A Subset of Lung Adenocarcinomas and Atypical Adenomatous Hyperplasia–Associated Foci Are Genotypically Related

Sartori, Giuliana; Cavazza, Alberto; Bertolini, Federica; Longo, Lucia; Marchioni, Alessandro; Costantini, Matteo; Barbieri, Fausto; Migaldi, Mario; Rossi, Giulio

doi:10.1309/thu13f3jrjvwlm30

Cited by 43 publications

(32 citation statements)

References 74 publications

(139 reference statements)

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“…Specifically, this association was a significant characteristic of patients with well to moderately differentiated tumors (grade 1/2), patients with tumors in early stages (stage I/II), and adenocarcinoma patients. KRAS mutations are known to be commonly associated with adenocarcinoma subtype and early staged NSCLC, occurring even within premalignant lesions [34,35]. Therefore, our results point to a possible cooperation of CCND1 with KRAS in early pathogenesis of NSCLC and development of adenocarcinoma subtype.…”

Section: Discussionsupporting

confidence: 57%

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

et al. 2015

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Cyclin D1 is one of the major cellular oncogenes, overexpressed in number of human cancers, including non-small cell lung carcinoma (NSCLC). However, it does not exert tumorigenic activity by itself, but rather cooperates with other altered oncogenes and tumor suppressors. Therefore, in the present study, we have examined mutual role of cyclin D1, KRAS, and PTEN alterations in the pathogenesis of NSCLC and their potential to serve as multiple molecular markers for this disease. CCND1 gene amplification and gene expression were analyzed in relation to mutational status of KRAS gene as well as to PTEN alterations (loss of heterozygosity and promoter hypermethylation) in NSCLC patient samples. Moreover, the effect of these co-alterations on patient survival was examined. Amplified CCND1 gene was exclusively associated with increased gene expression. Statistical analyses also revealed significant association between CCND1 overexpression and KRAS mutations in the whole group and in the groups of patients with adenocarcinoma, grade 1/2, and stage I/II. In addition, CCND1 overexpression was significantly related to PTEN promoter hypermethylation in the whole group and in the group of patients with squamous cell carcinoma and lymph node invasion. These joint alterations also significantly shortened patients' survival and were shown to be an independent factor for adverse prognosis. Overall results point that cyclin D1 expression cooperates with KRAS and PTEN alterations in pathogenesis of NSCLC, and they could serve as potential multiple molecular markers for specific subgroups of NSCLC patients as well as prognostic markers for this type of cancer.

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Section: Discussionsupporting

confidence: 57%

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

et al. 2015

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“…12 In humans, K-ras mutations were detected in 25% to 40% of atypical adenomatous hyperplasia, suggesting that K-ras mutation may be an early event in human lung cancer development. 22 The p53 tumor suppressor functions in a network of pathways, playing critical roles in cell cycle check points, apoptosis, DNA repair, and recombination. 9 Inactivation of the p53 gene plays an important role in the pathogenesis of human lung cancer.…”

Section: Discussionmentioning

confidence: 99%

Morphologic and Molecular Analysis of 39 Spontaneous Feline Pulmonary Carcinomas

et al. 2011

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The present study was performed to determine the morphologic change and selected molecular features of spontaneous lung tumors in cats examined at the North Carolina State University Veterinary Teaching Hospital. Thirty-nine primary lung carcinomas represented 0.69% of all feline cases admitted to the hospital. Most lung tumors were observed in aged cats (P < .0001), and no sex predilection was found (P < .4241). Persian cats with pulmonary carcinoma were overrepresented in the data set, at least 4 times more frequently than other breeds. The histologic tumor types included adenocarcinoma (64.1%), bronchioloalveolar carcinoma (20.5%), and adenosquamous carcinoma (15.4%). Metastasis was observed in about 80% of 39 cases, with decreasing order of intrapulmonary metastasis, intrathoracic carcinomatosis, regional lymph nodes, and distant organs, including digits. The size of the largest tumor mass was significantly associated with metastatic potential (P < .001). Based on immunohistochemistry, more than 80% (20 of 24) of feline lung tumors were positively labeled with either surfactant protein A or thyroid transcription factor 1. Epidermal growth factor receptor mutant and p53 proteins were detected in approximately 20% (5 of 24) and 25% (6 of 24) of the feline lung tumor cases, respectively. Limited sequencing analysis of K-ras and p53 genes in 3 selected normal and neoplastic lung tissues did not reveal any alteration. Results indicate that primary lung carcinomas are rare but aggressive tumors in cats, thereby warranting further studies on molecular carcinogenesis.

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“…The development of peripheral pulmonary ADC involves multiple genetic alterations [3]. Mutations of epidermal growth factor receptor (EGFR) or K-ras genes have been detected in preinvasive lesions such as AAH, AIS (formerly BAC), and ADC [2,[4][5][6][7][8][9][10][11][12]. Somatic mutations and increased expression of p53 were detected in advanced ADC [13].…”

Section: Introductionmentioning

confidence: 99%

“…Somatic mutations and increased expression of p53 were detected in advanced ADC [13]. While genetic alterations have been extensively studied in the multistep carcinogenesis model in the peripheral airway, epigenetic abnormalities have not been identified [2,3,6,7,9,10,14,15].…”

Section: Introductionmentioning

confidence: 99%

DNA methylation profile during multistage progression of pulmonary adenocarcinomas

et al. 2011

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Multiple genetic and epigenetic alterations are known to be involved in the carcinogenesis of peripheral pulmonary adenocarcinoma (ADC). However, epigenetic abnormalities have not been extensively investigated in the following multistage progression sequence: atypical adenomatous hyperplasia (AAH) to adenocarcinoma in situ (AIS), to invasive ADC. To determine the potential role of promoter methylation during ADC development of the lung, we examined methylation status in 20 normal, 20 AAH, 30 AIS, and 60 ADC lung tissues and compared methylation status among the lesions. The MethyLight assay was used to determine the methylation status of 18 CpG island loci, which were hypermethylated in ADC compared to noncancerous lung tissues. The mean number of methylated CpG island loci was significantly higher in ADC than in AAH and AIS, (p < 0.003 between ADC and AAH, p < 0.005 between ADC and AIS). Aberrant methylation of HOXA1, TMEFF2, and RARB was frequently observed in preinvasive lesions, including AAH and AIS. Furthermore, methylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was significantly more frequent in invasive ADC than AAH or AIS. Our results indicate that epigenetic alterations are involved in the multistep progression of pulmonary ADC development, and aberrant CpG island methylation accumulates during multistep carcinogenesis. In addition, aberrant methylation of HOXA1, TMEFF2, and RARB occurred in preinvasive lesions, which indicates that epigenetic alterations of these genes are involved in the early stages of pulmonary ADC development. In contrast, hypermethylation of PENK, BCL2, RUNX3, DLEC1, MT1G, GRIN2B, CDH13, CCND2, and HOXA10 was more frequent in invasive ADC than in preinvasive lesions, which indicates that methylation of these genes occurs later during tumor invasion in the AAH-AIS-ADC sequence.

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A Subset of Lung Adenocarcinomas and Atypical Adenomatous Hyperplasia–Associated Foci Are Genotypically Related

Cited by 43 publications

References 74 publications

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients’ outcome

Morphologic and Molecular Analysis of 39 Spontaneous Feline Pulmonary Carcinomas

DNA methylation profile during multistage progression of pulmonary adenocarcinomas

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