Delineating genotype and parent-of-origin effect on the phenotype in MSH6-associated Lynch syndrome.

BACKGROUND: This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease-causing MSH6 germline variants. PATIENTS AND METHODS: A cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross-validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC). RESULTS: No significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77-1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43-1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46-0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52-1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65-1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64-1.19). DISCUSSION AND CONCLUSION: No evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.

Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated "Big Bang" pathway to CRC in three of the four Lynch syndromes.

BACKGROUND: Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes. MATERIALS AND METHODS: We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms. RESULTS: Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers. CONCLUSIONS: Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports.

A comprehensive characterization of the spectrum of MUTYH germline pathogenic variants in Latin America.

MUTYH-Associated Polyposis (MAP) is caused by biallelic pathogenic germline variants in the MUTYH gene. However, individuals harboring monoallelic MUTYH pathogenic variants in the presence of a positive family history have been reported to have a twofold increased risk of colorectal cancer (CRC) and extra colonic cancers. Our aim was to characterize the spectrum of monoallelic and biallelic germline MUTYH pathogenic variants in Latin American patients and to describe their clinical and genetic characteristics. Patients were identified from eight high-risk genetic cancer centers of five Latin American countries. Statistical analysis was performed using the two-sided P test using the Vassarstats statistical tools. Statistical significance was set at a p value ≤ 0.05. Of the 105 unrelated patients with cancer or colorectal polyposis, 84.8% and 15.2% carried pathogenic monoallelic and biallelic MUTYH variants, respectively. The most common pathogenic variants were p.Gly396Asp and p.Tyr179Cys (55% and 23%, respectively). The mean age at first diagnosis was 48.29 years (range 31-71) and 49.90 years (range 27-87) in biallelic and monoallelic MUTYH patients, respectively. CRC was the only cancer diagnosed in patients with biallelic MUTYH pathogenic variants (75%), while breast cancer (46.1%) was more common than CRC (24.7%) in individuals with monoallelic MUTYH pathogenic variants. We reported a high frequency of European founder variants in our diverse population. Some phenotypic differences from current studies were identified, such as a higher breast cancer burden in monoallelic carriers and a complete absence of extra-colon tumors in biallelic patients.

Exploring Stakeholders' Perspectives on Implementing Universal Germline Testing for Colorectal Cancer: Findings From a Clinical Practice Survey.

PURPOSE: New guidelines recommend considering germline genetic testing for all patients with colorectal cancer (CRC). However, there is a lack of data on stakeholders' perspectives on the advantages and barriers of implementing universal germline testing (UGT). This study assessed the perspectives of members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) regarding the implementation of UGT for patients with CRC, including readiness, logistics, and barriers. METHODS: A cross-sectional survey was sent to 317 active members of CGA-IGC. The survey included sections on demographics, clinical practice specialty, established institutional practices for testing, and questions pertaining to support of and barriers to implementing UGT for patients with CRC. RESULTS: Eighty CGA-IGC members (25%) participated, including 42 genetic counselors (53%) and 14 gastroenterologists (18%). Forty-seven (59%) reported an academic medical center as their primary work setting, and most participants (56%) had more than 10 years of clinical practice. Although most participants (73%) supported UGT, 54% indicated that changes in practice would be required before adopting UGT, and 39% indicated that these changes would be challenging to implement. There was support for both genetics and nongenetics providers to order genetic testing, and a majority (57%) supported a standardized multigene panel rather than a customized gene panel. Key barriers to UGT implementation included limited genetics knowledge among nongenetics providers, time-consuming processes for obtaining consent, ordering tests, disclosing results, and lack of insurance coverage. CONCLUSION: This study demonstrates wide support among hereditary GI cancer experts for implementation of UGT for patients with CRC. However, alternative service delivery models using nongenetics providers should be considered to address the logistical barriers to UGT implementation, particularly the growing demand for genetic testing.

Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement.

The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

A Breast Cancer Polygenic Risk Score Is Feasible for Risk Stratification in the Norwegian Population.

