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

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.

Prevalence of somatic mutl homolog 1 promoter hypermethylation in Lynch syndrome colorectal cancer

Cancer ◽  
2014 ◽  
Vol 121 (9) ◽  
pp. 1395-1404 ◽  
Author(s):  
Leticia Moreira ◽  
Jenifer Muñoz ◽  
Míriam Cuatrecasas ◽  
Isabel Quintanilla ◽  
Maria Liz Leoz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lynch Syndrome ◽  
Promoter Hypermethylation ◽  
Mutl Homolog 1

scholarly journals Associations of dietary methyl donor intake with MLH1 promoter hypermethylation and related molecular phenotypes in sporadic colorectal cancer

2008 ◽  
Vol 29 (9) ◽  
pp. 1765-1773 ◽  
Author(s):  
S. de Vogel ◽  
B. W.C. Bongaerts ◽  
K. A.D. Wouters ◽  
A. D.M. Kester ◽  
L. J. Schouten ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Promoter Hypermethylation ◽  
Sporadic Colorectal Cancer ◽  
Methyl Donor ◽  
Mlh1 Promoter ◽  
Molecular Phenotypes

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

Molecular biology from bench-to-bedside: Which colorectal cancer patients to refer for genetic counseling

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4113-4113
Author(s):  
L. H. Jensen ◽  
L. Dysager ◽  
J. Lindebjerg ◽  
S. Kølvraa ◽  
L. Byriel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Family History ◽  
Lynch Syndrome ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Wild Type ◽  
Mlh1 Promoter ◽  
Dna Quality ◽  
Colorectal Cancer Patients

4113 Background: The single most common cause of hereditary colorectal cancer is the Lynch syndrome, which is associated with deficiency of the mismatch repair genes MLH1, MSH2, or MSH6. Most MLH1 negative tumors are sporadic in origin, and they can be identified if harbouring a BRAF V600E mutation or hypermethylation of the MLH1 promoter. If Lynch syndrome is detected in a patient and its family, screening can prevent death from new colorectal cancer. A family history should always be obtained, but in small families or patients with de-novo mutations and mutations with late or low penetrance, this is not sufficient. The aim of this study was to validate our previously suggested clinically applicable strategy based on molecular characteristics for identifying which patients to refer for genetic counselling. Methods: The strategy was validated in an unselected cohort of 287 colorectal cancer patients. All tumors was tested for MLH1, MSH2, and MSH6 with immunohistochemistry. DNA from MLH1 negative tumors was sequenced for BRAF mutations. If wild-type, MLH1 promoter was analyzed with methylation specific multiplex ligation-dependent probe amplification (MLPA). MLH1 negative tumors were considered sporadic if BRAF V600E mutation or MLH1 promoter hypermethylation was found. A follow up was done on patients with MSH2 or MSH6 negative tumors and MLH1 negative cases not shown to be sporadic. Results: Most tumors, 251 (88%), stained positive for all three proteins. Six (2%) had negative MSH2 and one (<1%) isolated loss of MSH6. MLH1 was negative in 29 cases (10%). DNA quality allowed BRAF analysis in 27 of these with 14 mutations and 13 wild-type. DNA quality allowed MLPA in four of the 13 BRAF wild-type, and all four were methylated. Subsequently, Lynch syndrome could not be ruled out in 18 patients. A follow-up at 8–10 years revealed four definite Lynch syndrome and four highly suspicious. Conclusions: An easy and clinically applicable step-wise approach with immunohistochemistry (100%), BRAF sequencing (10%), and methylation analysis (5%) identified several patients with hereditary cancer. The family history should be supplemented with a molecular screening for whom to send for genetic counselling. No significant financial relationships to disclose.

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.

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.

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