Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Abstract

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_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_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_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_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_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

PMS2-associated Lynch syndrome: Past, present and future

“…A third method of estimating cancer risks is to gather prospective data, and a global collaboration has now been formed to gather such data. The Prospective LS Database (PLSD) has currently published multiple reports on penetrance (23,(31)(32)(33). Their most recent study estimated risks of 11% (95% CI: 3-37%) and 8% (95% CI: 2-29%) for path_PMS2 carriers up to age 70 for men and women, respectively (32).…”

“…The Prospective LS Database (PLSD) has currently published multiple reports on penetrance ( 23 , 31 – 33 ). Their most recent study estimated risks of 11% (95% CI: 3–37%) and 8% (95% CI: 2–29%) for path_PMS2 carriers up to age 70 for men and women, respectively ( 32 ). Cancer risk estimates from the PLSD are aimed at determining the risks while under surveillance, which is important information when counselling patients.…”

“…Firstly, a recent study compared retrospective International Mismatch Repair Consortium (IMRC) and prospective cancer risks from the PLSD ( 32 ). Retrospective studies are aimed at determining the cancer risk without colonoscopy and polypectomy, while prospective studies include patients that undergo surveillance and therefore estimate risk despite colonoscopy.…”

The Prospective Lynch Syndrome Database: background, design, main results and complete MySQL code

“…In the context of LS, if two or more carcinogenetic pathways may be operating simultaneously, proving an adenoma to be a precursor of cancer does not exclude other carcinogenetic pathways to colon cancer. The idea of the PLSD was to measure by how much colonoscopy reduced colorectal cancer incidence – it came as a surprise that colorectal cancer was apparently not reduced as a result of colonoscopy [ 1 ]. The design of the PLSD, however, did not include any initial paradigm and the design allowed unexpected results: The PLSD reports on the observed empirical evidence based on assumption-free data.…”

“…Additional tables including more attributes of the carriers may be added to the MySQL database, and additional views/functions may be added to answer additional questions and to analyze more substrata. Further calculations of cumulative incidence should be based on Poisson distributions as previously published [ 1 ].…”