Lynch Syndrome Patients Research Articles

Risk of Gastric Cancer and Utility of Endoscopic Screening for Lynch Syndrome Patients

Background: Lynch syndrome (LS) is an autosomal dominant hereditary condition associated with a genetic predisposition to several cancers. Prior studies have shown an increased risk of gastric cancer (GC) in LS patients. The aim of this study was to synthesize the evidence for gastric cancer risk across Lynch syndrome-associated mutations and to assess the diagnostic utility of endoscopic screening for gastric cancer in these patients. Methods: A systematic literature review and meta-analysis of LS-associated gastric cancer risk and the diagnostic utility of endoscopic gastric cancer screening was conducted in accordance with PRISMA guidelines and GRADE methodology. Results: The results of this study found an elevated risk of GC in LS patients. Cumulative lifetime risk of GC in LS patients ranged from 2.6% to 38.7% when assessing across all LS mutations. Cumulative incidence ranged from 2.0% to 41.0%. When assessing cumulative incidence across specific LS mutations, MSH2 mutation carriers showed the highest cumulative incidence. RR across specific mutation carriers was generally highest in MSH2 carriers. A meta-analysis of 5 studies reporting diagnostic utility of endoscopic screening for gastric cancer in LS patients revealed a 2% incidence of GC (95% CI, 1.4%−2.9%). Conclusions: Gastric cancer risk in LS patients is greater than in the general population. Endoscopic screening yields low rates of GC in LS patients. Higher quality studies including RCTs are required to more accurately define GC risk and the yield of endoscopic surveillance in LS patients.

Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy.

Targetable alterations such as BRAFV600E mutation and NTRK fusion are enriched in microsatellite instability-high (MSI-H) colorectal cancer (CRC). MSI-H with targetable alterations (MSI-H altered) might present unique opportunities for both targeted therapy and immunotherapy. We systematically evaluated the molecular characteristics and immune-related features of MSI-H altered and MSI-H without targetable alterations (MSI-H wt) CRC patients in our study. Among 1938 continuously enrolled CRC patients, 126 patients with MSI-H status (6.50%) were included in this retrospective study. Genomic and transcriptomic data were investigated by next-generation sequencing (NGS) and gene expression profiling (GEP), respectively. BRAFV600E, NTRK1, and FGFR2 mutations were the most frequent targetable alterations in MSI-H CRC patients. The MSI-H altered phenotype was significantly associated with older age (p< 0.001), right side (p=0.024) and females (p= 0.036). No lynch syndrome (LS) patients were identified in MSI-H altered group. The tumor mutational burden (TMB), and tumor neoantigen burden (TNB) of MSI-H altered and wt subgroups were comparable (p<0.05). Subsequently, transcriptomic study analysis further revealed MSI-H altered CRC patients were linked to an immune-active tumor microenvironment with higher levels of Teff IFN-gamma, CYT, and MERCK 18 signatures, and lower levels of the IPRES gene signature, EMT and TGF Beta signatures. In addition, case study supported MSI-H CRC patient harboring targetable alterations might also achieved a long-term disease-free survival benefit from immunotherapy. Our study preliminary revealed MSI-H altered as a novel subtype of MSI-H CRC patients with unique molecular signatures and immune-active tumor microenvironment. Given the accessibility of immune checkpoint inhibitors (ICIs) treatment, our results might provide clinical evidence for immunotherapy in MSI-H CRC patients with targetable alterations.

MyLynch: A Patient-Facing Clinical Decision Support Tool for Genetically-Guided Personalized Medicine in Lynch Syndrome.

