Mo1742 - Worldwide Variation in Yield of Universal Lynch Syndrome Screening: A Case for Universal Screening in Low Colorectal Cancer Prevalence Regions

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.

Download Full-text

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

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.1512 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 1512-1512 ◽

Cited By ~ 1

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.

Download Full-text

Real‑world outcome of universal screening for Lynch syndrome in Japanese patients with colorectal cancer highlights the importance of targeting patients with young‑onset disease

Molecular and Clinical Oncology ◽

10.3892/mco.2021.2409 ◽

2021 ◽

Vol 15 (6) ◽

Author(s):

Atsushi Yamada ◽

Yui Matsuoka ◽

Sachiko Minamiguchi ◽

Yoshihiro Yamamoto ◽

Tomohiro Kondo ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Real World ◽

Universal Screening ◽

Japanese Patients ◽

Young Onset

Download Full-text

A Single Institution Experience in Compliance with Universal Screening for Lynch Syndrome in Colorectal Cancer

Journal of Gastrointestinal Surgery ◽

10.1007/s11605-014-2687-x ◽

2014 ◽

Vol 19 (3) ◽

pp. 543-550 ◽

Cited By ~ 14

Author(s):

Amy L. Hill ◽

Kirandeep K. Sumra ◽

Marcia M. Russell ◽

James Yoo ◽

Clifford Y. Ko ◽

...

Keyword(s):

Colorectal Cancer ◽

Lynch Syndrome ◽

Universal Screening ◽

Single Institution

Download Full-text

Swiss cost-effectiveness analysis of universal screening for Lynch syndrome of patients with colorectal cancer followed by cascade genetic testing of relatives

Journal of Medical Genetics ◽

10.1136/jmedgenet-2021-108062 ◽

2021 ◽

pp. jmedgenet-2021-108062

Author(s):

Islam Salikhanov ◽

Karl Heinimann ◽

Pierre Chappuis ◽

Nicole Buerki ◽

Rossella Graffeo ◽

...

Keyword(s):

Colorectal Cancer ◽

Genetic Testing ◽

Cost Effectiveness ◽

Lynch Syndrome ◽

Universal Screening ◽

Cost Effective ◽

Dna Testing ◽

Cost Effectiveness Ratio ◽

Current Strategy ◽

The Cost

BackgroundWe estimated the cost-effectiveness of universal DNA screening for Lynch syndrome (LS) among newly diagnosed patients with colorectal cancer (CRC) followed by cascade screening of relatives from the Swiss healthcare system perspective.MethodsWe integrated decision trees with Markov models to calculate incremental cost per quality-adjusted life-year saved by screening all patients with CRC (alternative strategy) compared with CRC tumour-based testing followed by DNA sequencing (current strategy).ResultsThe alternative strategy has an incremental cost-effectiveness ratio of CHF65 058 compared with the current strategy, which is cost-effective according to Swiss standards. Based on annual incidence of CRC in Switzerland, universal DNA screening correctly identifies all 123 patients with CRC with LS, prevents 17 LS deaths and avoids 19 CRC cases, while the current strategy leads to 32 false negative results and 253 LS cases lost to follow-up. One way and probabilistic sensitivity analyses showed that universal DNA testing is cost-effective in around 80% of scenarios, and that the cost of DNA testing and the number of invited relatives per LS case determine the cost-effectiveness ratio.ConclusionResults can inform policymakers, healthcare providers and insurance companies about the costs and benefits associated with universal screening for LS and cascade genetic testing of relatives.

Download Full-text

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

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4807 ◽

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

Download Full-text