Increased KRAS G12C Prevalence, High Tumor Mutational Burden, and Specific Mutational Signatures Are Associated With MUTYH Mutations - A Pan-Cancer Analysis

Sep 21, 2026

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This pan-cancer study characterizes MUTYH alterations and evaluates links between MUTYH mutations and potentially actionable biomarkers, including specific genomic alterations, tumor mutational burden (TMB), and mutational signatures. Using a large comprehensive genomic dataset from patients profiled during routine clinical tissue next-generation sequencing, the analysis found MUTYH alterations in 2.8% of 229,120 solid tumors (about 55% predicted germline). MUTYH-altered cancers showed higher TMB and more frequent KRAS G12C alterations, while PD-L1 expression was not associated. In silico results linked MUTYH signatures to increased neoantigen hydrophobicity, and patient survival was similar between groups. The findings support pharmacologic targeting potential in MUTYH-mutated malignancies, including KRAS G12C inhibitors and immune checkpoint blockade.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Abstract

Implications for Practice

Introduction

DNA damage and MUTYH function

MUTYH-associated polyposis and KRAS G12C relevance

Methods

Comprehensive Genomic Profiling Cohort

Increased KRAS G12C Prevalence, High Tumor Mutational Burden, and Specific Mutational Signatures Are Associated With MUTYH Mutations: A Pan-Cancer Analysis Umut Disel1,*,, Smruthy Sivakumar2,, Tim Pham3,, Zoe Fleischmann2,, R.I. Anu4, Ethan S. Sokol2,, Razelle Kurzrock5, 1Acıbadem Adana Hospital, Department of Medical Oncology, Adana, Turkey 2Foundation Medicine, Inc., Cambridge, MA, USA 3Center for Personalized Cancer Therapy, Moores Cancer Center, UCSD, San Diego, CA, USA 4Department of Cancer Biology and Therapeutics, Department of Clinical Biochemistry, MVR Cancer Center and Research Institute Chuloor, Calicut, Kerala, India 5WIN Consortium for Personalized Cancer Therapy, Medical College of Wisconsin, Milwaukee, WI, USA *Corresponding author: Umut Disel, MD, Adana Acıbadem Hospital, Adana, Turkey. Tel: +903224554791; Email: [doctorhope@gmail.com](doctorhope@gmail.com) Abstract The aim of this study was to determine the pan-cancer landscape of MUTYH alterations and the relationship between MUTYH mutations and potentially actionable biomarkers such as specific genomic alterations, tumor mutational burden, and mutational signatures. We used a large pan-cancer comprehensive genomic dataset from patients profiled (tissue next generation sequencing) during routine clinical care. Overall, 2.8% of 229 120 solid tumors had MUTYH alterations, of which 55% were predicted germline. Thirty tumor types had a 2% or greater MUTYH mutation rate. MUTYH-altered versus -WT cancers had significantly higher tumor mutational burden and more frequent alterations in KRAS G12C, but not in KRAS in general; these observations were statistically significant, especially in colorectal cancers. Across cancers, PD-L1 expression levels (immunohistochemistry) were not associated with MUTYH alteration status. In silico computation demonstrated that MUTYH mutational signatures are associated with higher levels of hydrophobicity (which may reflect higher immunogenicity of neoantigens) relative to several other signature types such as microsatellite instability. Survival of patients with MUTYH-altered versus-WT tumors was similar. In conclusion, comprehensive genomic profiling suggests that several features of MUTYH-altered cancers may be pharmacologically targetable. Drugs such as sotorasib (targeting KRAS G12C) and immune checkpoint inhibitors, targeting the increased mutational load and higher neo-antigen hydrophobicity/immunogenicity merit investigation in MUTYH-mutated malignancies. Key words: KRAS G12C; genomic alterations; tumor mutational burden; MUTYH mutations. Implications for Practice Of 229120 tumors, 2.8% harbored MUTYH alterations (~55% germline), which correlated with higher mutational burden, more hydrophobic (possibly immunogenic) mutational signatures, and KRASG12C mutations. Immunotherapy and KRASG12C inhibitors warrant investigation in MUTYH-mutated cancers. Introduction Exposure to carcinogens, including oxidizing agents, alkylating agents, DNA cross-linking agents, and radiation is capable of damaging DNA.1 The MUTYH gene is located on the short arm of chromosome 1 (1p34.1) and is responsible for coding the MYH glycosylase enzyme. This enzyme is part of the DNA base excision repair system, which repairs oxidized DNA damage. 8-Oxoguanine (8-oxoG), a major oxidized form of guanine generated by reactive oxygen species, is highly mutagenic due to its mispairing with adenine.2 The function of MUTYH is in preventing oxidative damage-induced mutations, such as GC>TA transversions. Accumulation of 8-oxoG in DNA causes somatic mutations, eventually leading to cancer and neurodegenerative diseases.3,4 MUTYH-associated polyposis (MAP) is an autosomal recessive disorder characterized by colorectal adenomatous polyps that confers a very high risk of colorectal cancer (CRC), predisposition to duodenal adenomas and a modest increase in risk for non-CRC malignancies.5 Colorectal cancer cells in patients with MAP fail to rep

FAQs

What is the goal of this pan-cancer analysis of MUTYH alterations?

The study aims to map the pan-cancer landscape of MUTYH alterations and determine how MUTYH mutations relate to genomic alterations, tumor mutational burden, and mutational signatures that could inform actionable biomarkers.

How common are MUTYH alterations in the analyzed tumors, and are they often germline?

MUTYH alterations were found in 2.8% of 229,120 solid tumors, and 55% of those cases were predicted to be germline.

What key biomarker associations were observed for MUTYH-altered cancers?

Compared with MUTYH-WT cancers, MUTYH-altered tumors had significantly higher tumor mutational burden and more frequent KRAS G12C alterations, but PD-L1 expression levels were not associated with MUTYH status.

Sep 21, 2026

Uploaded by Himbo