Pathogenic variants in the mismatch repair (MMR) genes results in Lynch Syndrome (LS), which is the most common hereditary cancer syndrome, estimated to hit 1 in 300 individuals. The risk to develop cancer in LS-patients depends on the specific MMR gene in which pathogenic variants occur in: MLH1, MSH2, MSH6, or PMS2. Cancer may develop in various organs including colorectum, endometrium, ovaries, stomach, small bowel, biliary tract, pancreas, and urinary tract. Both accurate estimates of these cancer risks in planning individualized screening programs as well as high-quality of the established programs are essential to prevent and diagnose cancers in early stages improving prognoses for LS-patients.
Historically, LS cancer risk estimates have been based on retrospectively collected cohorts associated with substantial ascertainment bias. Recently, prospective observational data has broadened the cancer spectrum and refined the risk assessment. Since LS tumors are characterized by aberrant MMR pathway and microsatellites instability (MSI), the universal testing for microsatellite instability-high (MSI-H) and DNA mismatch repair deficiency (dMMR) holds a great potential to improve the diagnosis and identification of LS. Nevertheless, technologies that combine individual clinical information and family phenotypes with molecular analysis and cancer penetrance data are necessary to establish more individualized cancer risk estimates and provide clinicians and patients with real-time information to plan personalized treatment and surveillance.
Among LS-associated tumors, colorectal cancer (CRC) is the most studied. For carriers of pathogenic variants path_MLH1, path_MSH2, or path_MSH6, the lifetime risk of CRC from birth to 70 years is estimated to be very broad, spanning from 20 to 60%. At the moment, CRC screening mostly consists of surveillance colonoscopy to remove eventual adenomas and thereby prevent CRC, but the lifetime risk of CRC is still approximately 50% for LS-patients. It is unclear whether this is due to a lack of adenoma as a precursor of CRC in LS, or maybe insufficient quality of the colonoscopies, both relevant issues to be investigated in future research.
To improve overall survival in LS-patients, it is necessary to focus research efforts also on the risk estimation and potential of preventing and treating extracolonic tumors, as they are the main cause of death among LS-patients. For example, very few data are available on the quality and the effects of gynecologic and urologic screening programs in LS and the quality of these.
Parallelly to improve the cancer risk estimates and screening programs, studies on the treatment of LS-related tumors are warranted, with great attention to the recent advances in immunotherapy for patients with MSI-H cancers
The scope of this Research Topic is to explore new potential approaches to improve the identification of LS-patients, technologies for individualized cancer risk estimation to guide a more personalized cancer treatment and screening programs, and issues focusing on quality improvement of established surveillance programs. This could include a wide range of studies on tools and methods, e.g., new pathways, biomarkers, mutations and modifiers, prognostic and predictive tools, and new technologies in diagnostics and therapy. These innovations may be translational or implemented in the clinic. We are interested in both original and review articles that may add novel perspectives to improve the prognosis for LS patients.
Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.
Pathogenic variants in the mismatch repair (MMR) genes results in Lynch Syndrome (LS), which is the most common hereditary cancer syndrome, estimated to hit 1 in 300 individuals. The risk to develop cancer in LS-patients depends on the specific MMR gene in which pathogenic variants occur in: MLH1, MSH2, MSH6, or PMS2. Cancer may develop in various organs including colorectum, endometrium, ovaries, stomach, small bowel, biliary tract, pancreas, and urinary tract. Both accurate estimates of these cancer risks in planning individualized screening programs as well as high-quality of the established programs are essential to prevent and diagnose cancers in early stages improving prognoses for LS-patients.
Historically, LS cancer risk estimates have been based on retrospectively collected cohorts associated with substantial ascertainment bias. Recently, prospective observational data has broadened the cancer spectrum and refined the risk assessment. Since LS tumors are characterized by aberrant MMR pathway and microsatellites instability (MSI), the universal testing for microsatellite instability-high (MSI-H) and DNA mismatch repair deficiency (dMMR) holds a great potential to improve the diagnosis and identification of LS. Nevertheless, technologies that combine individual clinical information and family phenotypes with molecular analysis and cancer penetrance data are necessary to establish more individualized cancer risk estimates and provide clinicians and patients with real-time information to plan personalized treatment and surveillance.
Among LS-associated tumors, colorectal cancer (CRC) is the most studied. For carriers of pathogenic variants path_MLH1, path_MSH2, or path_MSH6, the lifetime risk of CRC from birth to 70 years is estimated to be very broad, spanning from 20 to 60%. At the moment, CRC screening mostly consists of surveillance colonoscopy to remove eventual adenomas and thereby prevent CRC, but the lifetime risk of CRC is still approximately 50% for LS-patients. It is unclear whether this is due to a lack of adenoma as a precursor of CRC in LS, or maybe insufficient quality of the colonoscopies, both relevant issues to be investigated in future research.
To improve overall survival in LS-patients, it is necessary to focus research efforts also on the risk estimation and potential of preventing and treating extracolonic tumors, as they are the main cause of death among LS-patients. For example, very few data are available on the quality and the effects of gynecologic and urologic screening programs in LS and the quality of these.
Parallelly to improve the cancer risk estimates and screening programs, studies on the treatment of LS-related tumors are warranted, with great attention to the recent advances in immunotherapy for patients with MSI-H cancers
The scope of this Research Topic is to explore new potential approaches to improve the identification of LS-patients, technologies for individualized cancer risk estimation to guide a more personalized cancer treatment and screening programs, and issues focusing on quality improvement of established surveillance programs. This could include a wide range of studies on tools and methods, e.g., new pathways, biomarkers, mutations and modifiers, prognostic and predictive tools, and new technologies in diagnostics and therapy. These innovations may be translational or implemented in the clinic. We are interested in both original and review articles that may add novel perspectives to improve the prognosis for LS patients.
Please note: manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic.