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Published on: June 7, 2019
Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma
L Liu1, N J Lassam, J M Slingerland
1Oncology Research Division, Toronto Hospital, Ontario, Canada.
Abstract:
The gene encoding the cell cycle inhibitor p16INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16INK4A in the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16INK4A gene in the development of some cases of familial melanoma.
Insights
A novel mutation in the p16INK4A gene causes inherited melanoma. This germline mutation leads to a non-functional protein, increasing melanoma predisposition in affected families.
Area of Science:
- Genetics
- Cancer Biology
- Molecular Oncology
Background:
- The p16INK4A gene, located at chromosome 9p21, is a cell cycle inhibitor implicated in melanoma susceptibility.
- While some familial melanoma cases link to p16INK4A mutations, its role remains unclear in many families.
Purpose of the Study:
- To investigate the role of the p16INK4A gene in a family with inherited melanoma.
- To identify and characterize novel mutations in the p16INK4A gene associated with familial melanoma.
Main Methods:
- Genetic analysis of a melanoma-prone family to detect p16INK4A mutations.
- Functional assays to assess the activity of the mutant p16INK4A protein.
- Analysis of p16INK4A allele status in tumor tissue.
Main Results:
- A novel mutation (in-frame deletion of Asp96 and Leu97) in exon 2 of the p16INK4A gene was identified and segregated with melanoma in the family.
- The mutant p16INK4A protein demonstrated impaired binding to cdk4 and failed to inhibit fibroblast colony formation.
- Loss of the wild-type p16INK4A allele and retention of the mutant allele were observed in a patient's metastatic lesion.
Conclusions:
- Germline mutations in the p16INK4A gene predispose individuals to melanoma.
- The identified p16INK4A mutation contributes to melanoma development by producing a functionally deficient protein.
- The p16INK4A gene is implicated in the pathogenesis of certain familial melanoma cases.
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