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Updated: Jun 16, 2026
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Novel and recurrent p14 mutations in Italian familial melanoma
F Binni1, I Antigoni, P De Simone
1Medical Genetics, Sapienza University, S. Camillo-Forlanini Hospital, Rome, Italy.
Abstract:
CDKN2A and CDK4 are the only known high-penetrant genes conferring proneness to cutaneous melanoma. The CDKN2A locus consists of four exons and encodes several alternate transcripts, two of which are p16(INK4a) and p14(ARF), and originate from different open reading frames. Exon 1alpha is specific for p16(INK4a), while exon 1beta characterizes p14(ARF). Most CDKN2A mutations are located in exons 1alpha and 2, while exon 1beta variations have been identified in rare melanoma-prone pedigrees. In a previous study, we investigated 155 Italian melanoma cases, including 94 familial melanomas (FAMs) and 61 sporadic multiple primary melanomas (MPMs), for p16(INK4a)/CDK4 germline alterations and identified 15 p16(INK4a) and 1 CDK4 point mutations. In the present work, we extended our search to p14(ARF) mutations and CDKN2A deletions in the remaining samples. We identified the recurrent g.193+1G> A mutation in two FAM cases, while an additional pedigree displayed the previously undescribed variant g.161G> A. Multiplex ligation-dependent probe amplification (MLPA) screening for copy variations resulted negative in all cases. In Italy, the overall frequency of p14(ARF) mutations is 3.2% in FAM and 0% in sporadic MPM. Re-evaluation of our patients' cohort emphasizes that the chance of identifying CDKN2A/CDK4 mutations in FAM is mainly influenced by the number of affected family members and the presence of one or more MPM cases. Accordingly, mutation rate rises to 61% in selected cases. Further studies are expected in order to investigate CDKN2A rarer mutations, including atypical deletions and inherited epimutations.
Insights
This study investigated CDKN2A and CDK4 gene mutations in Italian melanoma patients, identifying new p14(ARF) mutations in familial melanoma cases. Mutation detection rates significantly increase in families with multiple affected members or multiple primary melanomas.
Area of Science:
- Genetics
- Oncology
- Dermatology
Background:
- Cutaneous melanoma risk is strongly associated with high-penetrance genes CDKN2A and CDK4.
- The CDKN2A gene encodes p16(INK4a) and p14(ARF) through alternative transcripts, with mutations typically found in specific exons.
- Previous research identified p16(INK4a) and CDK4 mutations in Italian melanoma cases.
Purpose of the Study:
- To investigate p14(ARF) mutations and CDKN2A deletions in Italian melanoma patients not previously analyzed.
- To determine the frequency of p14(ARF) mutations in familial (FAM) and sporadic multiple primary melanoma (MPM) cases in Italy.
- To re-evaluate factors influencing CDKN2A/CDK4 mutation detection rates in familial melanoma.
Main Methods:
- Screening of remaining Italian melanoma samples for p14(ARF) mutations.
- Multiplex ligation-dependent probe amplification (MLPA) for CDKN2A deletions.
- Analysis of familial history, including number of affected members and presence of MPM, to assess mutation detection probability.
Main Results:
- Identified the recurrent g.193+1G>A and a novel g.161G>A p14(ARF) mutation in two familial melanoma cases.
- Found a 3.2% overall frequency of p14(ARF) mutations in familial melanoma and 0% in sporadic MPM.
- CDKN2A deletions were not detected using MLPA.
- Mutation detection rates in familial melanoma reached 61% in selected high-risk cases.
Conclusions:
- p14(ARF) mutations are present in Italian familial melanoma cases, though at a lower frequency than p16(INK4a).
- The likelihood of finding CDKN2A/CDK4 mutations in familial melanoma is significantly higher with multiple affected individuals and multiple primary melanomas.
- Further research is warranted for rarer CDKN2A mutations, including atypical deletions and epimutations.
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