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JCO Clinical Cancer Informatics Nov 2022This study aims to review and evaluate available informatics platforms for research and management purposes of Lynch syndrome (LS) to identify gaps and needs for future... (Review)
Review
PURPOSE
This study aims to review and evaluate available informatics platforms for research and management purposes of Lynch syndrome (LS) to identify gaps and needs for future development.
METHODS
LS informatics tools were identified through literature search in four publication databases (1 and Scopus). First, the LS and functional elements of every informatics tools for LS were introduced. Then, current existing LS informatics tools were reviewed and explained.
RESULTS
A detailed review of implemented studies shows that many types of informatics platforms are available for LS management (ie, prediction model, clinical decision support system, database website, and other tools for research and management purposes of LS). Moreover, several dimensions of existing LS informatics tools were discussed and features and positive findings were reported.
CONCLUSION
Reviewing the literature reveals that several LS informatics tools were focused on gene-specific estimate, cancer risk prediction, identifying/screening patients, supporting personalized care of individuals with LS, and storing mismatch repair mutations information. Nevertheless, these platforms do not fully cover the care and research purposes. For instance, future developments of LS tools require more attention to dynamic knowledgebase, extra-colonic lynch-related cancers on the basis of precision medicine, variants of unknown significance, and support from diagnosis to surveillance for patient follow-up. Insights and recommendations provided in this study could help researchers and developers to meet the existing challenges in future developments.
Topics: Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; Mass Screening; Informatics
PubMed: 36395439
DOI: 10.1200/CCI.22.00087 -
Pediatric Blood & Cancer Nov 2022The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch...
BACKGROUND
The association of childhood cancer with Lynch syndrome is not established compared with the significant pediatric cancer risk in recessive constitutional mismatch repair deficiency syndrome (CMMRD).
PROCEDURE
We describe the clinical features, germline analysis, and tumor genomic profiling of patients with Lynch syndrome among patients enrolled in pediatric cancer genomic studies.
RESULTS
There were six of 773 (0.8%) pediatric patients with solid tumors identified with Lynch syndrome, defined as a germline heterozygous pathogenic variant in one of the mismatch repair (MMR) genes (three with MSH6, two with MLH1, and one with MSH2). Tumor analysis demonstrated evidence for somatic second hits and/or increased tumor mutation burden in three of four patients with available tumor with potential implications for therapy and identification of at-risk family members. Only one patient met current guidelines for pediatric cancer genetics evaluation at the time of tumor diagnosis.
CONCLUSION
Approximately 1% of children with cancer have Lynch syndrome, which is missed with current referral guidelines, suggesting the importance of adding MMR genes to tumor and hereditary pediatric cancer panels. Tumor analysis may provide the first suggestion of an underlying cancer predisposition syndrome and is useful in distinguishing between Lynch syndrome and CMMRD.
Topics: Brain Neoplasms; Child; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA-Binding Proteins; Germ-Line Mutation; Humans; MutL Protein Homolog 1; MutS Homolog 2 Protein; Neoplastic Syndromes, Hereditary
PubMed: 35713195
DOI: 10.1002/pbc.29859 -
World Journal of Gastroenterology Aug 2015Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA... (Review)
Review
Hereditary non-polyposis colorectal cancer (HNPCC) was previously synonymous with Lynch syndrome; however, identification of the role of germline mutations in the DNA mismatch repair (MMR) genes has made it possible to differentiate Lynch syndrome from other conditions associated with familial colorectal cancer (CRC). Broadly, HNPCC may be dichotomized into conditions that demonstrate defective DNA MMR and microsatellite instability (MSI) vs those conditions that demonstrate intact DNA MMR. Conditions characterized by MMR deficient CRCs include Lynch syndrome (germline MMR mutation), Lynch-like syndrome (biallelic somatic MMR mutations), constitutional MMR deficiency syndrome (biallelic germline MMR mutations), and sporadic MSI CRC (somatic biallelic methylation of MLH1). HNPCC conditions with intact DNA MMR associated with familial CRC include polymerase proofreading associated polyposis and familial colorectal cancer type X. Although next generation sequencing technologies have elucidated the genetic cause for some HNPCC conditions, others remain genetically undefined. Differentiating between Lynch syndrome and the other HNPCC disorders has profound implications for cancer risk assessment and surveillance of affected patients and their at-risk relatives. Clinical suspicion coupled with molecular tumor analysis and testing for germline mutations can help differentiate the clinical mimicry within HNPCC and facilitate diagnosis and management.
Topics: Biomarkers, Tumor; Brain Neoplasms; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; DNA Mutational Analysis; Diagnosis, Differential; Genetic Predisposition to Disease; Heredity; Humans; Microsatellite Instability; Mutation; Neoplastic Syndromes, Hereditary; Pedigree; Phenotype; Predictive Value of Tests
PubMed: 26309352
DOI: 10.3748/wjg.v21.i31.9253 -
Revue Medicale de Liege May 2021A personal or family history of cancer has now become the primary cause of genetic consultations. In recent years, various genes have been identified that are associated...
A personal or family history of cancer has now become the primary cause of genetic consultations. In recent years, various genes have been identified that are associated with a more or less marked genetic predisposition to the development of cancers. The syndrome associated with the hereditary risk of breast and ovarian cancer and the Lynch syndrome are the most frequent ones, but there are many other, much less common, situations associated with familial cancer risk. In most cases, there are clear recommendations regarding the indications for genetic testing and the follow-up of patients identified as having a predisposition to cancer. At the CHU of Liège, we currently perform more than 1.400 oncogenetic consultations per year and we maintain a positivity rate of genetic tests performed in this indication higher than 10%. In this way, we allow a multidisciplinary care of patients with a high oncological risk and participate in a prevention and surveillance activity. We also pay increasing attention to the hereditary risk associated with pediatric cancers and to patients with multiple cancers, especially when these develop at an early age. Finally, the oncogenetic consultation must consider the psychological, ethical and legal aspects of a diagnosis that involves the patient and his or her future, but also the whole family.
Topics: Child; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Genetic Predisposition to Disease; Genetic Testing; Heredity; Humans; Ovarian Neoplasms
PubMed: 34080359
DOI: No ID Found -
Cancer Control : Journal of the Moffitt... Jan 2009Approximately 2% to 5% of endometrial cancers may be due to an inherited susceptibility. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC)... (Review)
Review
BACKGROUND
Approximately 2% to 5% of endometrial cancers may be due to an inherited susceptibility. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, an autosomal-dominant inherited cancer susceptibility syndrome caused by a germline mutation in one of the DNA mismatch repair genes, accounts for the majority of inherited cases. Lynch syndrome is associated with early onset of cancer and the development of multiple cancer types, particularly colon and endometrial cancer.
METHODS
The current status of knowledge regarding Lynch syndrome-associated endometrial cancer and methods for diagnosis, screening, and prevention of cancers is reviewed.
RESULTS
The lifetime cumulative risk of endometrial cancer for women with Lynch syndrome is 40% to 60%, which equals or exceeds their risk of colorectal cancer. No current evidence suggests either a survival advantage or disadvantage to endometrial cancer that is associated with Lynch syndrome when these cases are compared with sporadic cases. A combination of family and personal medical history and tumor testing provides an efficient basis for diagnosing Lynch syndrome in women with endometrial cancer. Current gynecologic cancer screening guidelines for women with Lynch syndrome include annual endometrial sampling and transvaginal ultrasonography beginning at age 30 to 35 years.
CONCLUSIONS
Diagnosing endometrial cancer patients with Lynch syndrome has important clinical implications for the individual and family members. Screening and prevention practices can decrease the likelihood of developing additional cancers.
Topics: Animals; Colorectal Neoplasms, Hereditary Nonpolyposis; Early Detection of Cancer; Endometrial Neoplasms; Female; Genetic Predisposition to Disease; Humans; Mass Screening; Risk Factors
PubMed: 19078925
DOI: 10.1177/107327480901600103 -
Familial Cancer Jun 2013Prediction models for the identification of Lynch syndrome have been developed to quantify an individual's risk of carrying a mismatch repair gene mutation and help... (Review)
Review
Prediction models for the identification of Lynch syndrome have been developed to quantify an individual's risk of carrying a mismatch repair gene mutation and help clinicians decide for whom further risk assessment and genetic testing is necessary. There are diverse clinical settings in which a healthcare provider has the opportunity to assess an individual for Lynch syndrome. Prediction models offer a potentially feasible and useful strategy to systematically identify at-risk individuals, whether they are affected with colorectal cancer or not, and to help with management of the implications of molecular and germline test results. Given the complexity of diagnostic information currently available to clinicians involved in identifying and caring for patients with Lynch syndrome, prediction models provide a useful and complementary aid in medical decision-making. Systematic implementation of prediction models estimates should be considered in routine clinical care and at various stages of cancer risk assessment and prevention. In this manuscript, we review the main prediction models developed for Lynch syndrome, focus on their specific features and performance assessed in several validation studies, compare the models with other clinical and molecular strategies for the diagnosis of Lynch syndrome, and discuss their potential uses in clinical practice.
Topics: Colorectal Neoplasms, Hereditary Nonpolyposis; Diagnosis, Computer-Assisted; Genetic Predisposition to Disease; Genetic Testing; Humans
PubMed: 23553450
DOI: 10.1007/s10689-013-9632-0 -
Journal For Immunotherapy of Cancer Jun 2022The development of cancer vaccines to induce tumor-antigen specific immune responses was sparked by the identification of antigens specific to or overexpressed in cancer... (Review)
Review
The development of cancer vaccines to induce tumor-antigen specific immune responses was sparked by the identification of antigens specific to or overexpressed in cancer cells. However, weak immunogenicity and the mutational heterogeneity in many cancers have dampened cancer vaccine successes. With increasing information about mutational landscapes of cancers, mutational neoantigens can be predicted computationally to elicit strong immune responses by CD8 +cytotoxic T cells as major mediators of anticancer immune response. Neoantigens are potentially more robust immunogens and have revived interest in cancer vaccines. Cancers with deficiency in DNA mismatch repair have an exceptionally high mutational burden, including predictable neoantigens. Lynch syndrome is the most common inherited cancer syndrome and is caused by DNA mismatch repair gene mutations. Insertion and deletion mutations in coding microsatellites that occur during DNA replication include tumorigenesis drivers. The induced shift of protein reading frame generates neoantigens that are foreign to the immune system. Mismatch repair-deficient cancers and Lynch syndrome represent a paradigm population for the development of a preventive cancer vaccine, as the mutations induced by mismatch repair deficiency are predictable, resulting in a defined set of frameshift peptide neoantigens. Furthermore, Lynch syndrome mutation carriers constitute an identifiable high-risk population. We discuss the pathogenesis of DNA mismatch repair deficient cancers, in both Lynch syndrome and sporadic microsatellite-unstable cancers. We review evidence for pre-existing immune surveillance, the three mechanisms of immune evasion that occur in cancers and assess the implications of a preventive frameshift peptide neoantigen-based vaccine. We consider both preclinical and clinical experience to date. We discuss the feasibility of a cancer preventive vaccine for Lynch syndrome carriers and review current antigen selection and delivery strategies. Finally, we propose RNA vaccines as having robust potential for immunoprevention of Lynch syndrome cancers.
Topics: Brain Neoplasms; Cancer Vaccines; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Immunotherapy; Neoplastic Syndromes, Hereditary
PubMed: 35732349
DOI: 10.1136/jitc-2021-004416 -
Chirurgia (Bucharest, Romania : 1990) Dec 2023Lynch syndrome, characterized by DNA mismatch repair deficiency, represents a significant paradigm among cancer predisposition syndromes and is notably associated with... (Review)
Review
Lynch syndrome, characterized by DNA mismatch repair deficiency, represents a significant paradigm among cancer predisposition syndromes and is notably associated with heightened susceptibility to various cancers, particularly colorectal and endometrial malignancies. The primary aim of this research paper is to scrutinize specific associations and delve into the underlying molecular mechanisms of Lynch syndrome. Genetic alterations in MMR genes, including MLH1, MSH2, MSH6, PMS2, and EPCAM, compromise DNA repair mechanisms, predisposing affected individuals to a spectrum of malignancies. This paper comprehensively investigates current screening methodologies and preventive measures tailored for individuals identified or at risk of Lynch syndrome. The integration of advanced sequencing technologies and refined bioinformatics tools has significantly improved mutation detection accuracy, facilitating precise identification of mutation carriers and their at-risk relatives. Moreover, this review emphasizes the evolving diagnostic landscape, which have revolutionized the identification of potential mutation carriers. The structured diagnostic algorithm, incorporating clinical criteria, tumor testing, and genetic analysis, plays a pivotal role in systematically identifying and managing individuals with Lynch syndrome. While the well-established association of Lynch syndrome with colorectal and endometrial cancers is recognized, emerging evidence suggests an increased risk for other types of malignancies. A crucial aspect of this literature review is to extensively analyze the less commonly acknowledged correlation between Lynch syndrome and prostate or testicular malignancies. Understanding these correlations holds significant importance in guiding tailored screening protocols and preventive strategies for individuals carrying Lynch syndrome-associated genetic mutations. The comprehensive assessment of this diverse spectrum of cancers underscores the necessity for tailored surveillance strategies and multidisciplinary approaches to effectively manage and mitigate risks in individuals harboring Lynch syndrome-associated genetic alterations.
Topics: Male; Female; Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; Treatment Outcome; Colorectal Neoplasms; Mutation; Endometrial Neoplasms; DNA Mismatch Repair; MutL Protein Homolog 1; MutS Homolog 2 Protein
PubMed: 38228591
DOI: 10.21614/chirurgia.2023.v.118.i.6.p.584 -
Clinical Gastroenterology and... Mar 2022Lynch syndrome is a form of hereditary colorectal cancer (CRC) caused by pathogenic germline variants (PV) in DNA mismatch repair (MMR) genes. Currently, many Western... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
Lynch syndrome is a form of hereditary colorectal cancer (CRC) caused by pathogenic germline variants (PV) in DNA mismatch repair (MMR) genes. Currently, many Western countries perform universal immunohistochemistry testing on CRC to increase the identification of Lynch syndrome patients and their relatives. For a clear understanding of health benefits and costs, data on its outcomes are required: proportions of Lynch syndrome, sporadic MMR-deficient (MMRd) cases, and unexplained MMRd cases.
METHODS
Ovid Medline, Embase, and Cochrane CENTRAL were searched for studies reporting on universal MMR immunohistochemistry, followed by MMR germline analysis, until March 20, 2020. Proportions were calculated, subgroup analyses were performed based on age and diagnostics used, and random effects meta-analyses were conducted. Quality was assessed using the Joanna Briggs Critical Appraisal Tool for Prevalence Studies.
RESULTS
Of 2723 identified articles, 56 studies covering 58,580 CRCs were included. In 6.22% (95% CI, 5.08%-7.61%; I = 96%) MMRd was identified. MMR germline PV was present in 2.00% (95% CI, 1.59%-2.50%; I = 92%), ranging from 1.80% to 7.27% based on completeness of diagnostics and age restriction. Immunohistochemistry outcomes were missing in 11.81%, and germline testing was performed in 76.30% of eligible patients. In 7 studies, including 6848 CRCs completing all diagnostic stages, germline PV and biallelic somatic MMR inactivation were found in 3.01% and 1.75%, respectively; 0.61% remained unexplained MMRd.
CONCLUSIONS
Age, completeness, and type of diagnostics affect the percentage of MMR PV and unexplained MMRd percentages. Complete diagnostics explain almost all MMRd CRCs, reducing the amount of subsequent multigene panel testing. This contributes to optimizing testing and surveillance in MMRd CRC patients and relatives.
Topics: Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; DNA Mismatch Repair; Humans; Immunohistochemistry
PubMed: 33887476
DOI: 10.1016/j.cgh.2021.04.021 -
Clinical Gastroenterology and... May 2014Colorectal cancer (CRC) is the most common gastrointestinal malignancy and the third cause of cancer death in men and women in the United States. The majority of CRC... (Review)
Review
Colorectal cancer (CRC) is the most common gastrointestinal malignancy and the third cause of cancer death in men and women in the United States. The majority of CRC cases diagnosed annually are due to sporadic events, but up to 6% are attributed to known monogenic disorders that confer a markedly increased risk for the development of CRC and multiple extracolonic malignancies. Lynch syndrome is the most common inherited CRC syndrome and is associated with mutations in DNA mismatch repair genes, mainly MLH1 and MSH2 but also MSH6, PMS2, and EPCAM. Although the risk of CRC and endometrial cancer may approach near 75% and 50%, respectively, in gene mutation carriers, the identification of these individuals and at-risk family members through predictive genetic testing provides opportunities for cancer prevention including specialized cancer screening, intensified surveillance, and/or prophylactic surgeries. This article will provide a review of the major advances in risk assessment, molecular genetics, DNA mutational analyses, and cancer prevention and management made since Lynch syndrome was first described 100 years ago.
Topics: Adult; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Female; Gastroenterology; Genetic Testing; History, 20th Century; History, 21st Century; Humans; Male; Middle Aged; Surgical Procedures, Operative; United States
PubMed: 23891921
DOI: 10.1016/j.cgh.2013.06.031