scholarly journals Comprehensive Paired Tumor/Germline Testing for Lynch Syndrome: Bringing Resolution to the Diagnostic Process

2019 ◽  
Vol 37 (8) ◽  
pp. 647-657 ◽  
Author(s):  
Monalyn U. Salvador ◽  
Melissa R.F. Truelson ◽  
Carla Mason ◽  
Beth Souders ◽  
Holly LaDuca ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Promoter Hypermethylation ◽  
Germline Mutations ◽  
Diagnostic Process ◽  
Consecutive Series ◽  
Clinical Diagnostic Laboratory ◽  
Diagnostic Laboratory ◽  
Mlh1 Promoter ◽  
Testing Algorithm ◽  
Germline Testing

PURPOSE The current diagnostic testing algorithm for Lynch syndrome (LS) is complex and often involves multiple follow-up germline and somatic tests. We aimed to describe the results of paired tumor/germline testing performed on a large cohort of patients with colorectal cancer (CRC) and endometrial cancer (EC) to better determine the utility of this novel testing methodology. MATERIALS AND METHODS We retrospectively reviewed a consecutive series of patients with CRC and EC undergoing paired tumor/germline analysis of the LS genes at a clinical diagnostic laboratory (N = 702). Microsatellite instability, MLH1 promoter hypermethylation, and germline testing of additional genes were performed if ordered. Patients were assigned to one of five groups on the basis of prior tumor screening and germline testing outcomes. Results for each group are described. RESULTS Overall results were informative regarding an LS diagnosis for 76.1% and 60.8% of patients with mismatch-repair–deficient (MMRd) CRC and EC without and with prior germline testing, respectively. LS germline mutations were identified in 24.8% of patients in the group without prior germline testing, and interestingly, in 9.5% of patients with previous germline testing; four of these were discordant with prior tumor screening. Upon excluding patients with MLH1 promoter hypermethylation and germline mutations, biallelic somatic inactivation was seen in approximately 50% of patients with MMRd tumors across groups. CONCLUSION Paired testing identified a cause for MMRd tumors in 76% and 61% of patients without and with prior LS germline testing, respectively. Findings support inclusion of tumor sequencing as well as comprehensive LS germline testing in the LS testing algorithm. Paired testing offers a complete, convenient evaluation for LS with high diagnostic resolution.

scholarly journals GenomeDiver: A platform for phenotype-guided medical genomic diagnosis

2020 ◽  
Author(s):  
Nathaniel Pearson ◽  
Christian Stolte ◽  
Kevin Shi ◽  
Faygel Beren ◽  
Noura S. Abul-Husn ◽  
...  
Keyword(s):  
Diagnostic Testing ◽  
Diagnostic Process ◽  
Genomic Sequencing ◽  
Sequencing Data ◽  
Clinical Diagnostic Laboratory ◽  
Diagnostic Laboratory ◽  
Phenotypic Data ◽  
Human Phenotype ◽  
Phenotype Data

ABSTRACTPurposeMaking a diagnosis from clinical genomic sequencing requires well-structured phenotypic data to guide genotype interpretation. A patient’s phenotypic features can be documented using the Human Phenotype Ontology (HPO), generating terms used to prioritize genes potentially causing the patient’s disease. We have developed GenomeDiver to provide a user interface for clinicians that allows more effective collaboration with the clinical diagnostic laboratory, with the goal of improving the success of the diagnostic process.MethodsGenomeDiver is designed to prompt reverse phenotyping of patients undergoing genetic testing, enriching the amount and quality of structured phenotype data for the diagnostic laboratory, and helping clinicians to explore and flag diseases potentially causing their patient’s presentation.ResultsWe show how GenomeDiver communicates the clinician’s informed insights to the diagnostic lab in the form of HPO terms for interpretation of genomic sequencing data. We describe our user-driven design process, the engineering of the software for efficiency, security and portability, and an example of the performance of GenomeDiver using simulated genomic testing data.ConclusionsGenomeDiver is a first step in a new approach to genomic diagnostics that enhances laboratory-clinician interactions, with the goal of directly engaging clinicians to improve the outcome of genomic diagnostic testing.

