061 Mutations of the INK4a locus in basal cell carcinomas

Kubo, Yuko; Urano, Yoshio; Arase, S.

doi:10.1016/s0923-1811(97)81766-5

Cited by 24 publications

(46 citation statements)

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“…It has previously been reported that 14% of squamous cell carcinomas have intragenic mutations or deletions in exon 2 of the INK4a/ARF locus affecting both p16 INK4a and p14 ARF . 6 In another report, exon 2 of the INK4a/ ARF locus was mutated in 24% of squamous lesions. 5 It is though apparent, that the cytoplasmic p16 INK4a did not inhibit the phosphorylation of Rb and consequently did not affect proliferation.…”

Section: Discussionmentioning

confidence: 95%

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Retinoblastoma protein function and p16INK4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16INK4a expression and infiltrative behavior

2004

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p16 INK4a is involved in many important regulatory events in the cell and the expression and function is closely associated with the retinoblastoma protein (Rb). Earlier, we have in colorectal cancer and in basal cell carcinoma showed that p16 INK4a is upregulated at the invasive front causing cell cycle arrest in infiltrative tumor cells via a functional Rb. This role for p16 INK4a as a regulator of proliferation when tumor cells infiltrate might besides a general cyclin-dependent kinase (cdk) inhibitory effect explain why p16 INK4a is deregulated in many tumor forms. The expression pattern of p16 INK4a in relation to Rb-function in squamous cancer and precancerous forms of the skin has not been fully detailed. We therefore characterized the expression of p16 INK4a , Rb-phosphorylation and proliferation in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma with special reference to infiltrative behavior. The expression of p16 INK4a varied between the lesions, with weak and cytoplasmic p16 INK4a expression and functional Rb in actinic keratosis. Strong nuclear and cytoplasmic p16 INK4a expression was observed in all carcinomas in situ in parallel with lack of Rb-phosphorylation but high proliferation indicating a nonfunctional Rb. Invasive squamous carcinoma showed a mixed p16 INK4a expression pattern where some tumors had strong cytoplasmic p16 INK4a expression, large fraction of Rb-phosphorylated cells and high proliferation. Interestingly, despite this disability of p16 INK4a to inhibit proliferation there was an upregulation of cytoplasmic p16 INK4a in infiltrative cells compared to tumor cells towards the tumor center. A similar scenario but strong and combined nuclear and cytoplasmic p16 INK4a expression in infiltrative cells, was observed in other invasive squamous cancers. This suggests that the p16 INK4a upregulation in infiltrative cells is governed independently of the subcellular localization or of the potential to affect proliferation via Rb, and suggests a potentially proliferation independent function for p16 INK4a in infiltrative behavior.

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Section: Discussionmentioning

confidence: 95%

“…4 In squamous cancer and associated skin lesions, the p16 INK4a gene is mutated in up to 24%. 5,6 Loss of heterozygosity of the 9p21 region has also been observed in squamous carcinomas of the skin. 2,7 The main biological function of p16 INK4a is to regulate the cell cycle by binding to cyclin-dependent kinases (cdk) 4/6.…”

mentioning

confidence: 99%

Retinoblastoma protein function and p16INK4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16INK4a expression and infiltrative behavior

2004

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“…Several studies have implicated this locus in SCC and mutations in exon 2, common to both p16 INK4A and p14 ARF , have been documented in a significant proportion of SCCs [Kubo et al, 1997;Soufir et al, 1999]. In addition, hypermethylation of the locus, in the absence of mutation was also demonstrated.…”

Section: Cdkn2a Locusmentioning

confidence: 98%

The genetics of skin cancer

Tsai

Tsao

2004

American J of Med Genetics Pt C

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Recent advances in molecular genetics have led to a better understanding of the biological underpinnings of skin cancer formation. As with most cancers, the RB, p53, and RAS pathways appear to play prominent roles in the pathogenesis of several skin cancer types. Although various components of these pathways may be differentially altered in squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and cutaneous melanoma, the final biochemical expression of these defects may be the same. With the unraveling of these genetic mechanisms, a more targeted approach to diagnosis and treatment may be possible in the near future.

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“…LOH encompassing 9p21-p22 has led to the hypothesis that the tumor-suppressor gene CDKN2A may play a critical role in cutaneous SCC development. Mutational analysis and loss of transcript expression further suggest that inactivation of CDKN2A is important for SCC progression (Chang et al, 1997;Kubo et al, 1997;Soufir et al, 1999;Mortier et al, 2002). Loss at 3p in SCC gave rise to the potential involvement of the known tumor-suppressor gene FHIT (3p14.2), whose involvement in oral SCC is established (Tanimoto et al, 2000).…”

Section: Loss Of Heterozygosity Studies In Nmscmentioning

confidence: 99%

Cytogenetic alterations in nonmelanoma skin cancer: A review

Ashton

Carless

Griffiths

2005

Genes Chromosomes & Cancer

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Since the advent of cytogenetic analysis, knowledge about fundamental aspects of cancer biology has increased, allowing the processes of cancer development and progression to be more fully understood and appreciated. Classical cytogenetic analysis of solid tumors had been considered difficult, but new advances in culturing techniques and the addition of new cytogenetic technologies have enabled a more comprehensive analysis of chromosomal aberrations associated with solid tumors. Our purpose in this review is to discuss the cytogenetic findings on a number of nonmelanoma skin cancers, including squamous- and basal cell carcinomas, keratoacanthoma, squamous cell carcinoma in situ (Bowen's disease), and solar keratosis. Through classical cytogenetic techniques, as well as fluorescence-based techniques such as fluorescence in situ hybridization and comparative genomic hybridization, numerous chromosomal alterations have been identified. These aberrations may aid in further defining the stages and classifications of nonmelanoma skin cancer and also may implicate chromosomal regions involved in progression and metastatic potential. This information, along with the development of newer technologies (including laser capture microdissection and comparative genomic hybridization arrays) that allow for more refined analysis, will continue to increase our knowledge about the role of chromosomal events at all stages of cancer development and progression and, more specifically, about how they are associated with nonmelanoma skin cancer.

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061 Mutations of the INK4a locus in basal cell carcinomas

Cited by 24 publications

References 0 publications

Retinoblastoma protein function and p16INK4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16INK4a expression and infiltrative behavior

Retinoblastoma protein function and p16INK4a expression in actinic keratosis, squamous cell carcinoma in situ and invasive squamous cell carcinoma of the skin and links between p16INK4a expression and infiltrative behavior

The genetics of skin cancer

Cytogenetic alterations in nonmelanoma skin cancer: A review

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