Background: Lynch Syndrome (LS) is a common inherited cancer syndrome which is estimated to affect 1 in 279 individuals. In the US, about 1 million individuals have LS, many of whom remain undiagnosed. The CDC recommends population screening for LS, classified as a Tier 1 condition, due to established guidelines for cancer prevention and early detection in individuals with pathogenic germline variants linked to LS.

Methods: We conducted an interim cross-sectional analysis of 2018-2022 data from the All of Us (AOU) Research Program to evaluate LS population screening. This longitudinal cohort study aims to recruit 1 million diverse Americans aged 18+, gathering participant surveys, electronic health records, and biospecimens for genetic condition analysis. We aimed to identify LS carriers with pathogenic or likely pathogenic (P/LP) variants in the MLH1, MSH2, MSH6, and PMS2 genes. We examined demographic data and personal and family cancer histories, stratifying results by genotype and comparing LS carriers with non-LS carriers. LS-related cancers included colorectal (CRC) and endometrial cancers (EC) as well as stomach, small intestine, ovarian, hepatobiliary tract, urinary/bladder/kidney, and pancreatic cancer.

Results: In our analysis of 217,872 individuals, 645 (0.3%) had P/LP variants: 63 (10%) in MLH1, 55 (9%) in MSH2, 212 (33%) in MSH6, and 316 (49%) in PMS2. Among those with available medical records (n=163,002), 476 LS carriers were identified. Of these, 284 (59.7%) were female with median age of 57 years, 65% self-identified as White; these demographics were similar to non-LS carriers. 18% with LS had at least one LS-related cancer, versus 4% of non-carriers (p<0.01). The most common cancers in carriers were CRC at 9.9% (versus 1.2% in non-carriers, p<0.01) and EC at 5.3% (versus 0.5% in non-carriers, p<0.01). Presence of other, non-LS cancers were similar between carriers and non-carriers (9.5% vs 11%, p=NS). The impact of carrier status on age of LS-related cancer presentation and gene-specific results are shown in Figures 1a&b. 73% of LS carriers were cancer-free compared to 85% of non-carriers (p<0.01). Absence of personal and family cancer history was noted in 67% of LS carriers.

Conclusion: Our findings indicate that population-based germline testing for LS may identify up to 67% of carriers who might otherwise go unrecognized if testing was limited to those with personal or family history of cancer. Similar to previous reports, the prevalence of LS was 1 in 338 where P/LP variants in the less penetrant genes MSH6 and PMS2 were more common than previously reported. This underscores the potential importance of population-level genetic screening to optimize identification of LS and additional studies are needed to assess the impact on preventative screening.

Figure 1. Cumulative Distribution of LS-associated Cancers, by Age at Presentation. (a) Comparison between LS-carriers and non-LS carriers; (b) Comparison between gene-specific LS carriers and non-LS carriers.

Jiheum Park

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