Lynch syndrome (LS) is a hereditary cancer susceptibility condition associated with varying cancer risks depending on which of the five causative genes harbors a pathogenic variant; however, lifestyle and medical interventions provide options to lower those risks. We developed MyLynch, a patient-facing clinical decision support (CDS) web application that applies genetically-guided personalized medicine (GPM) for individuals with LS. The tool was developed in R Shiny through a patient-focused iterative design process. The knowledge base used to estimate patient-specific risk leveraged a rigorously curated literature review. MyLynch informs LS patients of their personal cancer risks, educates patients on relevant interventions, and provides patients with adjusted risk estimates, depending on the interventions they choose to pursue. MyLynch can improve risk communication between patients and providers while also encouraging communication among relatives with the goal of increasing cascade testing. As genetic panel testing becomes more widely available, GPM will play an increasingly important role in patient care, and CDS tools offer patients and providers tailored information to inform decision-making. MyLynch provides personalized cancer risk estimates and interventions to lower these risks for patients with LS.

P078: Colon cancer is uncommon in Lynch syndrome patients having colonoscopy with chromoendoscopy

P078: Colon cancer is uncommon in Lynch syndrome patients having colonoscopy with chromoendoscopy

Clinicopathological and Dermoscopic Baselines in Patients with Lynch Syndrome.

Despite the fact that Lynch Syndrome (LS) patients may also develop extra-colonic malignancies, research evaluating the association between LS and skin cancers is currently very limited. We performed a monocentric clinical and dermoscopic study involving 42 LS patients which referred to the Dermatology Unit for cutaneous screenings. In total, 22 patients showed a mutation in MLH1 and 17 patients a MSH2 mutation. Out of the entire cohort, 83% of LS patients showed brown hairs and 78% brown eyes, and the most frequent phototypes were III and II (respectively, 71.5% and 21%). A positive medical history for an internal malignancy was present in 36% of patients, with colon cancer as the most frequent malignancy in 60% of cases. A total of 853 cutaneous lesions have been analyzed: 47% of patients showed a total number of nevi > 10. The main observed dermoscopic features were a uniform reticular pattern (77% of patients), a mixed pattern (9% of patients) and a uniform dermal pattern (14% of patients). Eruptive cherry angiomas were present in 24% of cases, eruptive seborrheic keratosis in 26% and viral warts in 7% of cases; basal cell carcinoma was detected in 7% of cases. We have not found specific associations with specific skin manifestations, and the clinical and dermoscopic appearance of the pigmented lesions reflected the features present in the general population. To date, there are currently no guidelines for skin screening in LS patients. According to our study, there is insufficient evidence to ensure increased surveillance in LS patients; further studies with larger samples of patients are needed to better investigate dermatological and dermoscopic features in LS carriers.

Non-classical phenotypes of mismatch repair deficiency and microsatellite instability in primary and metastatic tumors at different sites in Lynch syndrome.

Lynch syndrome is a genetic disease characterized by abnormal DNA replication caused by germline variation in the mismatch repair (MMR) gene. There are rare non-classical phenotypes with loss of MMR protein expression and inconsistent microsatellite stability (MSS) in Lynch syndrome-related colorectal cancers. However, the difference between microsatellite instability (MSI) of extraintestinal tumors in a patient with Lynch syndrome has been closely studied. Herein, we reported the non-classical phenotypes of mismatch repair deficiency (dMMR) and MSI in four cases of Lynch syndrome in patients with colorectal cancer and other primary and metastatic tumors. A retrospective analysis was conducted on four patients diagnosed with Lynch syndrome between 2018 and 2022 in the Department of Pathology of the Rocket Forces Specialized Medical Center. A one-step immunohistochemical (IHC) assay was employed to detect loss in the expression of Lynch syndrome-associated MMR proteins (MLH1, PMS2, MSH2, and MSH6). MSI detection was performed in both primary and metastatic tumors at different sites in the four patients using NCI 2B3D (BAT25, BAT26, D2S123, D17S250, and D5S346) and single nucleotide site (BAT25, BAT26, NR21, NR24, NR27, and MONO27) methods. In addition, related MMR gene germline variation, somatic mutations, and MLH1 gene promoter methylation were analyzed using next-generation sequencing and TaqMan probe-based methylation-specific polymerase chain reaction (MethyLight). Two of the four patients were heterozygous for MSH6 germline pathogenic variation, and the other two were heterozygous for MSH2 germline pathogenic variation. In all cases, IHC detection of protein expression of the MMR gene with germline variation was negative in all primary and metastatic tumors; non-classical phenotypes of dMMR and MSI were present between primary and metastatic tumors at different sites. dMMR in Lynch colorectal cancer demonstrated high MSI, whereas MSI in primary and metastatic tumors outside the intestine mostly exhibited MSS or low MSI. The non-classical dMMR and MSI phenotype are mostly observed in Lynch syndrome, even in the context of MMR protein expression loss. Extraintestinal tumors infrequently present with a high degree of MSI and often exhibit a stable or low degree of MSI.

