested its predictive interest in stages I and II NSCLC.

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“…Study design and patient accruement for the NSCLC (12), bladder cancer (13), HNSCC (14), and mesothelioma (15) case series have previously been described. In each study, subjects provide written informed consent according to institutional review board protocols.…”

Section: Methodsmentioning

confidence: 99%

Examination of a CpG Island Methylator Phenotype and Implications of Methylation Profiles in Solid Tumors

Marsit¹,

Houseman

Christensen³

et al. 2006

Cancer Research

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The CpG island methylator phenotype (CIMP), thoroughly described in colorectal cancer and to a lesser extent in other solid tumors, is important in understanding epigenetics in carcinogenesis and may be clinically useful for classification of neoplastic disease. Therefore, we investigated whether this putative phenotype exists in exposure-related solid tumors, where somatic gene alterations and enhanced clonal growth are selected for by carcinogens, and examined the ability of methylation profiles to classify malignant disease. We studied promoter hypermethylation of 16 tumor suppressor genes and 3 MINT loci (acknowledged classifiers of CIMP) in 344 bladder cancers, 346 head and neck squamous cell carcinomas (HNSCC), 146 non-small-cell lung cancer (NSCLC), and 71 malignant pleural mesotheliomas (MPM). We employed rigorous statistical methods to examine the distribution of promoter methylation and the usefulness of these profiles for disease classification. In bladder cancer, HNSCC, and NSCLC, there was a significant correlation (P < 0.0001) between methylation of the three MINT loci and methylation index, although the distribution of methylated loci varied significantly across these disease. Although there was a significant (P < 0.001) association between gene methylation profile and disease, rates of misclassification of each disease by their methylation profile ranged from 28% to 32%, depending on the classification scheme used. These data suggest that a form of CIMP exists in these solid tumors, although its etiology remains elusive. Whereas the gene profiles of hypermethylation among examined loci could not unequivocally distinguish disease type, the existence of CIMP and the relative preponderance of hypermethylation in these cancers suggest that methylation analysis may be clinically useful as a targeted screening tool.

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Homozygous deletion of p16^INK4aand tobacco carcinogen exposure in nonsmall cell lung cancer

Cited by 32 publications

References 24 publications

Association of p16 Homozygous Deletions with Clinicopathologic Characteristics and EGFR/KRAS/p53 Mutations in Lung Adenocarcinoma

Association of p16 Homozygous Deletions with Clinicopathologic Characteristics and EGFR/KRAS/p53 Mutations in Lung Adenocarcinoma

An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial

Examination of a CpG Island Methylator Phenotype and Implications of Methylation Profiles in Solid Tumors

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Homozygous deletion of p16INK4aand tobacco carcinogen exposure in nonsmall cell lung cancer

Cited by 32 publications

References 24 publications

Association of p16 Homozygous Deletions with Clinicopathologic Characteristics and EGFR/KRAS/p53 Mutations in Lung Adenocarcinoma

Association of p16 Homozygous Deletions with Clinicopathologic Characteristics and EGFR/KRAS/p53 Mutations in Lung Adenocarcinoma

An Apoptosis Methylation Prognostic Signature for Early Lung Cancer in the IFCT-0002 Trial

Examination of a CpG Island Methylator Phenotype and Implications of Methylation Profiles in Solid Tumors

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Homozygous deletion of p16^INK4aand tobacco carcinogen exposure in nonsmall cell lung cancer