A novel CDKN2A in-frame deletion associated with pancreatic cancer-melanoma syndrome

Dermatol Online J. 2020 Aug 15;26(8):13030/qt5t22m5gk.


Pancreatic cancer-melanoma syndrome (PCMS) is an inherited condition in which mutation carriers have an increased risk of malignant melanoma and/or pancreatic cancer. About 30% of PCMS cases carry mutations in CDKN2A. This gene encodes several protein isoforms, one of which, known as p16, regulates the cell-cycle by interacting with CDK4/CDK6 kinases and with several non-CDK proteins. Herein, we report on a novel CDKN2A germline in-frame deletion (c.52_57delACGGCC) found in an Italian family with PCMS. By segregation analysis, the c.52_57delACGGCC was proven to segregate in kindred with cutaneous melanoma (CM), in kindred with CM and pancreatic cancer, and in a single case presenting only with pancreatic cancer. In the literature, duplication mapping in the same genic region has been already reported at the germline level in several unrelated CM cases as a variant of unknown clinical significance. A computational approach for studying the effect of mutational changes over p16 protein structure showed that both the deletion and the duplication of the c.52_57 nucleotides result in protein misfolding and loss of interactors' binding. In conclusion, the present results argue that the quantitative alteration of nucleotides c.52_57 has a pathogenic role in p16 function and that the c.52_57delACGGCC is associated with PCMS.

Publication types

  • Case Reports

MeSH terms

  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / ultrastructure
  • Female
  • Gene Deletion
  • Germ-Line Mutation*
  • Humans
  • Male
  • Melanoma / etiology
  • Melanoma / genetics*
  • Middle Aged
  • Neoplastic Syndromes, Hereditary / etiology
  • Neoplastic Syndromes, Hereditary / genetics*
  • Pancreatic Neoplasms / etiology
  • Pancreatic Neoplasms / genetics*
  • Pedigree
  • Protein Structure, Quaternary


  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16

Supplementary concepts

  • Melanoma-Pancreatic Cancer Syndrome