Unexpected patterns in DNA mutations identified

Scientists from the Institute for Research in Biomedicine (IRB Barcelona) have discovered unexpected patterns in DNA mutations that differentiate individuals in terms of mutation risk.

Mutations occur continuously in every cell of our bodies and are major contributors to cancer, ageing, and neurodegeneration. Although mistakes in cellular processes during DNA replication and exposure to mutagenic chemicals contribute to these mutations, the exact distribution and patterns of these changes across human chromosomes remained unknown until now.

In previous research by the Genomic Data Science lab at IRB Barcelona, the scientists identified a DNA repair mechanism dedicated to reducing mutation risks in crucial parts of human chromosomes. The new study built upon these findings to determine whether mutation risk varies between individuals and, if so, to identify the mechanisms driving these differences.

Dr Fran Supek, ICREA researcher and head of the lab, said: “This research not only expands our understanding of the factors influencing mutation rate distribution, but it also has significant implications for cancer evolution, therapeutic strategies, and advancements in regenerative medicine.”

Big data approach

A comprehensive analysis of genome sequences from over 4,000 tumours from various organs was conducted. This study specifically targeted individual differences in susceptibility to mutations, unlike previous studies focusing on tissue-specific mutation risks.

The team employed a genomic big data approach, using machine learning algorithms to identify recurrent patterns across chromosome segments. They found 13 distinct patterns, with 10 corresponding to different types of tissue. The other three patterns were unexpectedly observed in almost all the tissues, exposing that the density of mutations in specific genes greatly varies between individuals.

TP53 and RB1

Additional data, including gene expression and genetic aberrations, was examined to understand these unexpected patterns in cancer cells. This analysis disclosed a surprising correlation between increased cell proliferation and alterations in mutation risks. Disruptions in TP53 and RB1, two crucial tumour-suppressor genes known to regulate the cell division cycle, were identified as key influencers that cause changes in the risk of mutations across chromosomes.

These chromosome segments presented altered mutation risks and large-scale remodelling of usually inactive chromosomal regions. PhD student Marina Salvadores, first author of the study, said: “This remodelling, which is correlated with increased cell proliferation, mirrored the changes in mutation risks, providing unique insight into the interplay between mutations and epigenetic alterations.”  

Mutation risk

Finding the cancer-causing genes most affected by changes in mutation risk between individuals provides a roadmap for anticipating the trajectory of cancer evolution, which is particularly relevant predicting the responses to cancer treatment, as it can help to forecast the development of drug-resistance mutations in tumours.

Also, the study demonstrates how the epigenome undergoes large changes in response to increased or disrupted cell proliferation. This understanding has implications for cell reprogramming and regenerative medicine, offering the possibility for future research and therapeutic interventions.

This study was published in Nature Cancer.