Mechanisms underlying mismatch repair deficiencies in normal cells

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Hereditary nonpolyposis colon cancer (HNPCC) is an autosomal dominant cancer predisposition linked to mismatch repair (MMR) gene mutations.
• HNPCC tumors exhibit microsatellite instability due to MMR deficiency, often involving inactivation of the remaining wild-type MMR gene copy.
• Recent studies suggested some germline MMR mutations might cause microsatellite instability even in non-tumor cells via dominant-negative effects.

Purpose of the Study:

• To investigate whether a specific MLH1 gene mutation (deletion of codon 618K) can induce genetic instability in untransformed cells.
• To evaluate the role of this MLH1 mutation in tumor initiation within a family exhibiting HNPCC.

Main Methods:

• Analysis of microsatellite markers in lymphoblast clones from an MLH1 mutation carrier.
• Examination of tumor samples to determine the status of both wild-type and mutant MLH1 alleles.

Main Results:

• No microsatellite mutations were detected in numerous lymphoblast clones from the MLH1 618K deletion carrier.
• Loss of the wild-type MLH1 allele was observed in two distinct tumors from the family, suggesting biallelic inactivation is necessary for tumor development.

Conclusions:

• The MLH1 618K deletion mutation alone does not appear to cause significant mismatch repair deficiency in the presence of a functional wild-type allele.
• Tumorigenesis in this HNPCC family likely requires the inactivation of both copies of the MLH1 gene.