Lynch Syndrome Families Research Articles

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

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. 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). 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). 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.

National Experiences from 30 Years of Provider-Mediated Cascade Testing in Lynch Syndrome Families-The Danish Model.

Cascade genetic testing and surveillance reduce morbidity and mortality in Lynch syndrome. However, barriers to conveying information about genetic disorders within families result in low uptake of genetic testing. Provider-mediated interventions may increase uptake but raise legal and ethical concerns. We describe 30 years of national experience with cascade genetic testing combining family- and provider-mediated contact in Lynch syndrome families in the Danish Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Register. We aimed to estimate the added value of information letters to family members in Lynch syndrome families (provider-mediated contact) compared to family members not receiving such letters and thus relying on family-mediated contact. National clinical practice for cascade genetic testing, encompassing infrastructure, legislation, acceptance, and management of the information letters, is also discussed. Cascade genetic testing resulted in 7.3 additional tests per family. Uptake of genetic testing was 54.4% after family-mediated and 64.9% after provider-mediated contact, corresponding to an odds ratio of 1.8 (p < 0.001). The uptake of genetic testing was highest in the first year after diagnosis of Lynch syndrome in the family, with 72.5% tested after provider-mediated contact. In conclusion, the Danish model combining family- and provider-mediated contact can increase the effect of cascade genetic testing.

Abstract 6102: Clinicopathological and genetics features of endometrial cancer in Algerian women: The first nation-wide study

Abstract Background: Endometrial cancer represents the fourth common cancer in women in Algeria and the fifth cause of cancer mortality. In the present study, we aimed to determine, clinical, tumor and genetics characteristics associated with endometrial cancer in Algerian women. In addition, we screened for germline pathogenic variants in MMR genes in endometrial cancer patients with strong family history of Lynch syndrome (LS). Materials and Methods: Our study population included 273 patients diagnosed with endometrial cancer between 2010 and 2021. Data were collected from three public hospitals that covered 29 provinces among 48 in Algeria. Patient and tumor information included: age at diagnosis, menopausal status, histological type, histological grade, TNM stage, FIGO stage, tumor markers CA125, ACE, CA19-9, family history with cancer and age at menarche . MLH1 (exons 1, 9, 10, 13, 16), MSH2 (exons 5, 6, 7, 12), MSH6 (exons 4 and 8) and PMS 2(exons 6 and 10) were screened by PCR-Sanger direct sequencing in 14 LS families . Results: The mean age at diagnosis was 58.88 years. The mean age at menarche was 13.5 years. The proportion of endometrial cancer patients with premenopausal status was 21.62%. The commonest histological type was endometrioid adenocarcinoma (66.79%) followed by clear cell carcinoma (8.10%), carcinosarcomas (3.86%), serous carcinoma (3.47%) and mucinous carcinoma (2.7%). We found that the proportion of tumors with histological grade I (34.74%), grade II (27.41%) and grade IV (21.40%) was commonest in 83.55% of the patients. Our results showed that 73.74% of the patients were diagnosed at stage I (50.19%), stage II (12.74%) and stage III (10.81%), respectively. For the FIGO staging, our results showed that 74.12% of the patients were diagnosed at stage I (52.89%), stage III (10.81%) and stage I (10.42%), respectively. 16.21%, 3.08%, 6.94% of the patients were positive for CA125, ACE and CA19-9, respectively. We noticed that 56 patients (20.43%) had a positive family history with HBOC syndrome (17), Lynch syndrome (26) and Cowden syndrome (13), respectively. We identified two distinct germline pathogenic variants in MLH1 gene in two LS families. We detected the new germline pathogenic variant MLH1 c.53_63delinsT in young patient diagnosed with endometrial cancer and colorectal cancer (CRC) at age 43y and 44 y, respectively. The rare pathogenic germline variant MLH1 c.1546C&amp;gt;T has been detected in young woman diagnosed with CRC at age 41y and endometrial and ovarian cancers at age 52y, respectively. Conclusions : In this first study, we reported some clinical, biological, tumor and genetics features of endometrial cancer in Algerian women. Interestingly, we noticed that the median age of diagnosis was younger that the average age in Europe and America. Genetic counseling and testing is recommended for endometrial cancer patients diagnosed before age 50 with a family history of Lynch syndrome. Citation Format: Farid Cherbal, Chiraz Mehemmai, Mouchira Saidi, Yasmine Santoudji, Djamel-Eddine Seddik, Asma-Lamia Boumehdi, Fatiha Gouaref, Kamel Bentabak, Hassen Mahfouf, Mohammed Oukkal. Clinicopathological and genetics features of endometrial cancer in Algerian women: The first nation-wide study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6102.

Loss of symbiotic and increase of virulent bacteria through microbial networks in Lynch syndrome colon carcinogenesis.

Through a pilot study, we performed whole gut metagenomic analysis in 17 Lynch syndrome (LS) families, including colorectal cancer (CRC) patients and their healthy first-degree relatives. In a second asymptomatic LS cohort (n=150) undergoing colonoscopy-screening program, individuals with early precancerous lesions were compared to those with a normal colonoscopy. Since bacteria are organized into different networks within the microbiota, we compared related network structures in patients and controls. Fecal prokaryote DNA was extracted prior to colonoscopy for whole metagenome (n=34, pilot study) or 16s rRNA sequencing (validation study). We characterized bacteria taxonomy using Diamond/MEGAN6 and DADA2 pipelines and performed differential abundances using Shaman website. We constructed networks using SparCC inference tools and validated the construction's accuracy by performing qPCR on selected bacteria. Significant differences in bacterial communities in LS-CRC patients were identified, with an enrichment of virulent bacteria and a depletion of symbionts compared to their first-degree relatives. Bacteria taxa in LS asymptomatic individuals with colonic precancerous lesions (n=79) were significantly different compared to healthy individuals (n=71). The main bacterial network structures, constructed based on bacteria-bacteria correlations in CRC (pilot study) and in asymptomatic precancerous patients (validation-study), showed a different pattern than in controls. It was characterized by virulent/symbiotic co-exclusion in both studies and illustrated (validation study) by a higher Escherichia/Bifidobacterium ratio, as assessed by qPCR. Enhanced fecal virulent/symbiotic bacteria ratios influence bacterial network structures. As an early event in colon carcinogenesis, these ratios can be used to identify asymptomatic LS individual with a higher risk of CRC.

A REVIEW TO HONOR THE HISTORICAL CONTRIBUTIONS OF PAULINE GROSS, ALDRED WARTHIN, AND HENRY LYNCH IN THE DESCRIPTION AND RECOGNITION OF INHERITANCE IN COLORECTAL CANCER.

The present manuscript aimed to review the historical development and most important contributions regarding Lynch Syndrome since its first description, more than a century ago. In 1895, a reputed pathologist from Michigan University, Dr. Aldred Scott Warthin, got intrigued by the family history of a local seamstress called Pauline Gross. According to her prevision, she would present an early death due to cancer, which actually happened (from the uterus). Historically, her family was designated "Family G", comprising a group recognized as the longest and most detailed cancer genealogy that has ever been studied. Warthin concluded that its members had genetic susceptibility for cancer, and they are, nowadays, considered the first reported Lynch Syndrome family. At that time, however, the medical cancer community was far less receptive to the association between heredity and cancer, despite the description of other families with similar heredograms. Unfortunately, this historical fact remained somewhat dormant until another investigator inaugurated a new era in the understanding of family cancer clusters. After reports and studies from this family and many others, the condition initially called Cancer Family Syndrome was changed to the eponym Lynch Syndrome. This was a recognition of the extensive and dedicated work developed by Dr. Henry Lynch in describing various characteristics of the disease, and his efforts to establish the correct recommendations for its diagnosis and treatment. Although the future announces there is still far to go for a complete understanding of Lynch Syndrome, the remarkable contributions of Pauline's intuition, Warthin's perseverance, and Lynch's work consistency must never be forgotten by those who already have or will still benefit from this knowledge.

Characteristics of glioblastomas and immune microenvironment in a Chinese family with Lynch syndrome and concurrent porokeratosis.

Lynch syndrome (LS)-associated glioblastoma (GBM) is rare in clinical practice, and simultaneous occurrence with cutaneous porokeratosis is even rarer. In this study, we analyzed the clinicopathological and genetic characteristics of LS-associated GBMs and concurrent porokeratosis, as well as evaluated the tumor immune microenvironment (TIME) of LS-associated GBMs. Immunohistochemical staining was used to confirm the histopathological diagnosis, assess MMR and PD-1/PD-L1 status, and identify immune cell subsets. FISH was used to detect amplification of EGFR and PDGFRA, and deletion of 1p/19q and CDKN2A. Targeted NGS assay analyzed somatic variants, MSI, and TMB status, while whole-exome sequencing and Sanger sequencing were carried out to analyze the germline mutations. In the LS family, three members (I:1, II:1 and II:4) were affected by GBM. GBMs with loss of MSH2 and MSH6 expression displayed giant and multinucleated bizarre cells, along with mutations in ARID1A, TP53, ATM, and NF1 genes. All GBMs had TMB-H but not MSI-H. CD8+ T cells and CD163+ macrophages were abundant in each GBM tissue. The primary and recurrent GBMs of II:1 showed mesenchymal characteristics with high PD-L1 expression. The family members harbored a novel heterozygous germline mutation in MSH2 and FDPS genes, confirming the diagnosis of LS and disseminated superficial actinic porokeratosis. LS-associated GBM exhibits heterogeneity in clinicopathologic and molecular genetic features, as well as a suppressive TIME. The presence of MMR deficiency and TMB-H may serve as predictive factors for the response to immune checkpoint inhibitor therapy in GBMs. The identification of LS-associated GBM can provide significant benefits to both patients and their family members, including accurate diagnosis, genetic counseling, and appropriate screening or surveillance protocols. Our study serves as a reminder to clinicians and pathologists to consider the possibility of concurrent genetic syndromes in individuals or families.

Abstract 4177: Genetic testing for hereditary colorectal cancer syndromes in Algerian patients: A multicenter study

Abstract Background To date, 5% to 6 % of all colorectal cancers (CRCs) are associated with germline pathogenic variants in cancer predisposition genes that confer inherited predisposition to CRC. The use of genetic testing to identify individuals at risk for hereditary CRC syndromes can help to prevent the development of cancer and in the clinical management of the colorectal patients in the areas of both prevention and treatment. We report here the experience of our research laboratory of genetic testing for hereditary polyposis syndromes and Lynch syndrome (LS), respectively, in 126 patients. Methods Fifty four (54) severe familial adenomatous polyposis (FAP) patients and 72-suspected Lynch syndrome (LS) patients, respectively, were selected from 2851 consecutive colorectal patients at five public hospitals during 2012-2019. Family histories of cancer were obtained from interviews, pedigrees and medical records of patients. Index cases and relatives diagnosed with FAP syndrome or Lynch syndrome have been tested for germline variants in APC, MLH1, MSH2, MSH6 and PMS2 genes, respectively, using PCR-Sanger Sequencing or by NGS using a cancer panel of 30 hereditary cancer genes (Color Genomics). Results We detected 13 germline pathogenic variants in APC gene in 17 unrelated families, one germline pathogenic variant in BMPRA1 gene in juvenile polyposis syndrome (JPS) patient; seven (7) germline pathogenic variants and 2 variants of uncertain clinical significance (VUS) in MMR genes. Interestingly, 4 novel germline pathogenic variants in APC gene and 3 novel germline pathogenic variants in MMR genes, respectively, have been detected in our study. The most occurring germline pathogenic variants in APC gene were c.3927_3931del and c.4728dup that were identified in four and two index cases in 6 unrelated FAP families, respectively. In Lynch syndrome patients, the rare germline pathogenic variant MLH1 c.1546C&amp;gt;T has been found in 21 individuals from 9 LS families, 6 of them related, with two large kindreds. In addition, the recurrent germline pathogenic variant MSH2 c.942+3A&amp;gt;T has been detected in five unrelated index cases with a strong family history of LS syndrome. Moreover, the rare germline VUS PMS2 c.989-107_989-106insA has been detected in 14 unrelated LS patients and could be reclassified as likely benign. Interestingly, our NGS analysis detected the novel BMPR1A pathogenic variant c.1474-1G&amp;gt;C in young JPS patient that has been misdiagnosed as FAP. The in-silico analysis for this novel variant showed an alteration of the wild type acceptor site and an activation of a cryptic acceptor site, respectively, most probably affecting splicing. Conclusions Our current study will contribute to the molecular genetics characterization of hereditary colorectal cancer syndromes in Algerian population that is relevant for clinical management in the areas of genetic testing, early diagnosis, treatment and prevention. Citation Format: Farid Cherbal, Asma-Lamia Boumehdi, Feriel Khider, Karima Landelouci, Abdelwahab Zemam, Sarah Sabri, Adam.Walid Damache, Mohammed Oukkal, Hassen Mahfouf, Ferhat Zebboudj, Mustapha Maaoui. Genetic testing for hereditary colorectal cancer syndromes in Algerian patients: A multicenter study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4177.

PD46-06 UROLOGICAL FOLLOW-UP AND MUTATIONAL PATTERNS IN LYNCH SYNDROME PATIENTS: A SINGLE CENTER EXPERIENCE

You have accessJournal of UrologyCME1 Apr 2023PD46-06 UROLOGICAL FOLLOW-UP AND MUTATIONAL PATTERNS IN LYNCH SYNDROME PATIENTS: A SINGLE CENTER EXPERIENCE Pietro Scilipoti, Mattia Longoni, Chiara Re, Giuseppe Rosiello, Alessandro Bertini, Mario de Angelis, Giorgio Gandaglia, Eugenio Ventimiglia, Umberto Capitanio, Andrea Salonia, Francesco Montorsi, Alberto Briganti, and Marco Moschini Pietro ScilipotiPietro Scilipoti More articles by this author , Mattia LongoniMattia Longoni More articles by this author , Chiara ReChiara Re More articles by this author , Giuseppe RosielloGiuseppe Rosiello More articles by this author , Alessandro BertiniAlessandro Bertini More articles by this author , Mario de AngelisMario de Angelis More articles by this author , Giorgio GandagliaGiorgio Gandaglia More articles by this author , Eugenio VentimigliaEugenio Ventimiglia More articles by this author , Umberto CapitanioUmberto Capitanio More articles by this author , Andrea SaloniaAndrea Salonia More articles by this author , Francesco MontorsiFrancesco Montorsi More articles by this author , Alberto BrigantiAlberto Briganti More articles by this author , and Marco MoschiniMarco Moschini More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003359.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Lynch Syndrome (LS) is a genetic dominant autosomal disease that predisposes to a broad spectrum of tumors, among which Upper Tract Urothelial Carcinoma (UTUC) is the third most common manifestation. We present the first results of our LS dedicated outpatient clinic with the aim of evaluating the incidence of UTUC, patterns of mutation and individuate the optimal follow up schemes among patients affected by LS. METHODS: We observed 23 LS patients from December 2021 to October 2022 at a tertiary referral center. We collected prospectively data regarding LS mutations, medical and family history and simultaneously started a strict follow up strategy. Genetic diagnosis was obtained both by Immunohistochemistry (IHC) and by genetic test (DNA sequencing). For each patient we applied Bethesda, EAU guidelines, Amsterdam I and II criteria. Follow up strategy was based on Ultrasound (US), urinalysis and urinary citology every two years. In high-risk cases (age >50 years, MSH2 mutation carriers and family history of UTUC) CT-scans where alternated with US every year in addition to urinary citology. RESULTS: Among this court 52.2% of patients (n=12) had a LS diagnosis after cancer manifestation, meanwhile 47.8% (n=11) through genetic counseling due to investigation in first degree relatives. Among our patient population, 8 patients (34.8%) had a diagnosis of colorectal cancer, 4 (17.4%) UTUC, 1 (4.3%) endometrial, 1 (4.3%) gastric, 1 (4.34%) skin cancer and 2 rare LS related cancer (Renal Clear Cell Carcinoma and Lung Cancer). MSH2 mutation was detected in 39.1% of cases (n=9), while MLH1 was found in 34.8% of cases (n=8). In subgroup analysis colorectal cancer's most common mutation was MSH2 (50%) followed by MLH1 (25%) and MSH6 (25%), while among UTUC cases, MSH2 was the most common (75%) and MLH1 was reported in 25% of cases. Median age at UTUC diagnosis was 60, while median age at colorectal cancer diagnosis was 49 (p=0.007). Bethesda and EAU guidelines criteria were more accurate (91% vs 90%) compared to Amsterdam I and II criteria (74%). No tumor diagnosis was made during the observational time. CONCLUSIONS: The current study is a first attempt to establish a dedicated LS outpatient clinic. This will let us observe the most frequent mutations, thus potentially in the future allow us to diagnose UTUC earlier and provide a refined follow up to LS patients. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e1172 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Pietro Scilipoti More articles by this author Mattia Longoni More articles by this author Chiara Re More articles by this author Giuseppe Rosiello More articles by this author Alessandro Bertini More articles by this author Mario de Angelis More articles by this author Giorgio Gandaglia More articles by this author Eugenio Ventimiglia More articles by this author Umberto Capitanio More articles by this author Andrea Salonia More articles by this author Francesco Montorsi More articles by this author Alberto Briganti More articles by this author Marco Moschini More articles by this author Expand All Advertisement PDF downloadLoading ...

Genome sequencing identifies complex structural MLH1 variant in unsolved Lynch syndrome.

Lynch syndrome is one of the most common cancer predisposition syndromes. It is caused by inherited changes in the mismatch repair pathway. With current diagnostic approaches, a causative genetic variant can be found in less than 50% of cases. A correct diagnosis is important for ensuring that an appropriate surveillance program is used and that additional high-risk family members are identified. We used clinical genome sequencing on DNA from blood and subsequent transcriptome sequencing for confirmation. Data were analyzed using the megSAP pipeline and classified according to basic criteria in diagnostic laboratories. Segregation analyses in family members were conducted via breakpoint PCR. We present a family with the clinical diagnosis of Lynch syndrome in which standard diagnostic tests, such as panel or exome sequencing, were unable to detect the underlying genetic variant. Genome sequencing in the index patient confirmed the previous diagnostic results and identified an additional complex rearrangement with intronic breakpoints involving MLH1 and its neighboring gene LRRFIP2. The previously undetected structural variant was classified as medically relevant. Segregation analysis in the family identified additional at-risk individuals which were offered intensified cancer screening. This case illustrates the advantages of clinical genome sequencing in detecting structural variants compared with current diagnostic approaches. Although structural variants are rare in Lynch syndrome families, they seem to be underreported, in part because of technical challenges. Clinical genome sequencing offers a comprehensive genetic characterization detecting a wide range of genetic variants.

P048: Novel frameshift MLH1 germline mutation in a Moroccan Lynch syndrome family

P048: Novel frameshift MLH1 germline mutation in a Moroccan Lynch syndrome family

A comparative cost analysis of two screening strategies for colorectal cancer in Lynch Syndrome in a South African tertiary hospital.

Lynch Syndrome (LS) individuals have a 25-75% lifetime risk of developing colorectal cancer. Colonoscopy screening decreases this risk. This study compared the cost of Strategy 1: screening colonoscopy for 1st degree relatives of patients that met the Revised Bethesda Criteria (i.e., probands) to Strategy 2: screening colonoscopy for 1st degree relatives of probands with genetic mutations for Lynch Syndrome based in a resource-constrained health care system. A comparative, health care provider perspective, cost analysis was conducted at a tertiary hospital, using a micro-costing, ingredient approach. Forty probands that underwent genetic testing between November 01, 2014 and October 30, 2015 and their first-degree relatives were costed according to Strategy 1 and Strategy 2. Unit costs of colonoscopy and genetic testing were estimated and used to calculate and compare the total costs per strategy in South African rand (R) converted to UK pounds (£). Sensitivity analyses were performed on colonoscopy adherence, relatives' positivity, and variable discount rates. The cost for Strategy 1 amounted to £653 344/R6 161 035 compared to £49 327/R 465155 for Strategy 2 (Discount rate 3%; Adherence 75%; and Positivity rate of relatives 45%). Base case analysis indicated a difference of 92% less in the total cost for Strategy 2 compared to Strategy 1. Sensitivity analyses showed that the difference in cost between the two strategies was not sensitive to variations in adherence, positivity or discount rates. Colonoscopy screening for LS and at-risk family members was tenfold less costly when combined with genetic analysis. The logistics of rolling out this strategy nationally should be investigated.

Relatives from Hereditary Breast and Ovarian Cancer and Lynch Syndrome Families Forgoing Genetic Testing: Findings from the Swiss CASCADE Cohort.

Cascade genetic testing of relatives from families with pathogenic variants associated with hereditary breast and ovarian cancer (HBOC) or Lynch syndrome (LS) has important implications for cancer prevention. We compared the characteristics of relatives from HBOC or LS families who did not have genetic testing (GT (−) group) with those who had genetic testing (GT (+) group), regardless of the outcome. Self-administered surveys collected cross-sectional data between September 2017 and December 2021 from relatives participating in the CASCADE cohort. We used multivariable logistic regression with LASSO variable selection. Among n = 115 relatives who completed the baseline survey, 38% (n = 44) were in the GT (−) group. Being male (OR: 2.79, 95% CI: 1.10–7.10) and without a previous cancer diagnosis (OR: 4.47, 95% CI: 1.03–19.42) increased the odds of being untested by almost three times. Individuals from families with fewer tested relatives had 29% higher odds of being untested (OR: 0.71, 95% CI: 0.55–0.92). Reasons for forgoing cascade testing were: lack of provider recommendation, lack of time and interest in testing, being afraid of discrimination, and high out-of-pocket costs. Multilevel interventions designed to increase awareness about clinical implications of HBOC and LS in males, referrals from non-specialists, and support for testing multiple family members could improve the uptake of cascade testing.

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.

Acceleration of the DNA methylation clock among lynch syndrome-associated mutation carriers

BackgroundDNA methylation (DNAm) age metrics have been widely accepted as an epigenetic biomarker for biological aging and disease. The purpose of this study is to assess whether or not individuals carrying Lynch Syndrome-associated mutations are affected in their rate of biological aging, as measured by the epigenetic clock.MethodsGenome-wide bisulfite DNA sequencing data were generated using DNA from CD4 + T-cells obtained from peripheral blood using 27 patient samples from Lynch syndrome families. Horvath’s DNAm age model based on penalized linear regression was applied to estimate DNAm age from patient samples with distinct clinical and genetic characteristics to investigate cancer mutation-related aging effects.ResultsBoth Lynch mutation carriers and controls exhibited high variability in their estimated DNAm age, but regression analysis showed steeper slope for the Lynch mutation carriers. Remarkably, six Lynch Syndrome-associated mutation carriers showed a strong correlation to the control group, and two sisters carrying Lynch Syndrome-associated mutations, with no significant difference in lifestyle and similar chronological age, were assigned very different DNAm age.ConclusionsFuture studies will be required to explore, in larger patient populations, whether specific epigenetic age acceleration is predictive of time-to-cancer development, treatment response, and survival. Epigenetic clock DNAm metrics may be affected by the presence of cancer mutations in the germline, and thus show promise of potential clinical utility for stratified surveillance strategies based on the relative risk for imminent emergence of tumor lesions in otherwise healthy Lynch Syndrome-associated mutation carriers.

Cost-effectiveness of population-wide genomic screening for Lynch syndrome in the United States

PurposeGenomic screening for Lynch syndrome (LS) could prevent colorectal cancer (CRC) by identifying high-risk patients and instituting intensive CRC screening. We estimated the cost-effectiveness of a population-wide LS genomic screening vs family history–based screening alone in an unselected US population. MethodsWe developed a decision-analytic Markov model including health states for precancer, stage-specific CRC, and death and assumed an inexpensive test cost of $200. We conducted sensitivity and threshold analyses to evaluate model uncertainty. ResultsScreening unselected 30-year-olds for LS variants resulted in 48 (95% credible range [CR] = 35-63) fewer overall CRC cases per 100,000 screened individuals, leading to 187 quality-adjusted life-years (QALYs; 95% CR = 123-260) gained at an incremental cost of $24.6 million (95% CR = $20.3 million-$29.1 million). The incremental cost-effectiveness ratio was $132,200, with an 8% and 71% probability of being cost-effective at $100,000 and $150,000 per QALY willingness-to-pay thresholds, respectively. ConclusionPopulation LS screening may be cost-effective in younger patient populations under a $150,000 willingness-to-pay per QALY threshold and with a relatively inexpensive test cost. Further reductions in testing costs and/or the inclusion of LS testing within a broader multiplex screening panel are needed for screening to become highly cost-effective.

Lynch-like Syndrome: Potential Mechanisms and Management.

Simple SummaryLynch-like syndrome (LLS) is defined as colorectal cancer cases with microsatellite instability (MSI) and loss of expression of MLH1, MSH2, MSH6, or PMS2 by immunohistochemistry (IHC) in the absence of a germline mutation in these genes that cannot be explained by BRAF mutation or MLH1 hypermethylation. The application of the universal strategy for the diagnosis of Lynch syndrome (LS) in all CRCs is leading to an increase in the incidence of cases of LLS. It has been described that risk of cancer in relatives of LLS patients is in between of that found in Lynch syndrome families and sporadic cases. That makes LLS patients and their families a challenging group for which the origin of CRC is unknown, being a mixture between unidentified hereditary CRC and sporadic cases. The potential causes of LLS are discussed in this review, as well as methods for identification of truly hereditary cases.Lynch syndrome is an autosomal dominant disorder caused by germline mutations in DNA mismatch repair (MMR) system genes, such as MLH1, MSH2, MSH6, or PMS2. It is the most common hereditary colorectal cancer syndrome. Screening is regularly performed by using microsatellite instability (MSI) or immunohistochemistry for the MMR proteins in tumor samples. However, in a proportion of cases, MSI is found or MMR immunohistochemistry is impaired in the absence of a germline mutation in MMR genes, BRAF mutation, or MLH1 hypermethylation. These cases are defined as Lynch-like syndrome. Patients with Lynch-like syndrome represent a mixture of truly hereditary and sporadic cases, with a risk of colorectal cancer in first-degree relatives that is between the risk of Lynch syndrome in families and relatives of sporadic colon cancer cases. Although multiple approaches have been suggested to distinguish between hereditary and sporadic cases, a homogeneous testing protocol and consensus on the adequate classification of these patients is still lacking. For this reason, management of Lynch-like syndrome and prevention of cancer in these families is clinically challenging. This review explains the concept of Lynch-like syndrome, potential mechanisms for its development, and methods for adequately distinguishing between sporadic and hereditary cases of this entity.

Pancreatic Cancer with Mutation in BRCA1/2, MLH1, and APC Genes: Phenotype Correlation and Detection of a Novel Germline BRCA2 Mutation.

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer death worldwide; most of cases are sporadic, however about 5% to 10% report a hereditary predisposition. Several hereditary syndromes have been associated with familial pancreatic cancer (FPC) onset, including hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), Familial atypical multiple mole melanoma (FAMMM), Familial adenomatous polyposis (FAP), Li–Fraumeni syndrome (LFS), Peutz–Jeghers syndrome (PJS), and Hereditary pancreatitis (HP).The aim of this study was to determine the mutational status of a cohort of 56 HBOC families, 7 LS families, 3 FAP and FAMMM families, and 1 LFS family with at least one case of PDAC. Mutation analysis of BRCA1/2, ATM, CHEK2, PALB2, RAD51C, RAD51D, NBN, CDH1, TP53, MLH1, MSH2, MSH6, and PMS2 genes, showedmutation in BRCA1/2, MLH1, and APC genes. We founda high mutation rate in patients belong HBOC and LS families, with a percentage of 28.6% in both syndromes and prevalence in HBOC of BRCA2 mutations with one case of double mutation in BRCA2 gene. In FAP family, we found a pathogenic mutation in APC gene in 1/3 families. We observed an early onset of PDAC and a lower survival in PDAC patients belonging to mutated families, while no evidence of possible pancreatic cancer cluster regions was found. Moreover, we identified a novel BRCA2 germline mutation, c.5511delT (p.Phe1837LeufsX3), not reported in any database, that segregated with disease in HBOC patients. Mutational analysis was extended to family membersof mutated patients, both healthy and cancer affected, which revealed 23 unaffected family members that inherited the proband’s mutation. Although correlative by its nature, the presence of a BRCA mutation in PDAC patients may have benefits in terms of optimized treatment and longer outcome.

