Inactivation of the p16 gene by hypermethylation and loss of heterozygosity in adenocarcinoma of the lung

Awaya, Hirokazu; Takeshima, Yukio; Amatya, Vishwa Jeet; Furonaka, Osamu; Kohno, Nobuoki; Inai, Kei

doi:10.1111/j.1440-1827.2004.01655.x

Cited by 15 publications

(24 citation statements)

References 21 publications

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“…By means of a different panel of microsatellite markers detecting specific chromosome regions comprising tumor suppressor genes (FHIT, Rb, p16, p53) 1,2,8,12,28,35,36 deeply involved in lung cancer and adenocarcinoma histotype in particular. Overall, we found LOH in 55.5% of the analyzed cases then supporting the previous observations by Dacic et al 9 concerning the finding of allelic losses in SH.…”

Section: Discussionmentioning

confidence: 99%

“…3,4,7,11,[17][18][19][23][24][25][29][30][31]40 Of note, EGFR mutational events seem to be quite specific of lung adenocarcinoma with BAC features. 17,18 In addition, a recent work by Dacic et al 9 suggested a common origin for SH and nm-BAC on the basis of the finding of similar patterns of allelic loss using a panel of 7 polymorphic microsatellite markers located on chromosomal regions encoding for tumor suppressor genes involved in pulmonary adenocarcinoma tumorigenesis.We report here the results of an immunohistochemical, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR)-based molecular study by means of loss of heterozygosity (LOH) analysis using a panel of markers identifying tumor suppressor genes thought to be key molecules in the neoplastic sequential events of lung adenocarcinomagenesis (FHIT, p16, Rb, p53) 1,2,8,12,28,35,36 and also direct sequencing of EGFR (exons 18-21), HER2 (exons 19 and 20), and K-RAS …”

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confidence: 99%

“…We report here the results of an immunohistochemical, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR)-based molecular study by means of loss of heterozygosity (LOH) analysis using a panel of markers identifying tumor suppressor genes thought to be key molecules in the neoplastic sequential events of lung adenocarcinomagenesis (FHIT, p16, Rb, p53) 1,2,8,12,28,35,36 and also direct sequencing of EGFR (exons 18-21), HER2 (exons 19 and 20), and K-RAS (exon 2) genes in a series of 11 SH. This work was aimed at further investigating the molecular mechanisms underlying SH tumorigenesis also in view of the relationship between SH and nm-BAC.…”

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confidence: 99%

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Microsatellite and EGFR, HER2 and K-RAS Analyses in Sclerosing Hemangioma of the Lung

Sartori

Bettelli

Schirosi

et al. 2007

American Journal of Surgical Pathology

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Sclerosing hemangioma (SH) is an uncommon pulmonary tumor thought to derive from primitive respiratory epithelium consisting of 2 cell populations (cuboidal surface and polygonal stromal cells) and sharing some clinical characteristics (frequent occurrence in nonsmoking women of Asian ethnicity) with bronchioloalveolar carcinoma with which it has been suggested a possible common origin. We investigated 11 cases of SH by immunohistochemistry, fluorescence in situ hybridization, and polymerase chain reaction-based microsatellite and mutational analyses with particular emphasis on possible alterations of microsatellite loci located at tumor suppressor genes (FHIT, p16, Rb, and p53) involved in lung adenocarcinoma genesis and EGFR, HER2, and K-RAS genes. Although EGFR expression was observed in all tested cases, none showed HER2 immunostaining. Fluorescence in situ hybridization and mutational analysis of EGFR and HER2 and also K-RAS sequencing did not reveal molecular alterations, whereas allelic losses at p16 and Rb loci (4 and 2 out of 9 tested cases, respectively) with an identical microsatellite allelic loss pattern in both cuboidal and polygonal cells were observed. The finding of microsatellite alterations in chromosomal regions related to genes deeply involved in early stage lung adenocarcinoma could suggest a possible link between SH and bronchioloalveolar carcinoma, but tumor pathway promoted by EGFR, HER2, and K-RAS does not represent a common molecular mechanism of tumorigenesis. Microsatellite alterations identified in cuboidal and polygonal cells further confirm the clonal and neoplastic nature of both components of SH. SH has 4 basic histologic patterns (solid, hemorrhagic, papillary, and fibrotic) often mixed with each other, and 2 cell populations consisting of surface cuboidal cells lining the papillae and polygonal stromal cells growing in the interstitium. 33 The tumor has been the subject of several controversies about its histogenesis and, although it is now accepted that the polygonal cells are neoplastic and take origin from primitive respiratory epithelium, some controversies remain about the nature of the surface cuboidal cells (entrapped alveoli? a complete differentiation of the polygonal ones?) and the relationship between the 2 cell types. 6,10,14,27,34,37,39,41 To date, no systemic metastases have been reported for this tumor, while it can show cellular atypia, foci of vascular invasion, and metastatic deposits into the regional lymph nodes. 20,32,38 However, none of these features seems to affect the good prognosis of patients with SH. 20It is surprising to note that both SH and nonmucinous type bronchioloalveolar carcinoma (nm-BAC) share several clinical characteristics, given that both neoplasms most commonly occur in nonsmoking, middle-aged women of East Asia ethnicity.33 Several works recently demonstrated that patients with nm-BAC or pulmonary adenocarcinoma with prominent BAC features are also frequently characterized by somatic and mutually exclusive mutations involvi...

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Microsatellite and EGFR, HER2 and K-RAS Analyses in Sclerosing Hemangioma of the Lung

Sartori

Bettelli

Schirosi

et al. 2007

American Journal of Surgical Pathology

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“…Clinical observations show that individuals with 9p21 LOH have better survival rates than those with homozygous deletion (16). Interestingly, experimental evidence suggests that the silencing of the remaining p16INK4A allele after allelic loss is predominantly due to epigenetic methylation rather than mutation (3).…”

Section: Loss Of Heterozygosity (Loh)mentioning

confidence: 99%

Molecular and Genetic Aspects of Lung Cancer

Zeyadi

2013

Biotechnology & Biotechnological Equipment

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“…), biallelic inactivation through LOH combined with hypermethylation was seen in 22% of ADCs, providing a mechanism for progressive CDKN2A deregulation [145]. The p16 gene encodes cell cycle proteins (inhibitor of CDK4 and CDK6) and negatively regulates cyclin D-dependent phosphorylation of the Rb gene product, thereby inhibiting cell cycle progression from G1 to S-phase by sequestration of E2F [146,147].…”

Section: Ink4amentioning

confidence: 99%

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2013

J Surg

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Detection of small peripheral ground-glass opacity nodules has increased due to the advances in imaging modalities and the widespread use of computed tomography screening. Pathologic examination of these nodules revealed that they have a pure lepidic or replacement growth pattern such as atypical adenomatous hyperplasia or adenocarcinoma in situ (formerly known as bronchioloalveolar carcinoma). When untreated, ground-glass opacity nodules gradually develop a solid component. The greater the solid component or the invasive component, the less favorable outcomes after treatment for patients with ground-glass opacity nodules. Based on the clinical, radiologic and pathologic findings, the concept of multistep progression from preinvasive atypical adenomatous hyperplasia through noninvasive adenocarcinoma in situ to invasive adenocarcinoma has been postulated. Recently, evidence has accumulated explaining this putative concept by molecular alterations, including activating mutation of oncogenes and inactivation of tumor suppressor genes by epigenetic changes or loss of heterozygosity. This review 1) comprehensively outlines the accumulated knowledge regarding radiologic and pathologic features of adenocarcinoma and its precursor which presents as ground-glass opacity and 2) summarizes the molecular basis of the multistep progression to lung adenocarcinoma. As a result, we believe identification of undiscovered molecular markers involved in the progression of lung adenocarcinoma is critical for early detection of lung cancer and the development of targeted therapeutic and chemoprevention strategies. IntroductionLung cancer is the leading cause of cancer deaths in the United States and worldwide with over 1.3 million deaths in 2008 [1][2][3]. Despite the fact that enormous resources have been spent on research involving molecular and therapeutic aspects of lung adenocarcinoma (ADC), there has been no significant improvement in the mortality associated with lung cancer for the past 25 years. This can be attributed in part to untimely diagnosis at advanced stages or recurrence occurring even after optimal treatment at early stages. About 70% of patients are diagnosed with lung cancer at advanced stages when there is little chance to cure [4]. Although patients diagnosed at early stages receive curative-intent complete resection by surgery, about 20% of them will not survive due to recurrence within 5 years [5][6][7][8][9][10][11][12]. One cause may be that patients already have microscopic systemic metastases in other distant organs at the time of surgery. In order to reduce the mortality and eventually to overcome lung cancer, understanding carcinogenesis and tumor progression is paramount.ADC is the most common histologic type of non-small cell lung cancer (NSCLC) in the United States, accounting for almost half of all lung cancers [13,14]. ADC tends to develop distant organ metastases easily even in early stage compared to squamous cell carcinoma, underscoring the need for early detection methods. A multistep...

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Inactivation of the p16 gene by hypermethylation and loss of heterozygosity in adenocarcinoma of the lung

Cited by 15 publications

References 21 publications

Microsatellite and EGFR, HER2 and K-RAS Analyses in Sclerosing Hemangioma of the Lung

Microsatellite and EGFR, HER2 and K-RAS Analyses in Sclerosing Hemangioma of the Lung

Molecular and Genetic Aspects of Lung Cancer

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