Germline MBD4 deficiency causes a multi-tumor predisposition syndrome

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Base excision repair (BER) is crucial for maintaining genomic stability.
• Deficiencies in DNA repair pathways are linked to increased cancer risk.
• MBD4 is a BER gene involved in repairing specific DNA mismatches.

Purpose of the Study:

• To investigate the role of MBD4 in inherited tumor predisposition.
• To characterize the clinical and molecular features of individuals with MBD4 variants.
• To understand the impact of MBD4 deficiency on tumor development.

Main Methods:

• Genetic analysis of five individuals from four families with bi-allelic MBD4 loss-of-function variants.
• Clinical data review for personal and family history of tumors.
• Analysis of mutational signatures and somatic mutations in MBD4-deficient colorectal adenomas.

Main Results:

• Identified bi-allelic MBD4 variants in individuals with colorectal polyposis, acute myeloid leukemia, and uveal melanoma.
• MBD4 deficiency leads to a mutator phenotype in colorectal adenomas, characterized by mutational signature SBS1.
• MBD4-deficient polyps showed distinct mutation profiles compared to sporadic colorectal tumors, with more AMER1 and fewer KRAS mutations.

Conclusions:

• Bi-allelic MBD4 variants cause an autosomal recessive multi-organ tumor predisposition syndrome.
• This study highlights the significant role of BER deficiencies, specifically MBD4, in cancer predisposition.
• Genetic testing for MBD4 is recommended for individuals with unexplained polyposis and multi-tumor phenotypes to guide management.