Constitutive deficiency in DNA mismatch repair.

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• DNA mismatch repair (MMR) gene mutations are linked to hereditary non-polyposis colorectal cancer (Lynch syndrome).
• Lynch syndrome I presents with colorectal cancer, while Lynch syndrome II includes extra-colonic tumors.
• Biallelic MMR gene mutations represent a distinct genetic entity.

Purpose of the Study:

• To summarize the distinct phenotype of individuals inheriting biallelic mutations in MMR genes.
• To differentiate this condition from Lynch syndrome I and II, and Turcot and Muir-Torre subtypes.

Main Methods:

• Literature review and phenotype summary of reported families with biallelic MMR mutations.
• Comparison of clinical presentation in individuals with complete or partial loss of MMR function.

Main Results:

• Individuals with biallelic MMR mutations exhibit a different cancer spectrum and age of onset compared to Lynch syndrome.
• Complete loss of MMR function leads to childhood onset of hematological and brain malignancies.
• Residual MMR function can result in gastrointestinal cancers with onset in the second to fourth decade.
• Café-au-lait spots are a common feature in individuals with biallelic MMR mutations.

Conclusions:

• Inheritance of biallelic MMR mutations constitutes a separate clinical entity from Lynch syndrome.
• The level of residual MMR protein function influences the age of onset and cancer types.
• Biallelic MMR mutations are associated with a unique set of clinical features, including café-au-lait spots.