Evaluating the clinical utility of universal screening to identify Lynch syndrome in stage III/III colorectal cancer patients: A prospective observational study in Japan.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 41-41
Author(s):  
Yasuaki Yamamoto ◽  
Yuichiro Tsukada ◽  
Takeshi Kuwata ◽  
Motohiro Kojima ◽  
Yumie Hiraoka ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Universal Screening ◽  
Clinical Utility ◽  
Braf V600e ◽  
Study Patient ◽  
Degree Relative ◽  
Western Countries ◽  
Dna Mismatch ◽  
Reflex Testing

41 Background: Universal screening for Lynch syndrome (LS) by identifying deficient DNA mismatch repair (MMR) in the tumor tissue of all new colorectal cancer (CRC) patients is widely accepted. The population prevalence of LS is approximately 3% in Western countries, whereas it is approximately 0.7% in Japan. In addition, the number of relatives diagnosed per proband is 3.6 in Western countries, whereas there are even fewer diagnoses per proband in Japan. To address the issue of LS remaining largely underdiagnosed in Japan, we prospectively evaluated the clinical utility of universal screening of LS in CRC patients. Methods: From March 2016 to August 2019, all consecutive new cases of stage II/III CRC underwent immunohistochemistry (IHC) screening for MMR using MLH1, MSH2, MSH6, and PMS2 antibodies. The patients negative for both MLH1 and PMS2 (MLH1-/PMS2-) were subjected to reflex testing for BRAF V600E mutation. Patients with both MLH1-/PMS2- and BRAF negative (cohort A, n = 14) and those with other IHC patterns (cohort B, n = 13) were referred for genetic counseling (GC) and genetic testing (GT). Furthermore, relatives of probands with confirmed LS were referred for GC/GT if they were willing. Results: Overall, 591 pts were enrolled in this study. Patient background were as follows: > 70 y/o, 35%; right-sided/left-sided colon/rectum, 24%/24%/53%; and cStage II/III, 65%/35%. Of 591 patients, 40 (6.8%) had MMR deficiency. Of 27 patients with MLH1-/PMS2-, 24 underwent BRAF reflex testing; only 10 of these patients tested positive for mutation. Of 27 patients recommended for GC, 25 were referred for GC and 22 for GT, which revealed 12 LS cases (2%, mutation genes:MLH1/PMS2/MSH2; 4/2/6). The frequency of LS diagnosis with respect to patient background was as follows: > 70/≤70 y, 1.0/2.6%; right-sided/left-sided colon/rectum, 5.8/0/1.3%; and cStage II/III, 2.6/1.0%. Interestingly, only 3 (25%) of 12 patients who underwent GC/GT in cohort A had LS compared with 9 (90%) of 10 patients in cohort B ( p= 0.004). Moreover, among 11 relatives of 5 families who were willing to undergo GC/GT, six (55%) had LS, of whom two were first-degree relatives (33%), one was a second-degree relative (50%), and three were third-degree relatives (100%). Conclusions: This study showed that universal screening of LS in CRC patients is significantly useful in Japan. Furthermore, implementing a reflex testing strategy demonstrated high adherence to guidelines and the appropriateness of our referrals for GC/GT.

Routine universal screening for Lynch syndrome in colorectal cancer patients in the community setting.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1512-1512 ◽  
Author(s):  
Jeffrey M. Goldberg ◽  
Andrea L. Lewis ◽  
Michelle Alabek ◽  
Cara Dreher ◽  
Sandra Elane Brooks
Keyword(s):  
Colorectal Cancer ◽  
Genetic Counseling ◽  
Lynch Syndrome ◽  
Universal Screening ◽  
Significant Proportion ◽  
Community Setting ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Community Based ◽  
Screening Protocol