BACKGROUND: Statistical associations of numerous single nucleotide polymorphisms with breast cancer (BC) have been identified in genome-wide association studies (GWAS). Recent evidence suggests that a Polygenic Risk Score (PRS) can be a useful risk stratification instrument for a BC screening strategy, and a PRS test has been developed for clinical use. The performance of the PRS is yet unknown in the Norwegian population. AIM: To evaluate the performance of PRS models for BC in a Norwegian dataset. METHODS: We investigated a sample of 1053 BC cases and 7094 controls from different regions of Norway. PRS values were calculated using four PRS models, and their performance was evaluated by the area under the curve (AUC) and the odds ratio (OR). The effect of the PRS on the age of onset of BC was determined by a Cox regression model, and the lifetime absolute risk of developing BC was calculated using the iCare tool. RESULTS: The best performing PRS model included 3820 SNPs, which yielded an AUC = 0.625 and an OR = 1.567 per one standard deviation increase. The PRS values of the samples correlate with an increased risk of BC, with a hazard ratio of 1.494 per one standard deviation increase (95% confidence interval of 1.406-1.588). The individuals in the highest decile of the PRS have at least twice the risk of developing BC compared to the individuals with a median PRS. The results in this study with Norwegian samples are coherent with the findings in the study conducted using Estonian and UK Biobank samples. CONCLUSION: The previously validated PRS models have a similar observed accuracy in the Norwegian data as in the UK and Estonian populations. A PRS provides a meaningful association with the age of onset of BC and lifetime risk. Therefore, as suggested in Estonia, a PRS may also be integrated into the screening strategy for BC in Norway.

Current chemoprevention approaches in Lynch syndrome and Familial adenomatous polyposis: a global clinical practice survey.

Background: International chemoprevention preferences and approaches in Lynch syndrome (LS) and APC-associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored. Aim: To describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey. Results: Ninety-six participants across four hereditary gastrointestinal cancer societies responded to the survey. Most respondents (91%, 87/96) completed information regarding their demographics and practice characteristics relating to hereditary gastrointestinal cancer and chemoprevention clinical practices. Sixty-nine percent (60/87) of respondents offer chemoprevention for FAP and/or LS as a part of their practice. Of the 75% (72/96) of survey respondents who were eligible to answer practice-based clinical vignettes based off of their responses to ten barrier questions regarding chemoprevention, 88% (63/72) of those participants completed at least one case vignette question to further characterize chemoprevention practices in FAP and/or LS. In FAP, 51% (32/63) would offer chemoprevention for rectal polyposis, with sulindac - 300 mg (18%, 10/56) and aspirin (16%, 9/56) being the most frequently selected options. In LS, 93% (55/59) of professionals discuss chemoprevention and 59% (35/59) frequently recommend chemoprevention. Close to half of the respondents (47%, 26/55) would recommend beginning aspirin at time of commencement of the patient's first screening colonoscopy (usually at age 25yrs). Ninety-four percent (47/50) of respondents would consider a patient's diagnosis of LS as an influential factor for aspirin use. There was no consensus on the dose of aspirin (≤100 mg, >100 mg - 325 mg or 600 mg) to offer patients with LS and there was no agreement on how other factors, such as BMI, hypertension, family history of colorectal cancer, and family history of heart disease, would affect the recommendation for aspirin use. Possible harm among older patients (>70 years) was identified as the most common reason to discourage aspirin use. Conclusion: Although chemoprevention is widely discussed and offered to patients with FAP and LS by an international group of hereditary gastrointestinal cancer experts, there is significant heterogeneity in how it is applied in clinical practice.

Cancer surveillance for transgender and gender diverse patients with Lynch syndrome: a practice resource of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer.

Transgender and gender diverse (TGD) populations with hereditary cancer syndromes face unique obstacles to identifying and obtaining appropriate cancer surveillance and risk-reducing procedures. There is a lack of care provider knowledge about TGD health management. Lynch syndrome (LS) is one of the most common hereditary cancer syndromes, affecting an estimated 1 in 279 individuals. There are no clinical guidelines specific for TGD individuals with LS, highlighting a need to improve the quality of care for this population. There is an urgent need for cancer surveillance recommendations for TGD patients. This commentary provides recommendations for cancer surveillance, risk-reducing strategies, and genetic counseling considerations for TGD patients with LS.

Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database.

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines.

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.

Is HLA type a possible cancer risk modifier in Lynch syndrome?

Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR-deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR-deficient cancers leads to a counter-selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors.

Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru.

