PMS2 monoallelic mutation carriers: the known unknown

Area of Science:

• Genetics
• Oncology
• Clinical Management

Background:

• Lynch syndrome is caused by germ-line mutations in mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2.
• While reduced penetrance is noted for PMS2 mutations, current clinical guidelines recommend similar screening for all MMR gene carriers.
• The study investigates the need for specific screening guidelines for PMS2 mutation carriers.

Purpose of the Study:

• To evaluate evidence for modifying cancer screening guidelines for individuals with monoallelic PMS2 germ-line mutations.
• To assess the age at onset and tumor spectrum of colorectal cancer (CRC) in PMS2 mutation carriers.
• To determine if current screening recommendations are appropriate for PMS2 carriers.

Main Methods:

• A comprehensive review of published reports and unpublished cases of PMS2 germ-line mutations.
• Analysis of data from 234 monoallelic PMS2 mutation carriers across 170 families.
• Discussion on potential modifications to cancer screening guidelines.

Main Results:

• Approximately 8% of colorectal cancer (CRC) cases in PMS2 carriers were diagnosed before age 30.
• Early-onset CRC in this cohort predominantly occurred in the left side of the colon.
• Despite reduced penetrance, early-onset CRC necessitates continued vigilance.

Conclusions:

• The underlying cause of early-onset CRC in some PMS2 mutation families remains unknown.
• The authors recommend maintaining current cancer surveillance guidelines for PMS2 mutation carriers.
• No reduction in screening frequency or age is advised for PMS2 carriers at this time.