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Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants., Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years., Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery., Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Many Lynch syndrome (LS) carriers remain unidentified, thus missing early cancer detection and prevention opportunities. Tested probands should inform their relatives about cancer risk and options for genetic counselling and predictive gene testing, but many fail to undergo testing. To assess predictive testing uptake and demographic factors influencing this decision in LS families, a cross-sectional registry-based cohort study utilizing the Finnish Lynch syndrome registry was undertaken. Tested LS variant probands (1184) had 2068 children divided among three generations: 660 parents and 1324 children (first), 445 and 667 (second), and 79 and 77 (third). Of children aged >18 years, 801 (67.4%), 146 (43.2%), and 5 (23.8%), respectively, were genetically tested. Together, 539 first-generation LS variant carriers had 2068 children and grandchildren (3.84 per carrier). Of the 1548 (2.87 per carrier) eligible children, 952 (61.5%) were tested (1.77 per carrier). In multivariate models, age (OR 1.08 per year; 95% CI 1.06-1.10), family gene (OR 2.83; 1.75-4.57 for MLH1 and 2.59; 1.47-4.56 for MSH2 compared with MSH6), one or more tested siblings (OR 6.60; 4.82-9.03), no siblings (OR 4.63; 2.64-8.10), and parent under endoscopic surveillance (OR 5.22; 2.41-11.31) were independent predictors of having genetic testing. Examples of parental adherence to regular surveillance and genetically tested siblings strongly influenced children at 50% risk of LS to undergo predictive gene testing. High numbers of untested, adult at-risk individuals exist even among well-established cohorts of known LS families with good adherence to endoscopic surveillance.

Lynch syndrome (LS) is an autosomal dominant cancer syndrome including increased life-long risk for colorectal (CRC) and endometrial (EC) cancer, but also for cancers of other types. The risk for CRC is up to 70-80 % and for EC up to 50-60 %. Due to screening and early diagnosing the mortality related to CRC and EC seems to be low. In spite of many studies on surveillance of mutation carriers, there is no comprehensive evaluation on causes of death in LS families. The disease history and cause of death of all the deceased, tested mutation carriers and their mutation negative relatives in the Finnish LS families (N = 179) was examined utilizing hospital records and relevant national registries. Out of 1069 mutation carriers 151 had succumbed; 97 (64 %) from cancer. Out of 1146 mutation-negative family 44 members had died; 11 (25 %) of them from cancer. In 12 (7.7 %) of the deceased mutation carriers no cancer had been diagnosed. The mean age of death from cancer was 63.2 years vs. 68.8 years from non-cancer causes. Only 7.9 % of the patients with CRC had died from CRC and 5 % of those with EC, respectively. 61 % of the cancer deaths were related to extra-colonic, extra-endometrial cancers. The cumulative overall and cancer specific death rates were significantly increased in Mut+ compared to Mut- family members. Even surveillance yields decrease in the life-long risk and mortality of the most common cancers CRC and EC in LS, almost all mutation carriers will contract with cancer, and two thirds of the deceased have died from cancer. This should be taken in account in genetic counseling. Mutation carriers should be encouraged to seek help for abnormal symptoms.