Germline truncating mutations in both MSH2 and BRCA2 in a single kindred

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Familial cancer syndromes often involve inherited mutations in specific genes.
• The potential for a single gene to predispose to both breast cancer (BC) and colorectal cancer (CRC) has been of interest.
• Understanding the genetic basis of hereditary cancer is crucial for risk assessment and management.

Purpose of the Study:

• To characterize a large family (MON1080) with multiple cases of BC and CRC.
• To identify the genetic mutations responsible for the observed cancer predisposition within the family.
• To investigate the combined effect of mutations in BRCA2 and MSH2 genes on cancer phenotype.

Main Methods:

• Linkage analysis to identify potential disease-associated genes.
• DNA sequencing to detect specific mutations in BRCA2 and MSH2.
• Immunohistochemistry and microsatellite instability studies.
• Quantitative real-time PCR and cDNA sequencing to characterize MSH2 deletion.

Main Results:

• A BRCA2 exon 3 (L105X) mutation was identified in affected family members.
• A large deletion in MSH2 exon 8 was found in one individual, confirming double heterozygosity for mutations in both BRCA2 and MSH2.
• No increased susceptibility to colorectal tumors in BRCA2 mutation carriers or breast tumors in MSH2 mutation carriers was observed.
• Double heterozygotes did not exhibit a distinct phenotype beyond that expected from individual gene mutations.

Conclusions:

• The MON1080 kindred carries disease-causing truncating mutations in both MSH2 and BRCA2.
• Inherited mutations in BRCA2 do not appear to increase colorectal cancer risk, nor do MSH2 mutations increase breast cancer risk within this cohort.
• Double heterozygosity for BRCA2 and MSH2 mutations did not result in an altered cancer phenotype in the studied individuals.