1512 Background: Identification of colorectal cancer (CRC) cases that are due to Lynch Syndrome (LS) is important to prevent secondary malignancies or development of additional malignancies among relatives. Utilization of clinical criteria to select CRC patients for laboratory testing fails to identify a significant proportion of patients whose CRC is due to LS. Therefore, universal screening for LS among CRC patients has been advocated by the Evaluation of Genomic Applications in Practice and Prevention Working Group. However, the feasibility of routine universal screening has not been evaluated in a community-based, non-research setting. We implemented a universal screening protocol for LS as part of routine care of CRC at Norton Healthcare, a multi-institutional community-based healthcare organization. Methods: Beginning in October 2009, all resected CRC tumors automatically underwent immunohistochemistry analysis (IHC) for Lynch Syndrome-associated mismatch repair gene (MMR) expression. Selected patients who underexpressed MLH1 also underwent testing for the BRAF V600E mutation. Patients who had a BRAF V600E mutation were considered to have sporadic CRC. All other patients with abnormal IHC were automatically referred for genetic counseling. We retrospectively reviewed the outcomes of genetic counseling in all patients referred through this universal screening protocol. Results: Between October 2009 and December 2011, 388 patients underwent resection of CRC, all of whom had IHC for MMR expression. Seventy patients were identified as having abnormal IHC. Sixty-two had MLH1/PMS2 underexpression, of which 18 underwent BRAF testing and 13 had a BRAF V600E mutation. Eight had MSH2/MSH6 underexpression. Nine patients have been confirmed to have LS, 31 have been found not to have LS, and 19 are in the process of evaluation. Seven patients declined genetic counseling, and 4 died before they could be adequately evaluated. Conclusions: Universal screening for CRC due to LS, using IHC with select BRAF V600E mutation testing and automated referral for genetic counseling, is feasible in the community setting. Funded in part with federal funds: NCI, NIH, Contract No. HHSN261200800001.

TUMOUR PATHOLOGY PREDICTS MICROSATELLITE INSTABILITY IN A POPULATION-BASED SERIES OF COLORECTAL CANCER CASES

2008 ◽  
Vol 31 (4) ◽  
pp. 12
Author(s):  
A J Hyde ◽  
D Fontaine ◽  
R C Green ◽  
M Simms ◽  
P S Parfrey ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Population Based ◽  
Pathological Features ◽  
Predictive Tool ◽  
Entire Cohort ◽  
Dna Mismatch ◽  
Bethesda Guidelines ◽  
Revised Bethesda Guidelines

Background: Lynch Syndrome is an autosomal dominant trait that accounts forapproximately 3% of all cases of colorectal cancer (CRC). It is caused by mutations in DNA mismatch repair (MMR) genes, most commonly MLH1 or MSH2. These MMR defects cause high levels of microsatellite instability (MSI-H) in the tumours. MSI testing of all CRCs to identify potential Lynch Syndrome cases is not practical, so the Bethesda Guidelines, which use clinical and pathological features, were created to identify those tumours most likely to be MSI-H^1. In 2007 Jenkins et. al. created MsPath, a tool based on the pathological features described in the rarely used 3^rd Bethesda criterion, to improve prediction of MSI-H tumours among CRC cases diagnosed before age 60 years^2. Methods: We collected a population-based cohort of 716 CRC cases diagnosed before age 75 years in Newfoundland. For each of these cases we collected family history, performed MSI analysis, and scored a number of pathological features for the purpose of evaluating the accuracy of the Bethesda Criteria and MsPath at predicting MSI-H tumours. Results: Our work validates the MsPath tool in the Newfoundland population for the same age group used to create the tool. We found it identified MSI-H cases with a sensitivity of 95% and specificity of 35% in our population of CRCcases diagnosed before age 60 years (n=290). We also tested this tool on our older population of CRCcases, diagnosed at ages 60 to 74 years (n=426). We found it to be at least as predictive in this population,with a sensitivity of 95% and a specificity of 42%. We then used our entire cohort (N=716) to compare MsPath with the other Bethesda criteria.Bethesda criteria 1, 2, 4 and 5 together predicted MSI-H cases with a sensitivity of 67% and a specificity of 51%. MsPath was better at identifying these cases, with a sensitivity of 95% and a specificity of 39%. Conclusions: We conclude that MsPath can be extended to include patients diagnosed with CRC before age 75 years. As well, we have found that MsPath is a better predictive tool than the Revised Bethesda Guidelines for identifying MSI-H cases within a population-based setting of colorectal cancer. References: 1. Umar, A. et. al. J Natl Cancer Inst 2004;96:261-8 2.Jenkins, M.A. et. al. Gastroenterology 2007;133:48-56

scholarly journals Recent advances in understanding Lynch syndrome

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2889 ◽  
Author(s):  
Sherief Shawki ◽  
Matthew F. Kalady
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Correct Diagnosis ◽  
Diagnostic Testing ◽  
Gene Mutations ◽  
The United States ◽  
Cancer Syndrome ◽  
Dna Mismatch ◽  
Recent Developments ◽  
Risk Patients

