P16 UV mutations in human skin epithelial tumors

Soufir, Nadem; Molès, Jeàn-Pierre; Vilmer, C; Moch, Clara; Vérola, O; Rivet, Jacqueline; Tesniere, Anne; Dubertret, Louis; Basset-Séguin, Nicole

doi:10.1038/sj.onc.1202915

Cited by 103 publications

(123 citation statements)

References 39 publications

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

“…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. In actinic keratosis, it is unclear whether the Rbpathway was functional or not due to the cytoplasmic localization of p16 INK4a in combination with low proliferation.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 98%

“…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

View full text Add to dashboard Cite

show abstract

“…In addition to treatmentrelated factors, unidentified susceptibility genes could explain these results to some extent. Inactivation of CDKN2A by genetic and epigenetic changes has been described in melanoma, squamous cell carcinoma, breast cancer and Hodgkin disease (Soufir et al, 1999;Brown et al, 2004;Debniak et al, 2007;Sinha et al, 2008). However, the association between germline mutations in CDKN2A and malignancies other than melanoma are still unclear.…”

Section: Discussionmentioning

confidence: 99%

Modification of second cancer risk after malignant melanoma by parental history of cancer

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The PM-PCR RHA method has previously been described in detail. 24,26 The method was designed for the identification of 25 established beta-PV types, namely genotypes 5,8,9,12,14,15,17,19,20,21,22,23,24,25,36,37,38,47,49,75,76,80,92,93 and 96.…”

Section: Dna Isolation and Pcr Reactions For Mutation Analysesmentioning

confidence: 99%

“…7 Mutations in the CDKN2A (INK4a-ARF) locus are reported in CSCC with frequencies ranging up to 24% in sporadic CSCC. [8][9][10] This gene maps to chromosome 9p21, which by alternative transcripts encodes for 2 cell cycle regulatory proteins, p16 INK4a (Exons 1a, 2 and 3) and p14 ARF (Exons 1b, 2 and 3). 10,11 The exact role of the CDKN2A gene in skin carcinogenesis is not well understood.…”

mentioning

confidence: 99%

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

Küsters‐Vandevelde

Leeuwen

Verdijk

et al. 2009

Intl Journal of Cancer

View full text Add to dashboard Cite

Genetic alterations in metastatic cutaneous squamous cell carcinoma (CSCC) which might serve as prognostic biomarkers are not well investigated. We investigated the mutation status and protein expression of the CDKN2A (INK4a-ARF) and TP53 genes in metastatic CSCCs and correlated this with clinicopathological variables, HPV presence, and survival data. Sequence analysis was performed on formalin-fixed and paraffin-embedded tissue of 35 metastases and their primary tumors, and was correlated with immunohistochemical stainings for p53, p16 and p14. Beta-PV and alpha-PV DNA was detected using PCRbased assays. Kaplan-Meier and Cox regression methods were used for survival assessment. CDKN2A was mutated in 31% of the metastases and their primary tumors, while the TP53 gene was mutated in 51% of the metastases. P53 protein expression was significantly associated with missense type of mutations (p 5 0.002). No persistent HPV types were detected. CDKN2A mutations were significantly associated with disease-specific death (p 5 0.001). A significant difference was observed in disease-specific survival between patients with or without a CDKN2A mutation (p 5 0.010), while this was not the case for TP53. At univariate Cox's regression analysis tumor size (p 5 0.010), invasion depth (p 5 0.030) and CDKN2A mutations (p 5 0.040) were significantly related to shorter disease-specific survival. At multivariate Cox's regression only tumor size had an adverse effect on survival (p 5 0.002). In conclusion, our study indicates that the CDKN2A mutation status might be of prognostic value in metastatic CSCCs. In most cases, CDKN2A and TP53 mutations are early genetic events in CSCC tumorigenesis. The possible role of HPV in metastatic CSCC needs further exploration.Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in Caucasians, after basal cell carcinoma, and its incidence is still rising. 1 Generally the risk of metastasis is reported up to 5%, while immunocompromised patients have a larger tendency to metastasize (5-10%). 1,2 The outcome of these patients once metastasized is poor, with a 5-year survival rate between 25 and 50%. 3,4 Genetic alterations in CSCCs which might serve as prognostic biomarkers are not well investigated.TP53 mutations are the most frequent genetic alterations in CSCC with incidences of up to 50%. 5,6 TP53 mutations are early events in skin carcinogenesis, with a similar mutation frequency of 50% in actinic keratosis, a precancerous skin lesion that potentially can progress to CSCC. 7 Mutations in the CDKN2A (INK4a-ARF) locus are reported in CSCC with frequencies ranging up to 24% in sporadic CSCC. [8][9][10] This gene maps to chromosome 9p21, which by alternative transcripts encodes for 2 cell cycle regulatory proteins, p16 INK4a (Exons 1a, 2 and 3) and p14 ARF (Exons 1b, 2 and 3). 10,11 The exact role of the CDKN2A gene in skin carcinogenesis is not well understood. Especially in metastatic CSCCs alterations in the CDKN2A gene have not been investigated. In a small previous stud...

show abstract

P16 UV mutations in human skin epithelial tumors

Cited by 103 publications

References 39 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

Modification of second cancer risk after malignant melanoma by parental history of cancer

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

Contact Info

Product

Resources

About