Background: Genetic testing for hereditary cancers is inconsistently applied within the healthcare systems in Latin America. In Peru, the prevalence and spectrum of cancer-predisposing germline variants is thus poorly characterized. Purpose: To determine the spectrum and prevalence of cancer-predisposing germline variants and variants of uncertain significance (VUS) in high-risk individuals located in a Peruvian low-resource setting city. Methods: Individuals presenting clinical criteria for hereditary cancer syndromes or being unaffected with familial history of cancer were included in the study. Samples from a total of 84 individuals were subjected to a high-throughput DNA sequencing assay that targeted a panel of 94 cancer predisposition genes. The pathogenicity of detected germline variants was classified according to the established American College of Medical Genetics and Genomics (ACMG) criteria. All pathogenic variants were validated by cycling temperature capillary electrophoresis. Results: We identified a total of eight pathogenic variants, found in 19 out of 84 individuals (23%). Pathogenic variants were identified in 24% (10/42) of unaffected individuals with family history of cancer and in 21% (9/42) of individuals with a cancer diagnosis. Pathogenic variants were identified in eight genes: RET (3), BRCA1 (3), SBDS (2), SBDS/MLH1 (4), MLH1 (4), TP53 (1), FANCD2 (1), DDB2/FANCG (1). In cancer cases, all colon cancer cases were affected by pathogenic variants in MLH1 and SBDS genes, while 20% (2/10) of the thyroid cancer cases by RET c.1900T>C variants were affected. One patient with endometrial cancer (1/3) had a double heterozygous pathogenic variant in DDB2 and FANCG genes, while one breast cancer patient (1/14) had a pathogenic variant in TP53 gene. Overall, each individual presented at least 17 VUS, totaling 1926 VUS for the full study population. Conclusion: We describe the first genetic characterization in a low-resource setting population where genetic testing is not yet implemented. We identified multiple pathogenic germline variants in clinically actionable predisposition genes, that have an impact on providing an appropriate genetic counselling and clinical management for individuals and their relatives who carry these variants. We also reported a high number of VUS, which may indicate variants specific for this population and may require a determination of their clinical significance.

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

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.

Patterns of germline and somatic testing after universal tumor screening for Lynch syndrome: A clinical practice survey of active members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer.

Clinical guidelines recommend universal tumor screening (UTS) of colorectal and endometrial cancers for Lynch syndrome (LS). There are limited guidelines for how to integrate germline testing and somatic tumor testing after a mismatch repair deficient (dMMR) tumor is identified. We sought to characterize current practice patterns and barriers to preferred practice among clinical providers in high-risk cancer programs. A clinical practice survey was sent to 423 active members of the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC) with a follow-up survey sent to 103 clinician responders. The survey outlined clinical vignettes and asked respondents their preferred next test. The survey intended to assess: (1) the role of patient age and family history in risk assessment and (2) barriers to preferred genetic testing. Genetic test options included targeted germline testing based on dMMR expression, germline testing for LS, germline testing with a multigene cancer panel including LS, or paired tumor/germline testing including LS. In October 2020, 117 of 423 (28%) members completed the initial survey including 103 (88%) currently active clinicians. In April 2021, a follow-up survey was sent to active clinicians, with 45 (44%) completing this second survey. After selecting their preferred next germline or paired tumor/germline tumor test based on the clinical vignette, 39% of respondents reported wanting to make a different choice for the initial genetic test without any testing barriers. The proportion of respondents choosing a different initial genetic test was dependent on the proband's age at diagnosis and specified family history. The reported barriers included patient's lack of insurance coverage, patient unable/unwilling to self-pay for proposed testing, and inadequate tumor tissue. Responders reported insurance, financial constraints, and limited tumor tissue as influencing preferred genetic testing in high-risk clinics, thus resulting in possible under-diagnosis of LS and impacting potential surveillance and cascade testing of at-risk relatives.

First international workshop of the ATM and cancer risk group (4-5 December 2019).

The first International Workshop of the ATM and Cancer Risk group focusing on the role of Ataxia-Telangiectasia Mutated (ATM) gene in cancer was held on December 4 and 5, 2019 at Institut Curie in Paris, France. It was motivated by the fact that germline ATM pathogenic variants have been found to be associated with different cancer types. However, due to the lack of precise age-, sex-, and site-specific risk estimates, no consensus on management guidelines for variant carriers exists, and the clinical utility of ATM variant testing is uncertain. The meeting brought together epidemiologists, geneticists, biologists and clinicians to review current knowledge and on-going challenges related to ATM and cancer risk. This report summarizes the meeting sessions content that covered the latest results in family-based and population-based studies, the importance of accurate variant classification, the effect of radiation exposures for ATM variant carriers, and the characteristics of ATM-deficient tumors. The report concludes that ATM variant carriers outside of the context of Ataxia-Telangiectasia may benefit from effective cancer risk management and therapeutic strategies and that efforts to set up large-scale studies in the international framework to achieve this goal are necessary.

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study.

BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. OBJECTIVE: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. METHODS: Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. RESULTS: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. CONCLUSION: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.