# Comprehensive Analysis of Human Colorectal Cancers Harboring Polymerase Epsilon Mutations

## TL;DR

This study explores how mutations in DNA polymerase epsilon (POLe) affect mutation patterns in colorectal cancer.

## Contribution

The study uses AI to show that POLe driver mutations do not co-occur with driver mutations in other genes in colorectal cancer.

## Key findings

- Driver POLe mutations are not associated with driver mutations in other genes.
- Structural analysis reveals POLe mutations impact Mg2+ coordination in the active site.
- Colorectal cancer mutations accumulate through complex, not singular, mechanisms.

## Abstract

DNA polymerase epsilon (POLe) is the leading strand replicative polymerase. POLe mutations located primarily in the proofreading domain cause replication errors and increase mutation burden in cancer cells. Consequently, POLe has been classified as a cancer driver gene. Certain POLe frameshift mutations that affect the proofreading domain are purified in cancer cells, but point mutations in other domains have also been reported. Here we use an artificial intelligence algorithm to determine what other mutations co-occur with POLe mutations in colorectal cancers. We partitioned POLe mutations into driver, passenger, and WT (no mutation), then assessed mutations in other genes in these three groups. We found that a driver POLe mutation is not likely to associate with driver mutations in other genes. Thus, driver mutations in colorectal cancers appear to purify in a manner that is independent of POLe. Mutations that affect POLe function do not necessarily increase the frequency of driver mutations in other genes. Structural analysis shows that many POLe driver mutations affect coordination of the Mg2+ ion in the active site. Our data show that the accumulation of colorectal cancer mutations is driven by complex factors.