DNA Mismatch Repair Proteins and BRAF V600E Detection by Immunohistochemistry in Colorectal Cancer Demonstrates Concordance with Next Generation Sequencing

Background and Aims: Multiple laboratory methods are used to screen patients with colorectal cancer (CRC) for mismatch repair (MMR) protein deficiency to identify possible Lynch syndrome patients. The goal of this study was to compare the agreement between ready-to-use immunohistochemistry (IHC) assays for MLH-1, PMS-2, MSH-2, MSH-6, and mutated BRAF at V600E and molecular methods in CRC cases. The inclusion of the BRAF V600E mutation testing is important for the identification of patients with sporadic CRC, as the BRAF V600E mutation is very rarely observed in patients with Lynch syndrome tumors. Methods: CRC cases were analyzed by ColoSeqTM tumor sequencing assay and VENTANA MMR IHC Panel that included anti-MLH1, anti-PMS2, anti-MSH2, anti-MSH6, and anti-BRAF V600E antibodies. Additionally, CRC cases with MLH1 IHC loss were evaluated for MLH1 promoter hypermethylation. Results: One hundred and eighteen cases were analyzed. The overall percent agreement (OPA) for each evaluated marker status compared to next-generation sequencing (NGS) exceeded 96%. Twenty-three cases were positive for the BRAF V600E mutation by IHC and NGS, and twenty cases showed loss of MLH1 protein and were positive for MLH1 hypermethylation. Samples with loss of MMR protein expression by IHC demonstrated genetic and/or epigenetic alterations that were consistent with the observed protein expression patterns. Conclusions: The results of this study indicate that ready-to-use IHC assays can correctly identify the loss of MMR proteins and the presence of mutated BRAF V600E protein, supporting the utility of the VENTANA MMR IHC Panel as an aid to stratify patients with sporadic CRC vs. potential Lynch syndrome.

A retrospective cohort study of genetic referral and diagnosis of Lynch syndrome in patients with cutaneous sebaceous lesions.

Immunohistochemistry (IHC) of cutaneous sebaceous lesions (SL) can be used to screen patients for Lynch syndrome (LS). There is little data on rates of genetic referral and outcomes of genetic testing for patients with SL. This single-center retrospective study characterizes 400 + patients with SL, including IHC results, genetics referrals, and outcomes of genetic testing. Retrospective chart reviews were performed for patients with a pathology-confirmed diagnosis of SL at the University of Michigan between January 2009 and December 2019. 447 patients with 473 SL were identified. Excluding 20 patients with known LS, IHC was conducted in 173 (41%) patients. 92/173 (53%) patients had abnormal results. 69 of these 92 (75%) patients were referred to genetics. 32 additional patients were referred with normal IHC (n = 22) or without IHC (n = 10). Of 101 patients referred, 65 (64%) were seen and 47 (47%) completed genetic testing. 7/47 (15%) had pathogenic variants associated with LS, six with concordant abnormal IHC and one without IHC. Cancer genetics referral of patients with SL, particularly for lesions with abnormal IHC, yields a significant rate of LS diagnosis. Providers should consider genetics referral for patients with SL.

