Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Germline alterations in DNA repair genes contribute to cancer predisposition.
• Specific mutational signatures associated with base excision repair (BER) defects require characterization.

Purpose of the Study:

• To identify and characterize the mutational signature associated with defects in the base excision repair pathway, specifically involving the MUTYH gene.
• To explore the potential of this signature as a biomarker for BER-related genomic instability.

Main Methods:

• Exome sequencing of colorectal cancers (CRCs) and adrenocortical carcinomas (ACCs).
• Analysis of somatic mutation spectra to identify characteristic patterns.
• Correlation of mutational signatures with germline pathogenic mutations in the MUTYH gene.

Main Results:

• A distinct mutational signature, enriched for C > A transversions in NpCpA or NpCpT contexts, was identified in colorectal cancers from MUTYH-associated polyposis (MAP) patients and those with germline MUTYH mutations.
• A similar mutational signature was observed in adrenocortical carcinomas associated with germline MUTYH mutations.
• This signature is indicative of MUTYH inactivation and BER deficiency.

Conclusions:

• MUTYH inactivation leads to a specific mutational signature.
• This signature can serve as a valuable marker for identifying base excision repair-related genomic instability in various cancer types, including CRC and ACC.