Improving detection of Lynch syndrome using a reflex immunohistochemistry algorithm for all patients with newly diagnosed colorectal cancer.

2012 ◽  
Vol 30 (34_suppl) ◽  
pp. 98-98
Author(s):  
Minggui Pan ◽  
Elizabeth Hoodfar ◽  
JoAnn Bergoffen ◽  
Regan Fulton ◽  
Laura Hofmeister ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Germline Mutation ◽  
Detection Rate ◽  
Promoter Hypermethylation ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Newly Diagnosed ◽  
Mlh1 Promoter ◽  
Mmr Proteins

98 Background: Identifying patients with Lynch syndrome has profound impact on the clinical care of patients and their families. Previous guidelines based on family history alone have shown low sensitivity. In our medical center, the detection rate of Lynch syndrome was <1% among colorectal cancer cases. Methods: We have developed a system-based algorithm using centralized testing by immunohistochemistry (IHC) for four mismatched repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2) as a screening method for all newly diagnosed colorectal cancer patients, followed by step wise testing of BRAF mutation, MLH1 promoter hypermethylation, +/- microsatellite instability, and germline mutation. Results: From April 1, 2011, to July 11, 2012, we have screened 116 patients. IHC detected absent expression of at least one of the MMR proteins in 18 cases. Three cases showed missing expression of MSH2/MSH6 and the presence of a germline mutation in MSH6 was confirmed in two cases. The newest case is still being investigated for germline mutation. Of the remaining 15 cases, 10 showed the presence of BRAF V600E mutation, two showed hypermethylation of the MLH1 promoter, and one showed germline MLH1 mutation. Two cases showed no BRAF V600E mutation, no MLH1 promoter hypermethylation or germline gene mutation. Overall, of 116 cases, three cases have confirmed Lynch syndrome with the detection of a germline mutation, two cases most likely have Lynch syndrome but without any detectable germline mutation of MLH1 or PMS2 using the current detecting methods. Conclusions: Our system-based screening algorithm using reflex immunohistochemistry of four MMR proteins has resulted in excellent detection rate of approximately 4% to 5% (5 out of 116 cases), consistent with the expected Lynch syndrome prevalence rate in the population. This represents a marked improvement over our previous family history-based approach in Lynch syndrome screening.

scholarly journals MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

2012 ◽  
Vol 20 (7) ◽  
pp. 762-768 ◽  
Author(s):  
Mireia Gausachs ◽  
Pilar Mur ◽  
Julieta Corral ◽  
Marta Pineda ◽  
Sara González ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Lynch Syndrome ◽  
Promoter Hypermethylation ◽  
Effectiveness Study ◽  
Mlh1 Promoter ◽  
Analytical Algorithm ◽  
Cost Effectiveness Study

The clinical and molecular characteristics of patients with personal history of colorectal cancer evaluated by cancer genetics counseling services.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 46-46
Author(s):  
Veena Krishnan ◽  
Cassandra Gurganus ◽  
Delmer Alfredo Montoya Motino ◽  
Gideon T Dosunmu ◽  
Sana Ozair ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Cancer Genetics ◽  
Germline Mutations ◽  
Personal History ◽  
Molecular Characteristics ◽  
Counseling Services ◽  
Polyposis Syndrome ◽  
History Of ◽  
Germline Testing

