scholarly journals Feasibility of Screening for Lynch Syndrome Among Patients With Colorectal Cancer

2008 ◽  
Vol 26 (35) ◽  
pp. 5783-5788 ◽  
Author(s):  
Heather Hampel ◽  
Wendy L. Frankel ◽  
Edward Martin ◽  
Mark Arnold ◽  
Karamjit Khanduja ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Cancer Surveillance ◽  
Study Cohort ◽  
Entire Study ◽  
Gene Testing ◽  
Revised Bethesda Guidelines ◽  
Repair Genes ◽  
Entire Study Cohort

Purpose Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups. Patients and Methods MSI testing and IHC for the four mismatch repair proteins was performed on 500 tumors from unselected patients with CRC. If either MSI or IHC was abnormal, complete mutation analysis for the mismatch repair genes was performed. Results Among the 500 patients, 18 patients (3.6%) had LS. All 18 patients detected with LS (100%) had MSI-high tumors; 17 (94%) of 18 patients with LS were correctly predicted by IHC. Of the 18 probands, only eight patients (44%) were diagnosed at age younger than 50 years, and only 13 patients (72%) met the revised Bethesda guidelines. When these results were added to data on 1,066 previously studied patients, the entire study cohort (N = 1,566) showed an overall prevalence of 44 of 1,566 patients (2.8%; 95% CI, 2.1% to 3.8%) for LS. For each proband, on average, three additional family members carried MMR mutations. Conclusion One of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance. For screening, IHC is almost equally sensitive as MSI, but IHC is more readily available and helps to direct gene testing. Limiting tumor analysis to patients who fulfill Bethesda criteria would fail to identify 28% (or one in four) cases of LS.

Mismatch Repair Genes and EPCAM germline mutations in patients with gastric or colorectal cancer with suspected of Lynch syndrome.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e13623-e13623 ◽  
Author(s):  
Nora Manoukian Forones ◽  
Fernanda Tereza Lima ◽  
Renan Paulo Martin ◽  
Leonardo Martins ◽  
Patricia Valera Lima Teixeira ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Germline Mutations ◽  
Mismatch Repair Genes ◽  
Repair Genes

scholarly journals Mismatch repair genes in Lynch syndrome: a review

2009 ◽  
Vol 127 (1) ◽  
pp. 46-51 ◽  
Author(s):  
Felipe Cavalcanti Carneiro da Silva ◽  
Mev Dominguez Valentin ◽  
Fábio de Oliveira Ferreira ◽  
Dirce Maria Carraro ◽  
Benedito Mauro Rossi
Keyword(s):  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Cancer Surveillance ◽  
Mismatch Repair Gene ◽  
Mismatch Repair Genes ◽  
Repair Gene ◽  
Dna Mismatch ◽  
Postmeiotic Segregation ◽  
Repair Genes

Lynch syndrome represents 1-7% of all cases of colorectal cancer and is an autosomal-dominant inherited cancer predisposition syndrome caused by germline mutations in deoxyribonucleic acid (DNA) mismatch repair genes. Since the discovery of the major human genes with DNA mismatch repair function, mutations in five of them have been correlated with susceptibility to Lynch syndrome: mutS homolog 2 (MSH2); mutL homolog 1 (MLH1); mutS homolog 6 (MSH6); postmeiotic segregation increased 2 (PMS2); and postmeiotic segregation increased 1 (PMS1). It has been proposed that one additional mismatch repair gene, mutL homolog 3 (MLH3), also plays a role in Lynch syndrome predisposition, but the clinical significance of mutations in this gene is less clear. According to the InSiGHT database (International Society for Gastrointestinal Hereditary Tumors), approximately 500 different LS-associated mismatch repair gene mutations are known, primarily involving MLH1 (50%) and MSH2 (40%), while others account for 10%. Much progress has been made in understanding the molecular basis of Lynch Syndrome. Molecular characterization will be the most accurate way of defining Lynch syndrome and will provide predictive information of greater accuracy regarding the risks of colon and extracolonic cancer and enable optimal cancer surveillance regimens.

