S1655 Dealing With the Inevitable: A Case of Lynch Syndrome Not Meeting the Amsterdam Criteria

AbstractPatients with Lynch syndrome have a high risk of colorectal cancer (CRC). In this study, we estimated the age- and sex-specific cumulative risks of CRC in Han Chinese patients with Lynch syndrome caused by the pathogenic germline mutations in MLH1 or MSH2 in Taiwan. Based on 321 mutation carriers and 419 non-mutation carriers from 75 pedigrees collected in an Amsterdam criteria family registry in Taiwan, the age- and sex-specific cumulative risks of CRC in male carriers of mutation in MLH1 and MSH2 at the age of 70 years were 60.3% (95% confidence interval (CI) = 31.1%–89.9%) and 76.7% (95% CI = 37.2%–99.0%), respectively. For females, the cumulative risks of CRC at the age of 70 were estimated to be 30.6% (95% CI = 14.3%–57.7%) and 49.3% (95% CI = 21.9%–84.5%) in the carriers of MLH1 and MSH2 germline mutations, respectively. In conclusion, the cumulative risks of CRC at the age of 70 in the Han Chinese patients is higher in mutation carriers than non-mutation carriers and male mutation carriers have a higher cumulative risk of developing CRC than the female mutation carriers.

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Performance of tumor testing for Lynch syndrome identification in patients with colorectal cancer: A retrospective single-center study

Tumori Journal ◽

10.1177/0300891618792460 ◽

2018 ◽

Vol 105 (1) ◽

pp. 76-83 ◽

Cited By ~ 3

Author(s):

Stefano Signoroni ◽

Maria Grazia Tibiletti ◽

Maria Teresa Ricci ◽

Massimo Milione ◽

Federica Perrone ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Characteristic Curve ◽

Age At Onset ◽

Area Under The Curve ◽

Single Center ◽

Germline Variants ◽

Amsterdam Criteria ◽

Clinicopathologic Parameters ◽

Msi Analysis

Objective: To investigate the performance of tumor testing approaches in the identification of Lynch syndrome (LS) in a single-center cohort of people with colorectal cancer (CRC). Methods: A retrospective analysis of data stored in a dedicated database was carried out to identify patients with CRC suspected for LS who were referred to Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, between 1999 and 2014. The sensitivity and specificity of immunohistochemistry (IHC) for mismatch repair (MMR) proteins and microsatellite instability (MSI) analysis (alone or combined) were calculated with respect to the presence of causative MMR germline variants. Results: A total of 683 patients with CRC suspected for LS were identified. IHC results of MMR protein analysis and MSI were assessed in 593 and 525 CRCs, respectively, while germline analysis was performed in 418 patients based on the IHC or MSI test result and/or clinical features. Univariate and multivariate analysis revealed a significant correlation of pathogenic MMR germline variants with all clinicopathologic features including Amsterdam criteria, presence of endometrial cancer, CRC site, age at onset, stage, and grade. The highest odds ratio values were observed for IHC and MSI (17.1 and 8.8, respectively). The receiver operating characteristic curve and area under the curve values demonstrated that IHC alone or combined with other clinicopathologic parameters was an excellent test for LS identification. Conclusions: This study confirms the effectiveness of tumor testing to identify LS among patients with CRC. Although IHC and MSI analysis were similarly effective, IHC could be a better strategy for LS identification as it is less expensive and more feasible.

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Lynch Syndrome: From Screening to Diagnosis to Treatment in the Era of Modern Molecular Oncology

Annual Review of Genomics and Human Genetics ◽

10.1146/annurev-genom-083118-015406 ◽

2019 ◽

Vol 20 (1) ◽

pp. 293-307 ◽

Cited By ~ 9

Author(s):

Stacey A. Cohen ◽

Colin C. Pritchard ◽

Gail P. Jarvik

Keyword(s):

Lynch Syndrome ◽

Mismatch Repair ◽

Treatment Options ◽

Cancer Therapeutics ◽

Cancer Predisposition Syndrome ◽

Molecular Oncology ◽

Repair Protein ◽

Amsterdam Criteria ◽

Common Etiology ◽

Somatic Alterations

Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline alterations in the mismatch repair genes and is the most common etiology of hereditary colorectal cancer. While Lynch syndrome was initially defined by the clinical Amsterdam criteria, these criteria lack the sensitivity needed for clinical utility. This review covers the evolution of screening for Lynch syndrome from the use of tumor microsatellite instability and/or somatic alterations in mismatch repair protein expression by immunohistochemistry to the newest methods using next-generation sequencing. Additionally, it discusses the clinical implications of the diagnosis of Lynch syndrome as it affects cancer therapeutics and the role of screening in noncolorectal Lynch-associated cancers. As molecular oncology continues to evolve, it is crucial to remain current on the increasing complexity of Lynch syndrome diagnostics and treatment options.

