Question 1

What does CDKN2A encode and why is it unusual?

Accepted Answer

CDKN2A is unique in encoding two completely separate tumor suppressor proteins from overlapping reading frames: p16INK4a, which inhibits CDK4/CDK6 to block pRb phosphorylation, and p14ARF, which sequesters MDM2 to stabilise p53. A single CDKN2A deletion therefore simultaneously disables both the RB and p53 pathways.

Question 2

Why is CDKN2A deleted so often in cancer?

Accepted Answer

Simultaneous inactivation of both p53 and pRb tumour suppressor pathways through deletion of a single chromosomal locus provides an enormous selective advantage. CDKN2A is homozygously deleted in ~50% of melanomas, ~30% of glioblastomas, and ~90% of pancreatic cancers — making it the most frequently deleted locus in cancer.

Question 3

What is p16 methylation?

Accepted Answer

p16INK4a (encoded by CDKN2A) is silenced by promoter CpG island hypermethylation in a wide range of cancers and even in normal ageing tissues and precancerous fields. This epigenetic silencing is one of the most common alterations in human cancer and is detectable in liquid biopsies.

CDKN2A Gene Function

Overview

More Tumor Suppressor Genes