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

When to Consider Lynch Syndrome in Non-Colon and Non-Endometrial Malignancies

2021 ◽  
pp. 000313482110318
Author(s):  
Aaron J. Arroyave ◽  
Alan W. Good ◽  
Andrew J. Ward ◽  
Amila L. Orucevic ◽  
James M. McLoughlin
Keyword(s):  
Lynch Syndrome ◽  
Review Article ◽  
Genetic Syndrome ◽  
Clinical Criteria ◽  
Dna Mismatch ◽  
Dna Mismatch Repair Genes ◽  
Associated Malignancy ◽  
Revised Bethesda Guidelines ◽  
Current Guidelines ◽  
Repair Genes

Lynch syndrome (LS) is a common genetic syndrome characterized by pathogenic mutations of DNA mismatch repair genes resulting in a hereditary predisposition to cancer. While typically associated with colonic and endometrial cancer, LS additionally influences the development of many other malignancies. The Amsterdam II and Revised Bethesda Guidelines are the established clinical criteria for diagnosing LS. These guidelines are based on the most general characteristics of LS and do not address specific characteristics of the less commonly LS-associated malignancies. For individuals that present initially with a non-colon and non-endometrial malignancy, recommendations and guidelines on when to consider screening for LS are limited. Therefore, it is essential that clinicians are familiar with distinct LS-associated patient- and tumor-specific characteristics, especially of the less common LS-associated cancers, so that LS’s diagnosis is not missed. In this review article, we focus on extra-colonic and extra-endometrial LS-associated cancers, paying particular attention to any established or currently investigated cancer features that help raise suspicion for LS and potentially lead to its earlier diagnosis. This review will also discuss current guidelines specific to each LS-associated malignancy.

scholarly journals Cancer risk and overall survival in mismatch repair proficient hereditary non-polyposis colorectal cancer, Lynch syndrome and sporadic colorectal cancer

2013 ◽  
Vol 13 (1) ◽  
pp. 109-119 ◽  
Author(s):  
Pilar Garre ◽  
Lorena Martín ◽  
Inmaculada Bando ◽  
Alicia Tosar ◽  
Patricia Llovet ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cancer Risk ◽  
Lynch Syndrome ◽  
Mismatch Repair ◽  
Sporadic Colorectal Cancer

Abstract 11159: Prolonged QRS Duration Predicts Outcomes in Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jacob Joseph ◽  
Brian L Claggett ◽  
Inder S Anand ◽  
Jerome L Fleg ◽  
Thao Huynh ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Primary Outcome ◽  
Statistical Significance ◽  
Study Cohort ◽  
Preserved Ejection Fraction ◽  
Entire Study ◽  
Increased Risk ◽  
Qrs Duration ◽  
Entire Study Cohort

Introduction: QRS widening on the surface electrocardiogram (ECG) is a marker of disease progression in heart failure (HF) with reduced ejection fraction. We hypothesized that prolonged QRS duration would similarly identify patients with HF with preserved ejection fraction (HFPEF) at high risk for cardiovascular (CV) events. Methods: We examined the relationship of baseline QRS duration to primary outcome [composite of CV death, aborted cardiac arrest, or HF hospitalization (HFH)] and HFH alone in TOPCAT, a multicenter, randomized, placebo-controlled trial of spironolactone in HFPEF. QRS duration was analyzed as a dichotomous variable (≥ 120 ms or < 120 ms). Multivariable analyses were conducted including variables that were significantly associated with QRS duration ≥ 120 ms (Table 1). Analyses were conducted in the entire study cohort as well as in separate analyses for only subjects enrolled from the Americas or from Russia/Georgia independently. Results: QRS duration was known in 3426 of 3445 TOPCAT patients. Compared to those with QRS duration < 120ms, 613 (17.9%) subjects had a QRS duration ≥ 120 ms and were older (72.9 years vs. 67.8 years; p < 0.0001) and more likely to be men (62% vs. 45%; p<0.0001). A QRS duration ≥ 120 ms was independently associated with an increased risk of primary outcome and HFH in the entire study cohort and in the subset of patients enrolled in the Americas but was of borderline statistical significance in Russia/Georgia (Table 1). No statistical interaction was observed between treatment with spironolactone and QRS duration (p value for interaction= 0.33). Conclusions: QRS duration identifies HFPEF subjects at a higher risk of adverse clinical outcomes; spironolactone had a similar effect on outcomes independent of QRS duration. This easily obtainable marker may be an important component of risk stratification in this syndrome.

Sign in / Sign up

Export Citation Format

Share Document