Endometrial cancer may be part of the MUTYH-associated polyposis cancer spectrum

Area of Science:

• Genomic instability and cancer biology
• DNA repair mechanisms
• Oncology

Background:

• The MUTYH gene encodes a DNA glycosylase crucial for preventing G:C→T:A transversions.
• Biallelic pathogenic germline MUTYH variants cause MUTYH-associated polyposis (MAP), a condition linked to increased cancer risk.
• The specific role of MUTYH loss of function in endometrial carcinogenesis remains incompletely understood.

Observation:

• A 61-year-old patient with MAP presented with endometrial carcinoma.
• Next-Generation Sequencing (NGS) revealed a high Tumor Mutational Burden (TMB) of 31.5 variants/Mb.
• The tumor exhibited an enrichment of G:C→T:A transversions and a driver pathogenic KRAS variant (c.34G>T, p.(Gly12Cys)).

Findings:

• The observed mutational signature in the endometrial cancer is consistent with impaired MUTYH DNA repair.
• The presence of a KRAS driver mutation in the context of high G:C→T:A transversions suggests a potential oncogenic role for MUTYH deficiency.
• Tumor-infiltrating lymphocyte (TIL) levels and immune phenotype were assessed, providing context for the tumor microenvironment.

Implications:

• This case provides the first evidence linking MUTYH loss of function to the specific mutational profile observed in endometrial cancer.
• MUTYH deficiency may represent a distinct pathway in endometrial oncogenesis, particularly in patients with MAP.
• Understanding this link could inform targeted therapies and risk stratification for endometrial cancer in MAP patients.