Lynch Syndrome In Colorectal Cancer Patients Research Articles

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

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.

Molecular testing for Lynch syndrome in people with colorectal cancer: systematic reviews and economic evaluation.

Inherited mutations in deoxyribonucleic acid (DNA) mismatch repair (MMR) genes lead to an increased risk of colorectal cancer (CRC), gynaecological cancers and other cancers, known as Lynch syndrome (LS). Risk-reducing interventions can be offered to individuals with known LS-causing mutations. The mutations can be identified by comprehensive testing of the MMR genes, but this would be prohibitively expensive in the general population. Tumour-based tests - microsatellite instability (MSI) and MMR immunohistochemistry (IHC) - are used in CRC patients to identify individuals at high risk of LS for genetic testing. MLH1 (MutL homologue 1) promoter methylation and BRAF V600E testing can be conducted on tumour material to rule out certain sporadic cancers. To investigate whether testing for LS in CRC patients using MSI or IHC (with or without MLH1 promoter methylation testing and BRAF V600E testing) is clinically effective (in terms of identifying Lynch syndrome and improving outcomes for patients) and represents a cost-effective use of NHS resources. Systematic reviews were conducted of the published literature on diagnostic test accuracy studies of MSI and/or IHC testing for LS, end-to-end studies of screening for LS in CRC patients and economic evaluations of screening for LS in CRC patients. A model-based economic evaluation was conducted to extrapolate long-term outcomes from the results of the diagnostic test accuracy review. The model was extended from a model previously developed by the authors. Ten studies were identified that evaluated the diagnostic test accuracy of MSI and/or IHC testing for identifying LS in CRC patients. For MSI testing, sensitivity ranged from 66.7% to 100.0% and specificity ranged from 61.1% to 92.5%. For IHC, sensitivity ranged from 80.8% to 100.0% and specificity ranged from 80.5% to 91.9%. When tumours showing low levels of MSI were treated as a positive result, the sensitivity of MSI testing increased but specificity fell. No end-to-end studies of screening for LS in CRC patients were identified. Nine economic evaluations of screening for LS in CRC were identified. None of the included studies fully matched the decision problem and hence a new economic evaluation was required. The base-case results in the economic evaluation suggest that screening for LS in CRC patients using IHC, BRAF V600E and MLH1 promoter methylation testing would be cost-effective at a threshold of £20,000 per quality-adjusted life-year (QALY). The incremental cost-effectiveness ratio for this strategy was £11,008 per QALY compared with no screening. Screening without tumour tests is not predicted to be cost-effective. Most of the diagnostic test accuracy studies identified were rated as having a risk of bias or were conducted in unrepresentative samples. There was no direct evidence that screening improves long-term outcomes. No probabilistic sensitivity analysis was conducted. Systematic review evidence suggests that MSI- and IHC-based testing can be used to identify LS in CRC patients, although there was heterogeneity in the methods used in the studies identified and the results of the studies. There was no high-quality empirical evidence that screening improves long-term outcomes and so an evidence linkage approach using modelling was necessary. Key determinants of whether or not screening is cost-effective are the accuracy of tumour-based tests, CRC risk without surveillance, the number of relatives identified for cascade testing, colonoscopic surveillance effectiveness and the acceptance of genetic testing. Future work should investigate screening for more causes of hereditary CRC and screening for LS in endometrial cancer patients. This study is registered as PROSPERO CRD42016033879. The National Institute for Health Research Health Technology Assessment programme.

Yield of routine molecular analyses in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome

Although early detection of Lynch syndrome (LS) is important, a considerable proportion of patients with LS remains unrecognized. We aimed to study the yield of LS detection by routine molecular analyses in colorectal cancer (CRC) patients until 70 years of age. We prospectively included consecutive CRC patients ≤70 years. Tumour specimens were analysed for microsatellite instability (MSI), immunohistochemical mismatch-repair protein expression and MLH1-promoter methylation. Tumours were classified as either: (a) likely caused by LS; (b) sporadic microsatellite-unstable (MSI-H); or (c) microsatellite-stable (MSS). Predictors of LS were determined by multivariable logistic regression. A total of 1117 CRC patients (57% males, median age 61 years) were included. Fifty patients (4.5%, 95% CI 3.4-5.9) were likely to have LS, and 71 had a sporadic MSI-H tumour (6.4%, 95% CI 5.1-8.0). Thirty-five patients likely to have LS (70%) were aged > 50 years. A molecular profile compatible with LS was detected in 10% (15/144) of patients aged ≤50, in 4% (15/377) of those aged 51-60 and in 3% (20/596) of patients > 61 years. Compared to MSS cases, patients likely to have LS were significantly younger (OR 3.9, 95% CI 1.7-8.7) and more often had right-sided CRCs (OR 14, 95% CI 6.0-34). In conclusion, molecular screening for LS in CRC patients ≤70 years leads to identification of a molecular profile compatible with LS in 4.5% of patients, with most of them not fulfilling the age criterion (≤50 years) routinely used for LS assessment. Routine use of MSI testing may be considered in CRC patients up to the age of 70 years, with a central role for the pathologist in the selection of patients.