Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome

Area of Science:

• Genetics
• Oncology
• Hereditary Cancer Syndromes

Background:

• Heterozygous germline PMS2 variants account for approximately 5% of Lynch syndrome (LS) cases.
• The prevalence of PMS2 variants in LS is likely underestimated due to complex screening challenges posed by homologous pseudogenes.
• Limited knowledge exists regarding the specific role of the PMS2 gene in the development of LS.

Purpose of the Study:

• To investigate the prevalence and clinical implications of PMS2 variants in Lynch syndrome.
• To characterize the spectrum of PMS2 variants and their association with cancer onset and type.
• To evaluate the diagnostic utility of somatic analyses in PMS2 variant carriers.

Main Methods:

• Identification and classification of 200 heterozygous PMS2 variants in 195 French patients, including 112 unique class-3/4/5 variants.
• Analysis of genomic rearrangements, specific variant frequencies (e.g., c.137G>T), and founder effects.
• Assessment of clinical data including age at tumor onset, cancer types, family history, and results of microsatellite instability and PMS2 expression analyses.

Main Results:

• Genomic rearrangements constituted 18% of identified PMS2 alterations.
• Among class-4/5 variant carriers, the median age of first tumor onset was 49 years, with colorectal (80%) and endometrial (8.1%) cancers being predominant.
• Tumors from PMS2 variant carriers frequently showed microsatellite instability (96%) and loss of PMS2 expression (76%).

Conclusions:

• PMS2 variants play a significant role in Lynch syndrome, often in families not meeting traditional Amsterdam criteria.
• While PMS2 variants may exhibit lower penetrance, they are associated with a risk of early-onset cancers, demonstrating variable penetrance.
• Somatic analyses for microsatellite instability and PMS2 expression are highly predictive in identifying carriers of pathogenic PMS2 variants.