Development and initial testing of a multi-stakeholder intervention for Lynch syndrome cascade screening: an intervention mapping approach

BackgroundLynch syndrome is an underdiagnosed hereditary condition carrying an increased lifetime risk for colorectal and endometrial cancer and affecting nearly 1 million people in the United States. Cascade screening, systematic screening through family members of affected patients, could improve identification of Lynch syndrome, but this strategy is underused due to multi-level barriers including low knowledge about Lynch syndrome, low access to genetics services, and challenging family dynamics.MethodsWe used intervention mapping, a 6-step methodology to create stakeholder-driven interventions that meet the needs of a target population, to develop an intervention to improve cascade screening for Lynch syndrome. The intervention development process was guided by input from key stakeholders in Lynch syndrome care and patients. We conducted usability testing on the intervention with Lynch syndrome patients using qualitative semi-structured interviewing and rapid qualitative analysis.ResultsWe developed a workbook intervention named Let’s Talk that addresses gaps in knowledge, skills, self-efficacy, outcome expectancy and other perceived barriers to cascade screening for Lynch syndrome. Let’s Talk contained educational content, goal setting activities, communication planning prompts and supplemental resources for patients to plan family communication. Evidence-based methods used in the workbook included information chunking, guided practice, goal setting and gain-framing. We conducted usability testing focused on the complexity and relative advantage of the intervention through 45-min virtual interviews with 10 adult patients with Lynch syndrome recruited from a national advocacy organization in the United States. Usability testing results suggested the intervention was acceptable in terms of complexity and relative advantage to other available resources, but additional information for communication with young or distant family members and a web-based platform could enhance the intervention’s usability.ConclusionsIntervention mapping provided a framework for intervention development that addressed the unique needs of Lynch syndrome patients in overcoming barriers to cascade screening. Future work is needed to transform Let’s Talk into a web-based tool and evaluate the effectiveness of the intervention in clinical practice with patients and genetic counselors. Intervention mapping can be useful to researchers as an evidence-based technique to develop stakeholder-centered interventions for addressing the needs of other unique populations.

Unifocal Peritoneal Malignant Mesothelioma as Initial Presentation of Lynch Syndrome: A Case Report and Brief Review

Abstract Introduction/Objective Peritoneal malignant mesothelioma (pMM) has scarcely been reported in the context of Lynch Syndrome (LS). No cases have directly led to a diagnosis of LS. We report an unusual case of pMM presenting as a localized mass, leading to the diagnosis of LS. Methods/Case Report A 55 year old female with no prior oncologic history presented with a solitary epigastric mass. Her mother and maternal relatives had colonic, gastric and ovarian cancers. Imaging studies revealed a perigastric mass abutting the left liver. The resected 9.8 cm mass showed a variegated histology with tubulopapillary formations and solid sheets. The neoplastic cells also showed variable cytologic features including anisocytosis, pleomorphic nuclei, multinucleation, prominent nucleoli, intranuclear pseudoinclusions, and rhabdoid features. A dense intratumoral and peritumoral lymphoplasmacytic infiltrate was present. Epithelioid pMM was confirmed with expression of cytokeratin 5/6, calretinin, WT-1, and thrombomodulin and loss of MOC31. Abnormal loss of MSH2 and MSH6 was seen (retained expression MLH1/PMS2 expression), suggesting high-level microsatellite instability. A germline pathogenic variant of MSH2 was identified. Results (if a Case Study enter NA) NA. Conclusion We report the first case of LS presenting as an atypical (unifocal) pMM showing variegated histology and lymphocytic infiltrate. Microsatellite instability in pMM is rare and has only been reported in known LS patients. Awareness of the pMM within LS is evolving and atypical features may prompt evaluation of DNA microsatellite repair system, with implications for the patient (treatment/screening) and their family.

