Somatic CpG hypermutation is associated with mismatch repair deficiency in cancer.

in Molecular systems biology by Aidan Flynn, Sebastian M Waszak, Joachim Weischenfeldt

TLDR

  • The study looked at how a type of mutation called somatic CpG hypermutation happens in cancer cells. They found that this mutation happens most often in certain types of cancer, like leukemia and high-grade glioma. They also found that a protein called MutSα is a common cause of this mutation and that it often happens near other mutations in the TP53 gene. The study also found that this mutation can affect how well cancer cells respond to a type of treatment called immune checkpoint inhibitors.

Abstract

Somatic hypermutation in cancer has gained momentum with the increased use of tumour mutation burden as a biomarker for immune checkpoint inhibitors. Spontaneous deamination of 5-methylcytosine to thymine at CpG dinucleotides is one of the most ubiquitous endogenous mutational processes in normal and cancer cells. Here, we performed a systematic investigation of somatic CpG hypermutation at a pan-cancer level. We studied 30,191 cancer patients and 103 cancer types and developed an algorithm to identify somatic CpG hypermutation. Across cancer types, we observed the highest prevalence in paediatric leukaemia (3.5%), paediatric high-grade glioma (1.7%), and colorectal cancer (1%). We discovered germline variants and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation in cancer, which frequently converged on CpG sites and TP53 driver mutations. We further observe an association between somatic CpG hypermutation and response to immune checkpoint inhibitors. Overall, our study identified novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy.

Overview

  • The study investigates somatic CpG hypermutation at a pan-cancer level in 30,191 cancer patients and 103 cancer types. The authors developed an algorithm to identify somatic CpG hypermutation and observed the highest prevalence in paediatric leukaemia, paediatric high-grade glioma, and colorectal cancer. The study also discovered germline variants and somatic mutations in the mismatch repair complex MutSα (MSH2-MSH6) as genetic drivers of somatic CpG hypermutation in cancer, which frequently converged on CpG sites and TP53 driver mutations. The study further observes an association between somatic CpG hypermutation and response to immune checkpoint inhibitors.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions, specifically the prevalence of somatic CpG hypermutation across different cancer types. The authors identified the highest prevalence in paediatric leukaemia, paediatric high-grade glioma, and colorectal cancer. The study also discovered an association between somatic CpG hypermutation and response to immune checkpoint inhibitors.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they identify novel cancer types that display somatic CpG hypermutation, strong association with MutSα-deficiency, and potential utility in cancer immunotherapy. The study also highlights the importance of understanding the genetic drivers of somatic CpG hypermutation in cancer and its potential impact on response to immune checkpoint inhibitors. Future research could build on these findings to explore unresolved questions, such as the role of other mismatch repair complexes in somatic CpG hypermutation, or the potential utility of somatic CpG hypermutation as a biomarker for personalized cancer immunotherapy.
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