Cross-Cancer Study Reveals Biallelic Inactivation of MUTYH and Base Excision Repair Defects in Different Types of Solid Tumors

Research Background

In daily life, cells are often exposed to endogenous and exogenous oxidative stress, originating from by-products of cellular respiration and various external compounds. MUTYH is a key component of the base excision repair (BER) pathway, responsible for repairing both endogenous and exogenous oxidative DNA damage. One of the most common products of oxidative damage is 8-oxo-7,8-dihydroguanine (8-oxoG). MUTYH functions by removing mispaired adenines to prevent G:C to T:A transversion mutations caused by oxidative damage, playing a vital role in tissues highly exposed to oxidative stress and frequent cell division.

Defects in the BER pathway are associated with an increased mutation burden and carcinogenesis. Biallelic germline pathogenic variants of the MUTYH gene can lead to MUTYH-associated polyposis (MAP), an autosomal recessive disorder typically manifested by adenomatous colorectal polyps and a significantly increased risk of colorectal cancer (CRC). Although some studies suggest that heterozygous MUTYH mutations may increase the late-life risk of CRC, this association remains controversial. This study aims to further investigate the prevalence and consequences of pathogenic MUTYH variants and MUTYH loss of heterozygosity (LOH) across various cancer types.

Research Source

This article was authored by Channing J. Paller (Johns Hopkins University), Hanna Tukachinsky (Foundation Medicine), Alexandra Maertens (Johns Hopkins University), Brennan Decker (Foundation Medicine), Julian R. Sampson (Cardiff University), and Jeremy P. Cheadle (University of Minnesota). The study was published in the “JCO Precision Oncology” journal on February 23, 2024, DOI: https://doi.org/10.1200/po.23.00251.

Research Process and Methods

Research Methods and Workflow

This study analyzed 354,366 solid tumor biopsy samples that were sequenced in routine clinical care. An algorithm was validated to distinguish whether MUTYH mutations were germline or somatic. The specific workflow is as follows:

1. Data Collection: Samples were collected from patients between August 2014 and February 2022 and underwent comprehensive genomic analysis via the FoundationOne or FoundationOne CDx platforms.

2. Sample Classification: The validated Somatic/Germline Zygosity (SGZ) algorithm was used to differentiate germline from somatic mutations, and MUTYH variants were extracted from various solid tumor samples.

3. Mutation Detection: Out of the 354,366 samples, 6,572 (1.9%) carried MUTYH gene variants. Among these, 6,110 were germline variants: 119 were biallelic, 9 were germline and somatic variants, and 5,982 were heterozygous.

4. Mutation Signature Analysis: For samples with MUTYH variants, the related mutation signature (COSMIC SBS18) characteristic of BER defects was analyzed.

Result Analysis and Interpretation

Main Results

1. Biallelic MUTYH Variants: Approximately 66% of samples with biallelic pathogenic MUTYH variants were CRC, showing a high mutation burden (TMB) and a significant COSMIC SBS18 signature, reflecting BER pathway defects.

2. Heterozygous MUTYH Variants and LOH: Among the 5,991 samples identified with germline heterozygous variants, approximately 12% of these cancer samples (738) exhibited somatic LOH of MUTYH and a high loss rate of chromosome 1p (where MUTYH is located).

3. Associative Analysis: Carriers of heterozygous variants had slightly higher prevalence rates in certain cancer types, such as adrenal cancer, pancreatic islet cell tumors, non-glial CNS tumors, gastrointestinal stromal tumors, and thyroid cancer.

4. Mutation Burden (TMB) and Gene Signature: The LOH sample group showed a high rate of chromosome 1p loss, elevated genomic LOH, and significantly increased TMB, supporting the characteristics of BER defects.

Conclusion and Significance

This study reveals the presence of MUTYH variants in a large cohort of solid tumor patients, suggesting that, aside from the known role of biallelic pathogenic MUTYH variants in cancer susceptibility, heterozygous MUTYH carriers may also contribute to different types of cancer through a somatic LOH mechanism, although this role requires further confirmation in subsequent studies. This provides a research basis for future treatment strategies targeting BER-deficient cancers.

Research Highlights

1. Cancer Susceptibility: The study is the first comprehensive analysis of the distribution and impact of MUTYH gene variants across various solid tumors, expanding the understanding of BER defects on cancer risk.

2. Associative Mechanism: The findings show that cancers with heterozygous MUTYH mutations and accompanying LOH have higher TMB and COSMIC SBS18 signatures, hinting at a late-stage second-hit mechanism.

3. Clinical Significance: The results suggest that MUTYH carriers may need personalized treatment strategies considering their mutation status, particularly targeting BER defects.

This systematic analysis provides valuable data and insights into the biological role and potential clinical applications of MUTYH variants, laying a solid foundation for future cancer research and treatment.