Canonical and uncanonical pathogenic germline variants in colorectal cancer patients by next-generation sequencing in a European referral center

Despite increasing use of next-generation sequencing (NGS), data concerning the gain in germline pathogenic variants (PVs) remain scanty, especially with respect to uncanonical ones. We aimed to verify the impact of different cancer predisposition genes (CPGs) on colorectal cancer (CRC) in patients referred for genetic evaluation. We enrolled for NGS, by Illumina TruSight Cancer panel comprising 94 CPGs, 190 consecutive subjects referred for microsatellite instability (MSI) CRC, polyposis, and/or family history. Overall, 51 (26.8%) subjects carried 64 PVs; PVs coexisted in 4 (7.8%) carriers. PVs in mismatch repair (MMR) genes accounted for one-third of variant burden (31.3%). Four Lynch syndrome patients (20%) harbored additional PVs (HOXB13, CHEK2, BRCA1, NF1 plus BRIP1); such multiple PVs occurred only in subjects with PVs in mismatch syndrome genes (4/20 versus 0/31; P= 0.02). Five of 22 (22.7%) patients with MSI cancers but wild-type MMR genes harbored PVs in unconventional genes (FANCL, FANCA, ATM, PTCH1, BAP1). In 10/63 patients (15.9%) with microsatellite stable CRC, 6 had MUTYH PVs (2 being homozygous) and 4 exhibited uncanonical PVs (BRCA2, BRIP1, MC1R, ATM). In polyposis, we detected PVs in 13 (25.5%) cases: 5 (9.8%) in APC, 6 (11.8%) with biallelic PVs in MUTYH, and 2 (3.9%) in uncanonical genes (FANCM, XPC). In subjects tested for family history only, we detected two carriers (18.2%) with PVs (ATM, MUTYH). Uncanonical variants may account for up to one-third of PVs, underlining the urgent need of consensus on clinical advice for incidental findings in cancer-predisposing genes not related to patient phenotype.

Risk of cancer in individuals with Lynch-like syndrome and their families: a systematic review

BackgroundLynch-like syndrome (LLS) tumors have similar clinicopathological features to Lynch syndrome (LS) tumors but have no identifiable pathogenic germline mismatch repair gene variant. However, cancer risks in LLS patients and first-degree relatives (FDRs) are not well defined.MethodsTo clarify LLS-associated cancer risks, a systematic review of all studies examining all cancer risks in LLS was performed. Searching of Medline, Embase, Pubmed, Cochrane and CINAHL databases and reference/citation checking identified relevant studies published between January 1, 1980 and February 11, 2021. Joanna Briggs Institute Appraisal Tools assessed the risk of bias.ResultsSix studies (five cohort/one cross-sectional) were eligible for study inclusion. One study found no difference in colorectal cancer (CRC) incidence between LLS and LS patients or CRC risks at aged 70 years. Three studies found CRC incidence in LLS FDRs was higher than the general population but lower than LS FDRs. Two studies showed no difference in CRC diagnosis age between LLS patients and LS patients. Endometrial cancer risks in LLS patients were higher than the general population but lower than LS patients.ConclusionEvidence of elevated CRC risks in LLS patients and FDRs supports increased colonoscopy surveillance strategies for LLS patients and FDRs in line with current recommendations for LS. Due to heterogeneity amongst LLS populations, extended intervals between screening may be advised for low-risk families. Studies to resolve the molecular characterization and definition of LLS are needed to clarify cancer risks associated with LLS which in turn may individualize surveillance strategies for LLS patients and families.

