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Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants., Methods: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path&#95;MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path&#95;MMR carriers who were first- or second-degree relatives of Lynch syndrome probands., Results: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path&#95;MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path&#95;MSH2 50% and 39%; for path&#95;MSH6 13% and 17% and for path&#95;PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups., Conclusions: Prospectively observed CRC incidences (PLSD) in path&#95;MLH1 and path&#95;MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path&#95;MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path&#95;PMS2 carriers subjected to colonoscopy, but not significantly so., (© 2022. The Author(s).)

Background: Due to increased risk of endometrial and ovarian cancer, women belonging to known Lynch Syndrome (LS) families are recommended to undergo germline testing. Current practice in Finland is to offer counselling to women with pathogenic variant and advocate risk-reducing surgery (RRS) after completion of childbirth. The present study aimed to clarify the impacts of positive germline testing on family planning and reproductive decisions of these women, which are relatively unknown., Methods: Seventy-nine carriers of germline MMR gene pathogenic variant (path&#95;MMR) were identified from the Finnish LS Registry as having genetic testing performed before the age of 45 years and not having undergone hysterectomy or oophorectomy. These women were sent a questionnaire concerning family planning, intimate relationships and psychosocial wellbeing., Results: Thirty-five women (44.3%) responded. Parity of path&#95;MMR carriers (2.1) was slightly higher than parity among Finnish women in general (1.8). No significant differences were found between parity, number of induced abortions or sterilizations before and after genetic testing. Only minority of subjects reported any influence on family planning (20%) or negative impact on feminine self and body image (14%)., Conclusions: The positive germline testing does not seem to have a major negative impact on family planning, intimate relationships or feminine self and body image. According to the open comments, counselling, supportive and empathic attitude of the professionals seem to have a significant impact on this. These results are a valuable addition to the counselling of LS women at reproductive age., (© 2021. The Author(s).)

Background: We previously reported that in pathogenic mismatch repair ( path&#95;MMR ) variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated., Methods: The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only path&#95;MMR variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis., Results: Ninety-nine path&#95;MMR carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 path&#95;MLH1 , 17 path&#95;MSH2, and 2 path&#95;MSH6 carriers. The number of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5-3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively ( p  < 0.001). Ten-year crude survival when the last colonoscopy had been < 1.5, 1.5-2.5, 2.5-3.5 or > 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively ( p  = 0.91)., Conclusions: In path&#95;MLH1 and path&#95;MSH2 carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of path&#95;MMR variant carriers with colonoscopy intervals of less than 3 years provides significant benefit., Competing Interests: Competing interestsToni Seppälä: a co-owner (20%) of Healthfund Finland Oy (educational and health care services in Finland, not related to patients or scope of this manuscript). Travel costs to a scientific meeting by Medtronic Finland. John Burn: a patent for high speed low cost tumor profiling pending to John Burn and QuantuMDx. All others: None declared., (© The Author(s). 2019.)

Background: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair ( path&#95;MMR ) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path&#95;MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal., Methods: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path&#95;MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers., Results: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path&#95;MLH1 , 45 path &#95; MSH2 , 10 path&#95;MSH6 and 1 path&#95;PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively ( p  = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier ( p  = 0.14)., Conclusions: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path&#95;MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path&#95;MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path&#95;MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path&#95;MMR carriers., Competing Interests: All reporting centers obtained informed consent for genetic testing and surveillance procedures. De-identified data was exported for the current study. No named registry needing approval was established for the current study.Not applicable.Toni Seppälä: a co-owner (20%) of Healthfund Finland Oy (educational and health care services in Finland, not related to patients or scope of this manuscript). Travel costs to a scientific meeting by Medtronic Finland. John Burn: a patent for high speed low cost tumor profiling pending to John Burn and QuantuMDx. All others: None declared.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path&#95;MLH1 ) despite follow-up with colonoscopy including polypectomy., Methods: The cohort included Finnish carriers enrolled in 3-yearly colonoscopy ( n  = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently ( n  = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence., Results: Cumulative CRC incidences in carriers of path&#95;MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively ( p  > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05)., Conclusions: The hypothesis that the high incidence of CRC in path&#95;MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path&#95;MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval.