Background
Lynch syndrome (LS), a hereditary cancer predisposition associated with a pathogenic variant (PV) in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2), confers increased risks of several cancers, notably colorectal cancer (CRC) and endometrial cancer (EC), as well as other rarer malignancies.

Objectives
The objective of this study is to estimate accurate cancer risks in LS, which are essential for establishing personalized surveillance.

Methods
Using data from the French OFELy registry, established in 2011 with the support of INCa, we estimated age-specific cumulative risks (penetrance) and relative risks for 12 cancer localizations according to age, sex and the implicated gene. To correct for selection bias inherent to the retrospective design, we applied the Genotype Restricted Likelihood (GRL) method with a “multi-trait phenotype” approach, accounting for all cancers of interest simultaneously when estimating penetrance for each cancer type.

Results
We analyzed data from 1,787 Lynch syndrome families (575 MLH1, 748 MSH2/EPCAM, 337 MSH6, 127 PMS2), comprising a total of 44,198 individuals. Among these individuals, 3,737 (8.5%) were non?carriers, 5,128 (11.6%) carriers, and 35,332 (79.9%) untested. We documented 9,383 primary tumors in LS spectrum, mainly colorectal (56%) and endometrial (9%).
Risk differences were observed across MMR genes. For CRC, a later increase in risk was confirmed for MSH6 and PMS2 carriers. Penetrance exceeds that of the general population at age 70 as early as 20–40 years for MLH1/MSH2, but only at 50 years for MSH6 and 60–70 years for PMS2 in men and women, respectively. For EC, penetrance at age 70 was lower than previously reported for all genes: 20.7% (3.9–60.7), 17.9% (8.1–47.5), 8.7% (4.8–18.9), and 1.7% (1.1–3.4) for MLH1, MSH2, MSH6, and PMS2, respectively.
Estimated ovarian cancer penetrance was consistent with the literature for MSH2 and MSH6 but lower for MLH1, with risks at age 40 of 0.3% (0.1–1.3) and 2.3% (0.7–7.9) for MLH1 and MSH2, respectively, and 0.7% (0.1–3.1) at age 45 for MSH6. For small bowel cancer, increased risk was confirmed from age 35 for MLH1 (1.1% (0.3–3.5)) and from age 40 for MSH2 (0.4% (0.1–6.1)). Gastric cancer risk was higher for MLH1 compared to MSH2 and MSH6, evident from age 40, with MLH1 risks of 2.3% (0.4–6.9) versus <0.1% for other genes. For pancreatic cancer, penetrance at age 45 was 3% (0.1–15) and 1.5% (0.1–10.5) for MLH1 and MSH2, respectively. Urinary tract cancer risk was higher at age 70 for MSH2 compared to MLH1 and MSH6, but did not exceed 1.5% at age 40 for any gene and remained <1% until age 55 for MSH6.
Relative risks for breast and prostate cancer were similar to those in the general population, confirming they are not part of the Lynch spectrum.

Conclusions/Implications
This study, based on one of the largest family series, provides robust cancer risk estimates in LS. These findings, compared with existing literature, will help update surveillance recommendations with a personalized approach according to the specific MMR gene PV.