THE ROLE OF MICROSATELLITE INSTABILITY IN COLORECTAL CANCER: A LITERATURE REVIEW

Relevance: According to Globocan 2020, colorectal cancer (CRC) incidence in Kazakhstan is lower than in all OECD countries except Mexico. However, the CRC incidence in Kazakhstan is steadily growing. In the structure of cancer incidence, CRC went up from 5th&#x0D; place in 2006 to 3rd place in 2021. More than 80% of tumors associated with Lynch syndrome were found to have microsatellite instability&#x0D; (MSI). Thus, MSI is detected in 12% of sporadic colon tumors., MSI in cancer is caused by a decreased activity of DNA repair genes due&#x0D; to hereditary and somatic causes.&#x0D; The study aimed to systematize the current literature data to consider the need and adequacy of prescribing preventive chemotherapy,&#x0D; personalizing the treatment of patients, and predicting the course of the disease in CRC.&#x0D; Methods: A review was made of the published results of scientific and clinical studies for 2006-2021 from the PubMed, MedLine,&#x0D; and Cancer Observe databases for the keywords “colon cancer,” “microsatellite resistance,” “adjuvant chemotherapy,” “PCR study,”&#x0D; “IGH-study.”&#x0D; Results: The value and adequacy of determining the IHC characteristics of the MSI status. The prognostic and predictive value of MSI&#x0D; in CRC has been proven. The optimal treatment options were selected depending on the status of MSI.&#x0D; Conclusion: Tumors with certain MSI status should be classified as a separate group of malignancies. Instability status determination is preferred in case of suspected Lynch syndrome in patients with stage II CRC, as well as in clinical and histological features&#x0D; characteristic of MSI (proximal localization of the primary tumor, mucinous histotype, poorly differentiated tumors, lymphocytic infiltration of the tumor). Further determination of these tumors’ molecular characteristics will help stratify patients who may respond&#x0D; differently to chemotherapy. Also, the MSI status determination can be an important prognostic marker in patients whose tumors have&#x0D; a somatic mutation in the BRAF gene.

A Previously Unrecognized Molecular Landscape of Lynch Syndrome in the Mexican Population

Lynch syndrome (LS) is the main hereditary colorectal cancer syndrome. There have been few reports regarding the clinical and molecular characteristics of LS patients in Latin America; this is particularly true in the Mexican population, where no information is available. The present study aims to describe the clinical and molecular spectrum of variants in a cohort of patients diagnosed with LS in Mexico. We present a retrospective analysis of 412 patients with suspected LS, whose main site of cancer diagnosis was the colon (58.25%), followed by the endometrium (18.93%). Next-generation sequencing analysis, with an extensive multigene panel, showed that 27.1% (112/414) had a variant in one of the genes of the mismatch repair pathway (MMR); 30.4% (126/414) had a variant in non-MMR genes such as CHEK2, APC, MUTYH, BRCA1, and BRCA2; and 42.5% (176/414) had no genetic variants. Most of the variants were found in MLH1. Pathogenic variants (PVs) in MMR genes were identified in 65.7% (96/146) of the total PVs, and 34.24% (45/146) were in non-MMR genes. Molecular and clinical characterization of patients with LS in specific populations allowed personalized follow-up, with the option for targeted treatment with immune checkpoint inhibitors and the development of public health policies. Moreover, such characterization allows for family cascade testing and consequent prevention strategies.

Determinants of adherence to recommendations on physical activity, red and processed meat intake, and body weight among lynch syndrome patients

This study aimed to identify determinants of adherence to lifestyle and body weight recommendations for cancer prevention among Lynch Syndrome (LS) patients. Cross-sectional baseline data of LS patients participating in the Lifestyle & Lynch (LiLy) study was used to assess determinants of adherence to the World Cancer Research Fund cancer prevention recommendations on body weight, physical activity, and red and processed meat intake. Adherence and potential determinants of adherence were assessed using questionnaires. Multivariable logistic regression analyses were conducted to identify determinants of adherence. Of the 211 participants, 50.2% adhered to the body weight recommendation, 78.7% adhered to the physical activity recommendation, and 33.6% adhered to the red and processed meat recommendation. Being younger and having a higher level of education were associated with adherence to the recommendation on body weight. Having knowledge about the recommendation was associated with adherence to the recommendations on physical activity and red and processed meat. Results confirm that knowledge about recommendations for cancer prevention is an important determinant for adherence and suggest that strategies to increase knowledge should be included in lifestyle promotion targeted at LS patients, along with behavior change techniques influencing other modifiable determinants.

