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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. [ABSTRACT FROM AUTHOR]

Introduction: Lynch syndrome-associated cancer develops due to germline pathogenic variants in one of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 or PMS2. Somatic second hits in tumors cause MMR deficiency, testing for which is used to screen for Lynch syndrome in colorectal cancer and to guide selection for immunotherapy. Both MMR protein immunohistochemistry and microsatellite instability (MSI) analysis can be used. However, concordance between methods can vary for different tumor types. Therefore, we aimed to compare methods of MMR deficiency testing in Lynch syndrome-associated urothelial cancers. Methods: Ninety-seven urothelial (61 upper tract and 28 bladder) tumors diagnosed from 1980 to 2017 in carriers of Lynch syndrome-associated pathogenic MMR variants and their first-degree relatives (FDR) were analyzed by MMR protein immunohistochemistry, the MSI Analysis System v1.2 (Promega), and an amplicon sequencing-based MSI assay. Two sets of MSI markers were used in sequencing-based MSI analysis: a panel of 24 and 54 markers developed for colorectal cancer and blood MSI analysis, respectively. Results: Among the 97 urothelial tumors, 86 (88.7%) showed immunohistochemical MMR loss and 68 were successfully analyzed by the Promega MSI assay, of which 48 (70.6%) were MSI-high and 20 (29.4%) were MSI-low/microsatellite stable. Seventy-two samples had sufficient DNA for the sequencing-based MSI assay, of which 55 (76.4%) and 61 (84.7%) scored as MSI-high using the 24-marker and 54-marker panels, respectively. The concordance between the MSI assays and immunohistochemistry was 70.6% (p = 0.003), 87.5% (p = 0.039), and 90.3% (p = 1.00) for the Promega assay, the 24-marker assay, and the 54-marker assay, respectively. Of the 11 tumors with retained MMR protein expression, four were MSI-low/MSI-high or MSI-high by the Promega assay or one of the sequencing-based assays. Conclusion: Our results show that Lynch syndrome-associated urothelial cancers frequently had loss of MMR protein expression. The Promega MSI assay was significantly less sensitive, but the 54-marker sequencing-based MSI analysis showed no significant difference compared to immunohistochemistry. Data from this study alongside previous studies, suggest that universal MMR deficiency testing of newly diagnosed urothelial cancers, using immunohistochemistry and/or sequencing-based MSI analysis of sensitive markers, offer a potentially useful approach to identification of Lynch syndrome cases. [ABSTRACT FROM AUTHOR]

A previous literature review found at least 4/9 (>=44.4%) CMMRD-associated ALL were T-ALL [[1]], and 8/88 (9.1%, 95% CI: 0.4-17.1%) childhood T-LBL patients were diagnosed with CMMRD in a consecutive series between 2007 and 2020 [[15]], suggesting an association of CMMRD with T cell lineage malignancies. For example, PCR-fragment length analysis has been shown to be insensitive to MSH6 deficiency in ALL relapse samples [[3]], and detected increased MSI in only 27% of CMMRD haematological malignancies and in 0% of non-neoplastic CMMRD tissues [[9]]. Here, 1/17 (5.9%, 95% CI: 0.2-28.7%) ALL patients with SMN had CMMRD, which is similar to the 14/189 (7.4%, 95% CI: 4.1-12.1%) pediatric non-Hodgkin lymphoma patients with SMN who had CMMRD in another recent study [[16]]. Constitutional mismatch repair deficiency (CMMRD, MIM #276300) is a rare, recessive pediatric and adolescent cancer syndrome, caused by pathogenic variants in a mismatch repair (MMR) gene: I MLH1 i , I MSH2 i , I MSH6 i , or I PMS2 i . [Extracted from the article]

Introduction and aims Lynch syndrome (LS) is a common heritable cancer predisposition syndrome. Tumours from patients with LS demonstrate microsatellite instability (MSI-high), a genetic signature detectable by low-cost DNA sequencing assays that is currently utilized in colorectal cancer screening. The utility of MSI assays for LS detection has not been extensively studied in unselected sebaceous skin tumours or duodenal tumours, where currently immunohistochemical (IHC) expression of mismatch repair (MMR) proteins is used. In addition, it has recently been suggested that cutaneous squamous cell carcinoma (cSCC) could be linked to LS; however MSI status has not been studied in patients with early-onset cSCC. Methods We investigated MSI status in archival formalin-fixed paraffin-embedded cases with ethical approval. We examined 110 sebaceous tumours (STs) (45 female patients, 65 male patients; median age 77 years), 50 duodenal tumours (DTs) (28 female patients, 22 male patients; median age 64 years), and 148 cSCCs selected from patients under 50 years of age (69 female patients, 79 male patients; median age 49 years). Immunohistochemistry (IHC) was performed on each MSI-high sample to determine the expression of MMR proteins MLH1, MSH2, MSH6 and PMS2. Samples that passed quality control were included in the analysis. Results A total of 42 of 106 STs (39.6%) were MSI-high. All STs had loss of at least one MMR protein. Overall, 10 of 41 (24%) DTs were MSI-high. All DTs had loss of at least one MMR protein. We found that 12 of 148 (8.1%) cSCCs were MSI-high and 5 of 12 SCCs exhibited loss of at least one MMR protein expression (41%). Conclusions MSI-high status correlated well with loss of MMR protein expression in STs and DTs samples. Future studies will help establish MSI status in tumours initially selected by MMR loss on IHC, informing its use as an adjunct to MMR IHC in LS detection in patients with STs and DTs. [ABSTRACT FROM AUTHOR]

Background: Lynch syndrome (LS) is under-diagnosed. UK National Institute for Health and Care Excellence guidelines recommend multistep molecular testing of all colorectal cancers (CRCs) to screen for LS. However, the complexity of the pathway has resulted in limited improvement in diagnosis., Methods: One-step multiplex PCR was used to generate sequencing-ready amplicons from 14 microsatellite instability (MSI) markers and 22 BRAF , KRAS , and NRAS mutation hotspots. MSI and BRAF/RAS variants were detected using amplicon-sequencing and automated analysis. The assay was clinically validated and deployed into service in northern England, followed by regional and local audits to assess its impact., Results: MSI analysis achieved 99.1% sensitivity and 99.2% specificity and was reproducible (r = 0.995). Mutation hotspot analysis had 100% sensitivity, 99.9% specificity, and was reproducible (r = 0.998). Assay-use in service in 2022-2023 increased CRC testing (97.2% (2466/2536) versus 28.6% (601/2104)), halved turnaround times, and identified more CRC patients at-risk of LS (5.5% (139/2536) versus 2.9% (61/2104)) compared to 2019-2020 when a multi-test pathway was used., Conclusion: A novel amplicon-sequencing assay of CRCs, including all biomarkers for LS screening and anti-EGFR therapy, achieved >95% testing rate. Adoption of this low cost, scalable, and fully automatable test will complement on-going, national initiatives to improve LS screening., Competing Interests: Competing interestsR. Gallon, J. Burn, M. S. Jackson, and M. Santibanez-Koref are named inventors on patents covering the microsatellite instability markers analysed: WO/2018/037231 (published March 1, 2018), WO/2021/019197 (published February 4, 2021), and GB2114136.1 (filed October 1, 2021). The other authors declare no conflicts of interest., (© The Author(s) 2024.)