Identification of Lynch Syndrome Carriers among Patients with Small Bowel Adenocarcinoma

Simple SummarySmall bowel adenocarcinoma (SBA) is associated with Lynch syndrome (LS). This is the first study to evaluate the identification of LS patients based on mismatch repair deficiency (MMRd) tumor among SBA. The authors found a 21.3% prevalence of MMRd tumors and a 10.1% prevalence of LS. A germline mutation was identified in 60% of patients with a MMRd tumor. This data suggests that universal tumor MMR testing among SBA patients should be implemented for the identification of LS.Background: Small bowel adenocarcinoma (SBA) is a rare disease which can be associated with Lynch syndrome (LS). LS tumors are characterized by the presence of microsatellite instability (MSI) and/or the loss of mismatch repair (MMR) protein expression. In SBA, the frequency of MMR deficient (MMRd) tumors varies from 5% to 35%. This study aims to describe the prevalence of LS carriers among patients with MMRd small bowel adenocarcinomas. Methods: A multicenter retrospective study with identification and MMR testing of all consecutive SBA between 2004 and 2020 in a multicenter Spanish study. Demographical data, tumor characteristics, follow-up and survival information were collected. Germline testing was driven by identification of MMRd tumors. Results: A total of 94 individuals diagnosed with SBA were recruited. We observed 20 (21.3%) MMRd tumors. In 9/15 (60%) patients with MMRd tumors, a pathogenic variant was identified (three MLH1, four MSH2, one MSH6 and one PMS2). Accordingly, the prevalence of LS among all SBA cases was 10.1%. Conclusions: More than one-fifth of SBA display MMRd and in more than a half is due to LS. Our data supports the implementation of universal MMR tumor testing among SBA for the identification of LS families.

Descriptive study on subjective experience of genetic testing with respect to relationship, family planning and psychosocial wellbeing among women with lynch syndrome

BackgroundDue to increased risk of endometrial and ovarian cancer, women belonging to known Lynch Syndrome (LS) families are recommended to undergo germline testing. Current practice in Finland is to offer counselling to women with pathogenic variant and advocate risk-reducing surgery (RRS) after completion of childbirth. The present study aimed to clarify the impacts of positive germline testing on family planning and reproductive decisions of these women, which are relatively unknown.MethodsSeventy-nine carriers of germline MMR gene pathogenic variant (path_MMR) were identified from the Finnish LS Registry as having genetic testing performed before the age of 45 years and not having undergone hysterectomy or oophorectomy. These women were sent a questionnaire concerning family planning, intimate relationships and psychosocial wellbeing.ResultsThirty-five women (44.3%) responded. Parity of path_MMR carriers (2.1) was slightly higher than parity among Finnish women in general (1.8). No significant differences were found between parity, number of induced abortions or sterilizations before and after genetic testing. Only minority of subjects reported any influence on family planning (20%) or negative impact on feminine self and body image (14%).ConclusionsThe positive germline testing does not seem to have a major negative impact on family planning, intimate relationships or feminine self and body image. According to the open comments, counselling, supportive and empathic attitude of the professionals seem to have a significant impact on this. These results are a valuable addition to the counselling of LS women at reproductive age.

Integrating Tumor Sequencing Into Clinical Practice for Patients With Mismatch Repair-Deficient Lynch Syndrome Spectrum Cancers.

INTRODUCTION:Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM.METHODS:Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol.RESULTS:Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF.DISCUSSION:Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.