A calibrated cell-based functional assay to aid classification of MLH1 DNA mismatch repair gene variants.

Functional assays provide important evidence for classifying the disease significance of germline variants in DNA mismatch repair genes. Numerous laboratories, including our own, have developed functional assays to study mismatch repair gene variants. However, previous assays are limited due to the model system employed, the manner of gene expression, or the environment in which function is assessed. Here, we developed a human cell-based approach for testing the function of variants of uncertain significance (VUS) in the MLH1 gene. Using clustered regularly interspaced short palindromic repeats gene editing, we knocked inMLH1 VUS into the endogenous MLH1 loci in human embryonic stem cells. We examined their impact on RNA and protein, including their ability to prevent microsatellite instability and instigate a DNA damage response. A statistical clustering analysis determined the range of functions associated with known pathogenic or benign variants, and linear regression was performed using existing odds in favor of pathogenicity scores for these control variants to calibrate our functional assay results. By converting the functional outputs into a single odds in favor of pathogenicity score, variant classification expert panels can use these results to readily reassess these VUS. Ultimately, this information will guide proper diagnosis and disease management for suspected Lynch syndrome patients.

Germline variants screening of MLH1, MSH2, MSH6 and PMS2 genes in 64 Algerian Lynch syndrome families: The first nationwide study.

Colorectal cancer is the second leading cause of cancer-related deaths in women and men in Algeria. Lynch syndrome (LS) is an autosomal dominant disease caused by heterozygous germline pathogenic variants in mismatch repair genes (MMR) and frequently predisposes to colorectal cancer. However, data about MMR germline pathogenic variants in Algerian patients are limited. This first nationwide study aims to describe clinicopathologic features and germline variants in MMR genes in Algerian families with suspected LS. Sixty-four (64) families with suspected LS were studied. Index cases with LS who fulfilled Amsterdam criteria were screened by PCR-direct sequencing for germline variants in MMR genes: MLH1 (exons 1, 9, 10, 13, 16), MSH2 (exons 5, 6, 7, 12), MSH6 (exons 4 and 8) and PMS2 (exons 6 and 10). We selected these specific risk exons genes since they have a higher probability of harboring pathogenic variants. In addition, two unrelated LS patients were screened by next-generation sequencing using a cancer panel of 30 hereditary cancer genes. Six germline pathogenic variants and one germline likely pathogenic variant were identified in 19 (29.68%) families (4 MLH1, 2 MSH2 and 1 MSH6). Of index cases and relatives who underwent genetic testing (n=76), 30 (39.47%) had MMR pathogenic gene variants, one (0.13%) had MMR gene likely pathogenic variant and three had MMR variant of uncertain significance, respectively. Two novel germline pathogenic variants in MLH1 (2) and one germline likely pathogenic variant in MSH6 (1) never published in individuals with LS have been detected in the present study. The recurrent MLH1 germline pathogenic variant c.1546C>T has been found in nine LS families, six of them related with two large kindreds, from four North central provinces of Algeria. In addition, the common MSH2 germline pathogenic variant c.942+3A>T has been detected in five unrelated patients with a strong LS family history. The accumulative knowledge about clinicopathological and genetic characteristics of LS in Algerian patients will impact clinical management in the areas of both prevention and treatment.

Lynch Syndrome: From Carcinogenesis to Prevention Interventions.

