The Prevalence and Molecular Landscape of Lynch Syndrome in the Affected and General Population

SIMPLE SUMMARY: Lynch syndrome accounts for 2–3% of all CRC cases. This retroactive and prospective study aimed to estimate the prevalence of Lynch syndrome and describe disease-causing variants in mismatch repair genes in a diagnostic setting and in the Estonian general population. For that, ten years (2012–2022) of data was gathered. In addition, a pilot study for estimating the improvement of Lynch syndrome diagnostics by raising the age limit of mismatch repair gene immunohistochemistry was conducted. We estimated the birth prevalence of LS in Estonia at 1:8638 (95% CI: 1:9859–7588) or 11.58 (95% CI: 10.14–13.18) for 100,000 LBs between 1930 and 2003. The prevalence of Lynch syndrome has increased approximately six-fold in ten years. Due to the improvement of awareness in families and patients sharing information with their family members, the latter receives the diagnosis eight years earlier when most individuals are still healthy, illustrating the benefit of genetic testing and therefore an opportunity for prevention. Furthermore, the pilot study proved to be beneficial. ABSTRACT: Background: Lynch syndrome (LS) is the most frequent genetically pre-disposed colorectal cancer (CRC) syndrome, accounting for 2–3% of all CRC cases. In Estonia, ~1000 new cases are diagnosed each year. This retroactive and prospective study aimed to estimate the prevalence of LS and describe disease-causing variants in mismatch repair (MMR) genes in a diagnostic setting and in the Estonian general population. Methods: LS data for the diagnostic cohort were gathered from 2012 to 2022 and data for the general population were acquired from the Estonian Biobank (EstBB). Furthermore, we conducted a pilot study to estimate the improvement of LS diagnostic yield by raising the age limit to >50 years for immunohistochemistry analysis of MMR genes. Results: We estimated LS live birth prevalence between 1930 and 2003 in Estonia at 1:8638 (95% CI: 1: 9859–7588). During the study period, we gathered 181 LS individuals. We saw almost a six-fold increase in case prevalence, probably deriving from better health awareness, improved diagnostic possibilities and the implementation of MMR IHC testing in a broader age group. Conclusion: The most common genes affected in the diagnostic and EstBB cohorts were MLH1 and PMS2 genes, respectively. The LS diagnosis mean age was 44.8 years for index cases and 36.8 years (p = 0.003) for family members. In the MMR IHC pilot study, 29% had LS.