Colorectal cancer affects about 4.4% of the population and is a leading cause of cancer-related death in the United States. Approximately 10% to 20% of cases occur within a familial pattern, and Lynch syndrome is the most common hereditary colorectal cancer syndrome. Lynch syndrome is a hereditary predisposition to forming colorectal and extracolonic cancers, caused by a germline mutation in one of the DNA mismatch repair genes. Identifying at-risk patients and making a correct diagnosis are the keys to successful screening and interventions which will decrease formation of and death from cancers. Knowledge of the genetics and the natural history of Lynch syndrome has continued to be uncovered in recent years, leading to a better grasp on how these patients and their families should be managed. Recent developments include the approach to diagnostic testing, more precise definitions of the syndrome and risk stratification based on gene mutations, surgical decision-making, and chemoprevention.

scholarly journals PD-9 Universal screening for Lynch syndrome: Reflex testing to improve appropriateness of genetic counseling and diagnosis

2020 ◽  
Vol 31 ◽  
pp. S214-S215
Author(s):  
A. Puccini ◽  
A. Damiani ◽  
L. Varesco ◽  
S. Zupo ◽  
L. Battistuzzi ◽  
...  
Keyword(s):  
Genetic Counseling ◽  
Lynch Syndrome ◽  
Universal Screening ◽  
Reflex Testing

scholarly journals Next Generation Sequencing in Molecular Diagnosis of Lynch Syndrome – a Pilot Study Using New Stratification Criteria

2018 ◽  
Vol 61 (3) ◽  
pp. 98-102 ◽  
Author(s):  
Ivana Kašubová ◽  
Veronika Holubeková ◽  
Katarína Janíková ◽  
Barbora Váňová ◽  
Zuzana Sňahničanová ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Next Generation Sequencing ◽  
Pilot Study ◽  
Lynch Syndrome ◽  
New Technologies ◽  
Braf V600e ◽  
Sporadic Colorectal Cancer ◽  
Next Generation ◽  
Gene Panel Testing ◽  
Generation Sequencing

The development of the new technologies such as the next-generation sequencing (NGS) makes more accessible the diagnosis of genetically heterogeneous diseases such as Lynch syndrome (LS). LS is one of the most common hereditary form of colorectal cancer. This autosomal dominant inherited disorder is caused by deleterious germline mutations in one of the mismatch repair (MMR) genes – MLH1, MSH2, MSH6 or PMS2, or the deletion in the EPCAM gene. These mutations eventually result in microsatellite instability (MSI), which can be easily tested in tumor tissue. According to the actual recommendations, all patients with CRC that are suspect to have LS, should be offered the MSI testing. When the MSI is positive, these patients should be recommended to genetic counseling. Here we report a pilot study about the application of NGS in the LS diagnosis in patients considered to have sporadic colorectal cancer. The inclusion criteria for the NGS testing were MSI positivity, BRAF V600E and MHL1 methylation negativity. We have used 5 gene amplicon based massive parallel sequencing on MiSeq platform. In one patient, we have identified a new pathogenic mutation in the exon 4 of the MSH6 gene that was previously not described in ClinVar, Human Gene Mutation Database, Ensembl and InSight databases. This mutation was confirmed by the Sanger method. We have shown that the implementation of new criteria for colorectal patients screening are important in clinical praxis and the NGS gene panel testing is suitable for routine laboratory settings.

Worldwide variation in lynch syndrome screening: case for universal screening in low colorectal cancer prevalence areas

2020 ◽  
Author(s):  
George Kunnackal John ◽  
Vipin Das Villgran ◽  
Christine Caufield-Noll ◽  
Francis Giardiello
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Universal Screening ◽  
Cancer Prevalence
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