5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers

Merlo, Adrian; Herman, James G.; Li, Mao; Lee, Dong Hoon; Gabrielson, Edward; Burger, Peter C.; Baylin, Stephen B.; Sidransky, David

doi:10.1038/nm0795-686

Cited by 1,779 publications

(1,150 citation statements)

References 33 publications

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“…It is well known that hypermethylation involving p16 is a frequent mechanism for loss of p16 expression in several common cancers (Merlo et al, 1995;Reed et al, 1996;Wong et al, 1997) but is substantially less frequent in bladder cancer (Spruck et al, 1994). However, regardless of the mechanism, our data support the hypothesis that loss of p16 protein expression is associated with the overexpression of RB recently reported to have similar biological and clinical signi®cance as loss of RB expression in bladder tumors (Cote et al, 1998;Grossman et al, 1998).…”

Section: Discussionsupporting

confidence: 88%

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

et al. 1999

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Recent studies have shown that patients whose bladder cancer exhibit overexpression of RB protein as measured by immunohistochemical analysis do equally poorly as those with loss of RB function. We hypothesized that loss of p16 protein function could be related to RB overexpression, since p16 can induce transcriptional downregulation of RB and its loss may lead to aberrant RB regulation. Conversely, loss of RB function has been associated with high p16 protein expression in several other tumor types. In the present study RB negative bladder tumors also exhibited strong nuclear p16 staining while each tumor with strong, homogeneous RB nuclear staining were p16 negative, supporting our hypothesis. To expand on these immunohistochemical studies additional cases were selected in which the status of the p16 encoding gene had been determined at the molecular level. Absent p16 and high RB protein expression was found in the tumors having loss of heterozygosity within 9p21 and a structural change (mutation or deletion) of the remaining p16 encoding gene allele, con®rming the staining results. These results strongly support the hypothesis that the RB nuclear overexpression recently associated with poor prognosis in bladder cancer is also associated with loss of p16 function and implies that loss of p16 function could be equally deleterious as RB loss in bladder and likely other cancers.

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Section: Discussionsupporting

confidence: 88%

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

et al. 1999

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“…Alterations in microsatellite size (microsatellite alterations) are present in many cancers, including lung carcinomas (Adachi et al, 1995;Fong et al, 1995;Mao et al, 1994;Merlo et al, 1994) and may re¯ect a form of genomic instability (Wistuba et al, 1998). We found MAs in 50% of the invasive tumors and in lesser percentages of histologically normal, preneoplastic and CIS foci.…”

Section: Discussionmentioning

confidence: 76%

“…MAs represent changes in the size of simple nucleotide repeat polymorphic microsatellite markers, resulting in altered electrophoretic mobility of one or both alleles. In lung cancers they have been reported to occur at frequencies ranging from 0 ± 45% (Adachi et al, 1995;Fong et al, 1995;Merlo et al, 1994). Although the mechanisms underlying MAs are currently unknown, they may represent a manifestation of genomic instability (Fishel, 1996).…”

Section: Introductionmentioning

confidence: 99%

Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma

et al. 1999

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To understand the molecular pathways involved in the pathogenesis of squamous cell lung carcinoma, we obtained DNA from 94 microdissected foci from 12 archival surgically resected tumors including histologically normal epithelium (n=13), preneoplastic lesions (n=54), carcinoma is situ (CIS) (n=15) and invasive tumors (n=12). We determined loss of heterozygosity (LOH) at 10 chromosomal regions (3p12, 3p14.2, 3p14.1-21.3, 3p21, 3p22-24, 3p25, 5q22, 9p21, 13q14 RB, and 17p13 TP53) frequently deleted in lung cancer, using 31 polymorphic microsatellite markers, including 24 that spanned the entire 3p arm. Our major ®ndings are as follows: (1) Thirty one percent of histologically normal epithelium and 42% of mildly abnormal (hyperplasia/metaplasia) specimens had clones of cells with allelic loss at one or more regions; (2) There was a progressive increase of the overall LOH frequency within clones with increasing severity of histopathological changes; (3) The earliest and most frequent regions of allelic loss occurred at 3p21, 3p22-24, 3p25 and 9p21; (4) The size of the 3p deletions increased with progressive histologic changes; (5) TP53 allelic loss was present in many histologically advanced lesions (dysplasia and CIS); (6) Analyses of 58 normal and non-invasive foci having any molecular abnormality, indicated that 30 probably arose as independent clonal events, while 28 were potentially of the same clonal origin as the corresponding tumor; (7) Nevertheless, when the allelic losses in the 30 clonally independent lesions and their clonally unrelated tumors were compared the same parental allele was lost in 113 of 125 (90%) of comparisons. The mechanism by which this phenomenon (known as allele speci®c mutations) occurs is unknown; (8) Four patterns of allelic loss in clones were found. Histologically normal or mildly abnormal foci had a negative pattern (no allelic loss) or early pattern of loss while all foci of CIS and invasive tumor had an advanced pattern. However dysplasias demonstrated the entire spectrum of allelic loss patterns, and were the only histologic category having the intermediate pattern. Our ®ndings indicate that multiple, sequentially occurring allele speci®c molecular changes commence in widely dispersed, apparently clonally independent foci, early in the multistage pathogenesis of squamous cell carcinomas of the lung.

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“…The pattern of genetic changes found in primary lung tumors are characteristic of, but not speci®c for, either NSCLC or SCLC. NSCLC specimens contain activating K-ras mutations in 20 ± 50% of the tumors (Rodenhuis and Slebos et al, 1990;Mills et al, 1995); 50% have deletions or mutations of p53 (Kondo et al, 1992;Mitsudomi et al, 1992); 60% show deletion or reduced expression of p16 INK4a (Kamb et al, 1994;Okamoto et al, 1994Okamoto et al, , 1995Merlo et al, 1995;Shapiro et al, 1995;Xiao et al, 1995); and up to 30% show deletion or reduced expression of Rb (Xu et al, 1991;Reissmann et al, 1993). SCLC specimens demonstrate overexpression of the myc family of protooncogenes due to gene ampli®cation in 10 ± 40% of the tumors (Little et al, 1983;Johnson et al, 1987;Takahashi et al, 1989;Noguchi et al, 1990); 80% have p53 mutations or deletions Hensel et al, 1991;Takahashi et al, 1991;Sameshima et al, 1992); and 90% have deletions of Rb (Yokota et al, 1988;Hensel et al, 1990).…”

Section: Human Lung Cancer: Molecular Characterizationmentioning

confidence: 99%

Modeling human lung cancer in mice: similarities and shortcomings

1999

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Lung cancer kills more Americans yearly than any other neoplastic process. Mortality rates have changed little over the past several decades, despite improvements in surgical techniques, radiation therapy and chemotherapy. The identi®cation of mutations in oncogenes and tumor suppressor genes in human lung tumor specimens, including K-ras, p53, p16 INK4a and Rb, o ers molecular explanations for tumor development and resistance to therapy. Mouse models of human lung cancer may advance our understanding of this disease. The examination of mice which develop lung cancer either spontaneously or due to carcinogen exposure, and the creation of mouse strains harboring the speci®c genetic mutations found in human lung cancer are among strategies being pursued.

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5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers

Cited by 1,779 publications

References 33 publications

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

Level of retinoblastoma protein expression correlates with p16 (MTS-1/INK4A/CDKN2) status in bladder cancer

Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma

Modeling human lung cancer in mice: similarities and shortcomings

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