The Prospective Lynch Syndrome Database reports enable evidence-based personal precision health care

Abstract

The aims of the Prospective Lynch Syndrome Database (PLSD) are to provide empirical prospectively observed data on the incidences of cancer in different organs, survival following cancer and the effects of interventions in carriers of pathogenic variants of the mismatch repair genes (path_MMR) categorized by age, gene and gender. Although PLSD is assumption-free, as with any study the ascertainment procedures used to identify the study cohort will introduce selection biases which have to be declared and considered in detail in order to provide robust and valid results. This paper provides a commentary on the methods used and considers how results from the PLSD reports should be interpreted. A number of the results from PLSD were novel and some in conflict with previous assumptions. Notably, colonoscopic surveillance did not prevent colo-rectal cancer, survival after colo-rectal, endometrial and ovarian cancer was good, no survival gain was observed with more frequent colonoscopy, new causes of cancer-related death were observed in survivors of first cancers due to later cancers in other organs, variants in the different MMR genes caused distinct multi-cancer syndromes characterized by different penetrance and phenotypes. The www.PLSD.eu website together with the InSiGHT database website (https://www.insight-group.org/variants/databases/) now facilitate evidence-based personalized precision health care for individual carriers at increased risk of cancer. The arguments are summarized in a final discussion on how to conceptualize current knowledge for the different practical purposes of treating cancers, genetic counselling and prevention, and for understanding /research on carcinogenetic mechanisms.

The “unnatural” history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance

“…In line with these observations, the Prospective Lynch Syndrome Database (PLSD, plsd.eu), the largest prospective database of known MMR carriers, demonstrated the development of a substantial number of CRCs despite colonoscopy with polypectomy. 50 Even in LS patients undergoing regular colonoscopy surveillance, CRC was the most frequent first cancer observed, 51 becoming clinically manifest as "incident cancers" (ie, diagnosed after the beginning of surveillance period). These findings were confirmed in an independent large series of MMR carriers.…”

Prospective observational data informs understanding and future management of Lynch syndrome: insights from the Prospective Lynch Syndrome Database (PLSD)

“…The PLSD aimed at migrating knowledge on LS from expert opinions based on retrospective studies to prospectively obtained empirical observations on cancer incidences, mortality and the effects of interventions in carriers of pathogenic MMR variants ( path_MMR ). A detailed discussion of methods was previously published [ 1 ]. Møller’s recent review paper paper [ 1 ] summarizes some findings from PLSD that are partially in conflict with what was expected based on previous research, and discusses the emerging knowledge of inherited colorectal cancers including LS during recent decades.…”

“…A detailed discussion of methods was previously published [ 1 ]. Møller’s recent review paper paper [ 1 ] summarizes some findings from PLSD that are partially in conflict with what was expected based on previous research, and discusses the emerging knowledge of inherited colorectal cancers including LS during recent decades. Of note, he also examines how to avoid lead-time bias, which was one of the detailed aims of PLSD.…”

“…A number of issues therefore need to be addressed by the LS research community. One immediate priority is the careful review of prospective data to reveal all possible source of bias, as highlighted by Moller [ 1 ]. Another is a time trend in the evolution of colonoscopy technology [ 17 ].…”

Fundamentals of personalised medicine in genetic testing-based oncology

“…This can be illustrated by the hereditary non-polyposis colorectal cancer (HNPCC), also referred to as Lynch syndrome. Its spectrum includes colonic cancer, but also cancers of the endometrium, ovary, bile ducts, urinary tract, stomach and brain [20]. Knowledge of this spectrum allows optimisation of prophylaxis by planning a test program or resection of healthy organs from the spectrum (depending on the risk of developing cancer).…”