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p16INK4a and p14ARF tumor suppressor genes are commonly inactivated in cutaneous squamous cell carcinoma
Victoria L Brown1, Catherine A Harwood, Tim Crook
1Centre for Cutaneous Research, St Bartholomew's and the Royal London School of Medicine and Dentistry, University of London, London, UK.
Abstract:
The p16(INK4a) and p14(ARF) tumor suppressor genes (TSGs) are encoded within the CDKN2A locus on chromosome 9p21 and function as cell cycle regulatory proteins in the p53 and RB pathways. Inactivation of these genes by genetic and epigenetic changes has been described in some human cancers, but their importance in cutaneous squamous cell carcinoma (SCC) has not been established. Our detailed examination of 40 cutaneous SCC revealed loss of heterozygosity of 9p21 markers in 32.5% of cases. Mutational analysis confirmed five point mutations in four of 40 SCCs. These mutations changed the amino acid sequence of p16(INK4a) in four tumors and p14(ARF) in three tumors. Promoter methylation of p16(INK4a) and p14(ARF) was detected in 13 of 36 (36%) and 16 of 38 (42%) cases, respectively. Absent protein expression was confirmed by immunohistochemistry in 13 of 16 (82%) of the tumors with biallelic inactivating events. Overall, the frequency of 9p21 alterations was 76% and for both p16(INK4a) and p14(ARF), promoter methylation is the commonest mechanism of gene inactivation. Alterations at this locus were significantly more common in tumors from immunocompetent compared with immunosuppressed individuals. These data confirm the importance of inactivation of p16(INK4a) and p14(ARF) TSGs in the pathogenesis of cutaneous SCCs.
Insights
The p16(INK4a) and p14(ARF) tumor suppressor genes are frequently altered in cutaneous squamous cell carcinoma (SCC). Promoter methylation is the primary mechanism of inactivation, particularly in immunocompetent individuals.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- The CDKN2A locus on chromosome 9p21 encodes p16(INK4a) and p14(ARF) tumor suppressor genes.
- These genes are crucial for regulating cell cycle via the p53 and RB pathways.
- Their role in cutaneous squamous cell carcinoma (SCC) pathogenesis was previously unclear.
Purpose of the Study:
- To investigate the frequency and mechanisms of p16(INK4a) and p14(ARF) inactivation in cutaneous SCC.
- To determine the clinical relevance of these genetic and epigenetic alterations.
Main Methods:
- Analysis of 40 cutaneous SCC samples.
- Assessed loss of heterozygosity (LOH) at 9p21 markers.
- Performed mutational analysis and promoter methylation studies for p16(INK4a) and p14(ARF).
- Utilized immunohistochemistry to confirm protein expression.
Main Results:
- Loss of heterozygosity at 9p21 was observed in 32.5% of cases.
- Point mutations affecting p16(INK4a) or p14(ARF) were found in 10% of tumors.
- Promoter methylation was the most common inactivation mechanism (36% for p16(INK4a), 42% for p14(ARF)).
- Overall 9p21 alterations occurred in 76% of SCCs, more frequently in immunocompetent individuals.
Conclusions:
- Inactivation of p16(INK4a) and p14(ARF) tumor suppressor genes is a significant event in the development of cutaneous SCC.
- Promoter methylation is the predominant mechanism driving gene inactivation at this locus.
- Alterations in these tumor suppressor genes are more prevalent in SCC from immunocompetent patients.
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