Simple SummaryPromoting proper preventive interventions to reduce morbidity and mortality is one of the most important challenges pertaining to inherited conditions. Lynch syndrome (LS) is an inherited disorder that predisposes to several kinds of tumor and is responsible for a relevant proportion of human colorectal and endometrial cancers. Recent knowledge has allowed for a better understanding of the genetic cause, pathogenesis, underlying immunological mechanisms, epidemiological distribution, and prevalence of this disease. This opens up unpredictable perspectives of translating such knowledge into validated programs for prevention and surveillance, in order to reduce the health impact of this disease through medical interventions before cancer development. In our review, we summarize the updated guidelines of the screening, surveillance, and risk-reducing strategies for LS patients. Moreover, we present novel opportunities in the treatment and prevention of LS patients through harnessing the immune system using immunocheckpoint inhibitors and vaccines.Lynch syndrome (LS) is the most common inherited disorder responsible for an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts, caused by a germline pathogenic variant affecting the DNA mismatch repair system. Surveillance and risk-reducing procedures are currently available and warranted for LS patients, depending on underlying germline mutation, and are focused on relevant targets for early cancer diagnosis or primary prevention. Although pharmacological approaches for preventing LS-associated cancer development were started many years ago, to date, aspirin remains the most studied drug intervention and the only one suggested by the main surveillance guidelines, despite the conflicting findings. Furthermore, we also note that remarkable advances in anticancer drug discovery have given a significant boost to the application of novel immunological strategies such as immunocheckpoint inhibitors and vaccines, not only for cancer treatment, but also in a preventive setting. In this review, we outline the clinical, biologic, genetic, and morphological features of LS as well as the recent three-pathways carcinogenesis model. Furthermore, we provide an update on the dedicated screening, surveillance, and risk-reducing strategies for LS patients and describe emerging opportunities of harnessing the immune system.

Detection of Microsatellite Instability in Colonoscopic Biopsies and Postal Urine Samples from Lynch Syndrome Cancer Patients Using a Multiplex PCR Assay.

Simple SummaryLynch syndrome is caused by inherited defects in genes which repair DNA, and predisposes affected individuals to cancers of the bowel, endometrium (uterus lining), and urinary tract, among others. Most of these cancers exhibit a characteristic pattern of DNA instability in Lynch syndrome patients. Here, we adapt an existing DNA instability test for use with small clinical samples, and show that it works with tumour biopsies taken during colonoscopic investigation just as effectively as with larger samples taken during surgery. We also analyse preoperative postal urine samples where DNA recovery is limited, identifying instability in samples from a Lynch syndrome patient with a urinary tract cancer, and a patient with a suspected endometrial cancer. The assay could enable earlier detection of these tumours, benefiting these patients.Identification of mismatch repair (MMR)-deficient colorectal cancers (CRCs) is recommended for Lynch syndrome (LS) screening, and supports targeting of immune checkpoint inhibitors. Microsatellite instability (MSI) analysis is commonly used to test for MMR deficiency. Testing biopsies prior to tumour resection can inform surgical and therapeutic decisions, but can be limited by DNA quantity. MSI analysis of voided urine could also provide much needed surveillance for genitourinary tract cancers in LS. Here, we reconfigure an existing molecular inversion probe-based MSI and BRAF c.1799T > A assay to a multiplex PCR (mPCR) format, and demonstrate that it can sample >140 unique molecules per marker from <1 ng of DNA and classify CRCs with 96–100% sensitivity and specificity. We also show that it can detect increased MSI within individual and composite CRC biopsies from LS patients, and within preoperative urine cell free DNA (cfDNA) from two LS patients, one with an upper tract urothelial cancer, the other an undiagnosed endometrial cancer. Approximately 60–70% of the urine cfDNAs were tumour-derived. Our results suggest that mPCR sequence-based analysis of MSI and mutation hotspots in CRC biopsies could facilitate presurgery decision making, and could enable postal-based screening for urinary tract and endometrial tumours in LS patients.

Methylated DNA markers discriminate between endometrial cancer and benign endometrium in women with Lynch syndrome (222)

Methylated DNA markers discriminate between endometrial cancer and benign endometrium in women with Lynch syndrome (222)