46 Background: Genetic susceptibility to colorectal cancer (CRC) include well-defined hereditary syndromes such as Lynch Syndrome, Familial Adenomatous Polyposis syndrome (FAP), MUTYH-Associated Polyposis syndrome (MAP) and other less common syndromes. National Comprehensive Cancer Network (NCCN) guidelines recommend that individuals meeting certain criteria have detailed risk assessment and potential genetic testing. Here, we describe the clinical and molecular characteristics of patients with personal history of CRC evaluated by cancer genetics counseling services. Methods: This is an IRB-approved retrospective chart-review study. Between 2016 and 2020, 1011 unique genetic counseling visits were conducted. Germline testing was recommended by a certified genetic counselor if medically necessary. All patients with a personal history of CRC were identified (N = 52) and their clinical and molecular characteristics were summarized. Results: The median age is 50 years-old (29-82). Thirty-five (67%) patients were females. Caucasians, African Americans and other ethnic backgrounds represented 75%, 19% and 6% respectively. The primary tumor location was in the right colon, left colon and rectum in 29%, 37% and 27% of our cohort respectively. In 7%, the primary location of the tumor was not available. In our cohort, 11 out of 52 (21%) patients had a pathogenic germline mutation and 9 patients (17%) had a germline variant of unknown significance (VUS). Among patients with pathogenic germline mutations (N = 11), 4 patients had MSH2 mutations (MSH2 c.1759+1G > A, MSH2 c. 1687dupT, MSH2 c.1861C > T and MSH2 c.811_814delTCTG), 1 patient had a MSH6 mutation (MSH6 c.1012A > T), 1 patient had a PMS2 mutation (PMS2 c.2182_2184delACTinsG), 3 patients had CHEK2 mutations (CHEK2 c.1100delC and CHEK2 c.470T > C (p.I157T)), 2 patients had MUTYH mutations (MUTYH c.1187G > A and MUTYH c.536A > G) and 1 patient had a BRCA2 mutation (BRCA2 c.2808_2811delACAA). One patient had a CHEK2 and a MUTYH mutation. The VUS mutations in our cohort were POLE c.1645T > C, POLE c.5480C > T, c.2999G > A, MLH1 c.1628A > G, CTNNA1 c.503G > A, MSH2 c.128A > G, NBN c.16C > T, ATM c.6537T > G and AXIN2, BRCA1, NTHL1 mutations. Conclusions: In our cohort of patients with personal history of CRC, the majority of patients (62%) had negative germline testing. An underlying pathogenic germline mutation and VUS were identified in 21% and 17% of the patients respectively. Lynch Syndrome was the most commonly diagnosed hereditary CRC syndrome with 6 out of 11 patients found to have MMR germline mutations. Other pathogenic mutations were identified in the CHEK2, MUTYH and BRCA2 genes.

scholarly journals Population-Based Molecular Screening for Lynch Syndrome: Implications for Personalized Medicine

2013 ◽  
Vol 31 (20) ◽  
pp. 2554-2562 ◽  
Author(s):  
Robyn L. Ward ◽  
Sian Hicks ◽  
Nicholas J. Hawkins
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Screening Program ◽  
Germline Mutations ◽  
Population Based ◽  
Molecular Profile ◽  
Molecular Screening ◽  
Protein Loss ◽  
True Value ◽  
Germline Testing

Purpose Molecular screening techniques are available to identify hereditary Lynch syndrome in people with newly diagnosed colorectal cancer (CRC). We aimed to determine whether decisions of patients or clinicians reduced detection of Lynch syndrome. Patients and Methods A prospective cohort of 245 consecutive individuals with mismatch repair–deficient CRC recruited from a population-based molecular screening program of all incident patient cases of CRC in a health care region of 1.2 million inhabitants. All incident CRCs were analyzed for mismatch repair protein loss, supported by BRAF mutation and microsatellite instability testing. Advice regarding referral for germline testing was provided to treating surgeons. Results The mean age of patients was 72.5 ± standard deviation of 12 years; 64% were women; 65% had BRAF-mutant cancers. Consent for germline testing was received from 194 patients (79%): 120 with low and 74 with high likelihood of Lynch syndrome based on tumor molecular profile. Of patients who consented, 143 provided samples for germline analysis, with 12 of 143 showing a mutation (8.4%; 95% CI, 4.4% to 14.2%). Among the 102 patients who chose not to provide a sample or did not consent, an estimated 5.3 of 102 had germline mutations (5.2%; 95% CI, 2.0% to 17.5%). Conclusion A universal screening strategy for Lynch syndrome is potentially effective because the overall estimate of germline mutations was 17.3 of 245 patient cases (7.1%; 95% CI, 2.8% to 18.2%). However, the true value of screening is likely to be greatly limited by the decisions and circumstances of patients in taking up germline testing.

Screening of colorectal cancer (CRC) patients for lynch syndrome (LS) emphasizes the need for public insurance coverage of genetic testing: Results of a national program by the Hellenic Society of Medical Oncology (HeSMO).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13141-e13141
Author(s):  
Zacharenia Saridaki ◽  
Emmanouil S. Saloustros ◽  
Nikolaos Tsoukalas ◽  
Thomas Makatsoris ◽  
Georgios Lypas ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Genetic Testing ◽  
Lynch Syndrome ◽  
Screening Program ◽  
Promoter Hypermethylation ◽  
Healthcare Services ◽  
Braf V600e ◽  
National Program ◽  
Female Ratio ◽  
Mlh1 Promoter

e13141 Background: Lynch Syndrome is associated with germline mutations in Mismatch Repair (MMR) genes ( MLH1, MSH2, MSH6, PMS2). CRC patients whose tumors exhibit high-level microsatellite instability (MSI-H) have an increased probability of LS. Although the diagnosis of LS has important implications for the patient and the family, germline genetic testing is not reimbursed by the Hellenic Public State Healthcare Services. To address this need HeSMO conducted a national program to screen and diagnose CRC patients with LS. Methods: All patients with CRC were eligible. Assessment for LS involved initially screening tumor tissue for the presence of MMR deficiency, either via molecular MSI testing or via immunohistochemistry (IHC) to detect the absence of one or more MMR proteins. Patients with an MMR-deficient tumor in the absence of a somatic cause (e.g. BRAF mutation or MLH1 promoter hypermethylation) underwent genetic counseling and germline testing to confirm a LS diagnosis. Results: From June 2017 to December 2018, 104 patients diagnosed with CRC were enrolled and tested. Median age of diagnosis was 58,5 years (range 32 - 89) and male-to-female ratio was 1.6:1. Fifty patients (48%) had tumors that exhibited the MSI-H phenotype. From the MSI-H tumors, 41 (82%) did not harbor the BRAF V600E mutation and 33 of them (80.5%) did not harbor an MLH1 promoter hypermethylation. Therefore, 33 patients were invited for genetic counseling and testing. Fifteen patients (45.45%) were diagnosed with LS: 6 ( 40 %) had a mutation in MLH1 (one of which had also a mutation in PMS2 gene), 4 (26.6%) in MSH6, 4 (26.6%) in MSH2 and 1 (6.6%) in PMS2. Conclusions: In our series, 30% of the CRC patients with MSI-H tumors were tested positive for LS. These results confirm the value of a universal screening program of CRC patients for LS. Hopefully, these results will convince the Hellenic Public State Healthcare Services to reimburse screening and germline genetic testing of CRC patients for LS.

107 Somatic MLH1 Promoter Hypermethylation Is a Frequent Event in Lynch Syndrome Colorectal Cancers

2013 ◽  
Vol 144 (5) ◽  
pp. S-25 ◽  
Author(s):  
Leticia Moreira ◽  
Jenifer Munoz ◽  
Miriam Cuatrecasas ◽  
Isabel Quintanilla ◽  
Maria Liz Leoz ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Promoter Hypermethylation ◽  
Colorectal Cancers ◽  
Mlh1 Promoter ◽  
Frequent Event

scholarly journals Patients with colorectal cancer associated with Lynch syndrome and MLH1 promoter hypermethylation have similar prognoses

2016 ◽  
Vol 18 (9) ◽  
pp. 863-868 ◽  
Author(s):  
Sigurdis Haraldsdottir ◽  
Heather Hampel ◽  
Christina Wu ◽  
Daniel Y. Weng ◽  
Peter G. Shields ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Promoter Hypermethylation ◽  
Mlh1 Promoter
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