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Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106256 ◽

2020 ◽

Vol 57 (7) ◽

pp. 487-499

Author(s):

Qing Wang ◽

Julie Leclerc ◽

Gaëlle Bougeard ◽

Sylviane Olschwang ◽

Stéphanie Vasseur ◽

...

Keyword(s):

Family History ◽

Lynch Syndrome ◽

Founder Effect ◽

Predictive Value ◽

Haplotype Analysis ◽

Genomic Rearrangements ◽

Colorectal Cancers ◽

Amsterdam Criteria ◽

Insight Into

BackgroundHeterozygous germline PMS2 variants are responsible for about 5% of Lynch syndrome (LS) but their prevalence is most likely underestimated because of complicated routine screening caused by highly homologous pseudogenes. Consequently, there is limited knowledge on the implication of the PMS2 gene in LS.MethodsWe report 200 PMS2 heterozygous variants identified in 195 French patients, including 112 unique variants classified as class-3/4/5.ResultsGenomic rearrangements account for 18% of alterations. The c.137G>T variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours from PMS2 variant carriers exhibited microsatellite instability (96%) and loss of PMS2 expression (76%), confirming the high predictive value of somatic analysis.ConclusionOur results provide further insight into the role of the PMS2 gene in LS. While PMS2 variants are mostly detected in families not fulfilling Amsterdam criteria, which supports their lower penetrance, they can nevertheless cause early-onset cancers, highlighting the variability of their penetrance.

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Report of a Novel Mutation inMLH1Gene in a Hispanic Family from Puerto Rico Fulfilling Classic Amsterdam Criteria for Lynch Syndrome

Gastroenterology Research and Practice ◽

10.1155/2014/527946 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

Juan M. Marqués-Lespier ◽

Yaritza Diaz-Algorri ◽

Maria Gonzalez-Pons ◽

Marcia Cruz-Correa

Keyword(s):

Colorectal Cancer ◽

Puerto Rico ◽

Lynch Syndrome ◽

Novel Mutation ◽

Clinical Manifestations ◽

Limited Information ◽

Protein Coding ◽

Genetic Sequencing ◽

Amsterdam Criteria ◽

Hispanic Family

In Puerto Rico, colorectal cancer (CRC) represents the second leading cause of cancer in men and women. Familial CRC accounts for 10–15% of the total CRC cases, while Lynch syndrome accounts for approximately 2–4% of cases. Limited information is available about the prevalence, clinical manifestations, and genetic mutations of hereditary CRC in US Hispanic individuals. In this paper we report a novel mutation in thehMLH1gene in a Puerto Rican Hispanic family with Lynch syndrome recruited through the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). Our proband was identified by applying Amsterdam and Bethesda criteria for Lynch syndrome, analysis of protein expression by immunohistochemistry, and genetic sequencing of the mismatch repair genes. A novel mutation at c.2044_2045 inhMLH1consisting of the deletion of two consecutive nucleotides (AT) at exon 18 was identified. This deletion causes a frameshift in the protein coding sequence at p.682 resulting in premature termination and a truncated MLH1 protein. To our knowledge, this mutation has not been previously reported in the literature. The detection of this novel mutation inMLH1further emphasizes the need for genetic testing in at-risk patients for hereditary CRC from various ethnic and racial backgrounds.

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Lynch syndrome I: A case report

Medicinski pregled ◽

10.2298/mpns0802079z ◽

2008 ◽

Vol 61 (1-2) ◽

pp. 79-82

Author(s):

Vesna Zivkovic ◽

Vuka Katic ◽

Jasmina Gligorijevic ◽

Zlatibor Andjelkovic ◽

Aleksandar Petrovic ◽

...

Keyword(s):

Colorectal Cancer ◽

Case Report ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Clinical Stage ◽

Family Members ◽

Advanced Rectal Cancer ◽

Degree Relative ◽

Mmr Genes ◽

Amsterdam Criteria

Introduction. Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndromes J and II, accounts for about 5-8% of colorectal cancers. Lynch syndrome I is an autosomal domi?nant inherited disorder characterized by early onset of colorectal cancer, predominance of proximal and multiple tumors, and microsatellite instability. In order to identify HNPCC, the international "Amsterdam criteria" have been used. Case report. The proband was a 40-year-old male who was admitted to hospital with a diagnosis of advanced rectal cancer. Left colectomy was carried out. A histopathologic diagnosis of poorly differentiated adenocarcinoma of clinical stage Dukes C was made. The family talking was done and it was revealed that the pro-band had five family members (one of first degree relative) with colorectal cancer, and two successive generations affected. All malignancy were diagnosed before 45 years of age. In one family member, metachronous transverse cancer was revealed 12 years after surgery for cecal adenocarcinoma. Discussion and conclusion. The main molecular cause for HNPCC is constitutional mutation in one of the mismatch repair (MMR) genes that regulate the excision of errors occurring during DNA replication. The most often are mutations of MLHI and MSH2 genes, and microsatellite instability is present in about 90-95% HNPCC. In this report, we present a case of an HNPCC patient who met the Amsterdam criteria for Lynch syndrome I. Family members that fulfill the Amsterdam criteria should be investigated for mutation in MMR genes. The genetic tests are not routinely available, so colonoscopic screening of all asymptomatic family members older than 25 has been recommended.

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A Novel Stop-Gain Mutation in MSH2 Gene Among a Persian Family Fulfilling Classic Amsterdam Criteria for Lynch Syndrome

10.21203/rs.3.rs-158152/v1 ◽

2021 ◽

Author(s):

Paniz Miar ◽

Sina Narrei ◽

Mohammad Amin Tabatabaiefar ◽

Mohammad Reza Pourreza ◽

Morteza Hashemzadeh-Chaleshtori ◽

...

Keyword(s):

Lynch Syndrome ◽

Pathogenic Variant ◽

Healthy Tissue ◽

Molecular Feature ◽

Mmr Genes ◽

Variant Filtering ◽

Amsterdam Criteria ◽

History Of ◽

Prevention Of Cancer ◽

Successive Generations

Abstract Purpose Lynch syndrome is the most common hereditary cancer syndromes due to a germline mutation in one of the mismatch-repair (MMR) genes. It results in early-onset colorectal cancer (CRC) and other Lynch-associated cancers in an autosomal dominant pattern. In this article, a new pathogenic variant in a Persian family with familial CRCs and positive Amsterdam II criteria has been described. Methods IHC-MMRs was done on tissue sections from tumor and its adjacent healthy tissue of the proband. Microsatellite instability (MSI) testing was also performed on DNA extracted from tumor and healthy tissue using Promega kit. Next Generation Sequencing (NGS) was finally done on genomic DNA of the proband using a 12-gene-panel including MMR genes. Variant filtering and prioritization were done using bioinformatics tools. Co-segregation analysis was used to evaluate the explored pathogenic variant. Results The proband was a 38-year woman at-diagnosis affected with CRC located in the sigmoid colon. The family history of cancer was observed in three successive generations. IHC was absent for MSH2 and MSH6, and MSI-High was reported from MSI testing. NGS analysis explored a new stop gained codon mutation on the first exon of MSH2 gene as a substitution of A to G MSH2: c.364A > T which was pathogenic according to the variant interpretation guidelines of American College of Medical Genetics and Genomics. Conclusion Revealing of a more obvious molecular feature of Lynch-syndrome among Iranian populations could lead to identification of at-risk people for early care and prevention of cancer.

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Identification and management of Lynch syndrome in the Middle East and North African countries: outcome of a survey in 12 countries

Familial Cancer ◽

10.1007/s10689-020-00211-3 ◽

2020 ◽

Author(s):

Mohammad Sina ◽

◽

Zeinab Ghorbanoghli ◽

Amal Abedrabbo ◽

Fahd Al-Mulla ◽

...

Keyword(s):

Family History ◽

Lynch Syndrome ◽

Genetic Services ◽

Mismatch Repair Gene ◽

North African ◽

African Countries ◽

Online Questionnaire ◽

Repair Gene ◽

Amsterdam Criteria ◽

History Of

Abstract Background Lynch syndrome (LS), the most common inherited form of colorectal cancer (CRC), is responsible for 3% of all cases of CRC. LS is caused by a mismatch repair gene defect and is characterized by a high risk for CRC, endometrial cancer and several other cancers. Identification of LS is of utmost importance because colonoscopic surveillance substantially improves a patient’s prognosis. Recently, a network of physicians in Middle Eastern and North African (ME/NA) countries was established to improve the identification and management of LS families. The aim of the present survey was to evaluate current healthcare for families with LS in this region. Methods A questionnaire was developed that addressed the following issues: availability of clinical management guidelines for LS; attention paid to family history of cancer; availability of genetic services for identification and diagnosis of LS; and assessment of knowledge of LS surveillance. Members of the network and authors of recent papers on LS from ME/NA and neighbouring countries were invited to participate in the survey and complete the online questionnaire. Results A total of 55 individuals were invited and 19 respondents from twelve countries including Algeria, Azerbaijan, Cyprus, Egypt, Iran, Jordan, Kuwait, Lebanon, Morocco, Palestine, Tunisia, and Turkey completed the questionnaire. The results showed that family history of CRC is considered in less than half of the surveyed countries. Guidelines for the management of LS are available in three out of twelve countries. The identification and selection of families for genetic testing were based on clinical criteria (Amsterdam criteria II or Revised Bethesda criteria) in most countries, and only one country performed universal screening. In most of the surveyed countries genetic services were available in few hospitals or only in a research setting. However, surveillance of LS families was offered in the majority of countries and most frequently consisted of regular colonoscopy. Conclusion The identification and management of LS in ME/NA countries are suboptimal and as a result most LS families in the region remain undetected. Future efforts should focus on increasing awareness of LS amongst both the general population and doctors, and on the improvement of the infrastructure in these countries.

