Related Experiment Video
Updated: Dec 8, 2025
Author Spotlight: Reprogramming Cancer Cells to iPSCs to Study Disease Progression and Treatment Targets
Published on: February 2, 2024
A novel CDKN2A in-frame deletion associated with pancreatic cancer-melanoma syndrome
Irene Bottillo1, Michele Valiante, Lucia Menale
1Division/Laboratory of Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome. i.bottillo@gmail.com.
Abstract:
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.
Insights
A novel CDKN2A gene deletion causes pancreatic cancer-melanoma syndrome (PCMS). This genetic alteration leads to p16 protein dysfunction, increasing cancer risks in affected families.
Area of Science:
- Genetics and Oncology
- Molecular Biology
Background:
- Pancreatic cancer-melanoma syndrome (PCMS) is an inherited disorder linked to increased risks of melanoma and pancreatic cancer.
- Mutations in the CDKN2A gene are found in approximately 30% of PCMS cases, with the p16 protein isoform playing a key role in cell-cycle regulation.
Observation:
- A novel CDKN2A germline in-frame deletion (c.52_57delACGGCC) was identified in an Italian family with PCMS.
- Segregation analysis confirmed the association of this deletion with cutaneous melanoma, combined pancreatic cancer and melanoma, and isolated pancreatic cancer.
Findings:
- The c.52_57delACGGCC deletion, along with previously reported duplications in the same region, was computationally analyzed for its effect on p16 protein structure.
- Both deletion and duplication of these nucleotides result in protein misfolding and loss of critical interactor binding, indicating a pathogenic mechanism.
Implications:
- The study establishes a pathogenic role for quantitative alterations at the c.52_57 nucleotide position in CDKN2A.
- The identified c.52_57delACGGCC deletion is confirmed as a causative variant for PCMS, aiding in genetic diagnosis and risk assessment.
Related Concept Videos
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...
02:34Inhibition of Cdk Activity