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Clinical, anamnestic, molecular and genetic criteria for Lynch syndrome

Advances in molecular oncology ◽

10.17650/2313-805x-2019-6-4-38-46 ◽

2019 ◽

Vol 6 (4) ◽

pp. 38-46

Author(s):

A. V. Semyanikhina ◽

N. I. Pospekhova ◽

M. G. Filippova ◽

D. A. Golovina ◽

A. O. Rasulov ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Expression Patterns ◽

Clinical Criteria ◽

Mmr Genes ◽

Leading Role ◽

Amsterdam Criteria ◽

Colorectal Cancer Patients ◽

Mmr Proteins

Lynch syndrome is the most common cancer-prone syndrome associated with a high risk of colorectal cancer (CRC), neoplasms of the upper gastrointestinal system, the urinary tract, the female reproductive system, brain tumours and others. The only known form of hereditary endometrial cancer is also diagnosed as part of Lynch syndrome. One or more pathogenic germline mutations in one of the mismatch repair (MMR) genes are the cause of Lynch syndrome. Mapping of MMR genes and the discovery of microsatellite instability (MSI) have given rise to the possibility of using these clue characteristics of the pathogenic process for the elaboration of a screening test for Lynch syndrome. Being highly accurate and superior to all previously developed clinical criteria and guidelines, MSI-testing along with the assessment of the expression patterns of MMR proteins by immunohistochemistry has taken the leading role in the early diagnosis of Lynch syndrome. This article focuses on a brief review about the main evolutionary stages of clinical, anamnestic, molecular and genetic criteria for Lynch syndrome together with the results of our own research on the accuracy of the Amsterdam criteria, the Bethesda guidelines and MSI-diagnostics in the determination of the indications for MMR-genotyping in colorectal cancer patients suspected for Lynch syndrome.

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Phenotypic Heterogeneity by Germline Mismatch Repair Gene Defect in Lynch Syndrome Patients

Acta Médica Portuguesa ◽

10.20344/amp.7774 ◽

2016 ◽

Vol 29 (10) ◽

pp. 587

Author(s):

Jorge Hernâni-Eusébio ◽

Elisabete Barbosa

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Microsatellite Instability ◽

Mismatch Repair ◽

Statistical Significance ◽

Phenotypic Correlation ◽

Mismatch Repair Gene ◽

Small Data ◽

Repair Gene ◽

Amsterdam Criteria

Introduction: Lynch syndrome is the most common form of hereditary colorectal cancer, being also responsible for endometrial and other types of cancers. It is associated with germline mutations in DNA mismatch repair genes and microsatellite instability. MLH1 and MSH2 mutations have a “classical” Lynch syndrome phenotype, with MSH2 having a higher association with extracolonic cancer. MSH6 and PMS2 mutations have an atypical phenotype. Clinical expression is heterogeneous, with correlation between mismatch repair mutated gene and phenotypic patterns.Material and Methods: We retrospectively analyzed data from patients fulfilling Amsterdam criteria or having mismatch repair gene mutations, between September 2012 and October 2015.Results: We identified 28 patients. Seventeen had colorectal cancer with right colon predominance. Five developed endometrial cancer (median age of diagnosis – 53), with no MSH6 mutations. Five developed other cancers. All mutated mismatch repair cases studied had microsatellite instability.Discussion: Most cases had MSH2 mutations despite MLH1 being described in the literature as the most frequently mutated. Interestingly, colorectal cancer patients showed no tendency for high inflammatory infiltrate. Despite the high incidence of synchronous and metachronous tumours, most patients underwent a partial colectomy. Prophylactic hysterectomy and adnexectomy was performed in menopausal/perimenopausal patients.Conclusion: A standardized registration of patient’s data may lead to better management and knowledge about Lynch syndrome. Use of Bethesda Guidelines might identify new cases non-identified by Amsterdam criteria. Microsatellite instability analysis must be performed in a much larger scale. The genotypic/phenotypic correlation described in the literature was not verified in our study with statistical significance, perhaps due to small data sample and insufficient clinical registration.

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