scholarly journals Microsatellite instability and MLH1 promoter hypermethylation in colorectal cancer

2007 ◽  
Vol 13 (12) ◽  
pp. 1867 ◽  
Author(s):  
Yaron Niv
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Promoter Hypermethylation ◽  
Mlh1 Promoter

Use of microsatellite instability in non-hereditary advanced colorectal cancer to predict response to chemotherapy and overall survival: A study of the Dutch Colorectal Cancer Group (DCCG)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4118-4118
Author(s):  
M. Koopman ◽  
G. A. Kortman ◽  
L. Mekenkamp ◽  
M. J. Ligtenberg ◽  
N. Hoogerbrugge ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Microsatellite Instability ◽  
Early Stage ◽  
Tissue Microarrays ◽  
Primary Tumors ◽  
Mlh1 Promoter ◽  
Cancer Group ◽  
Response To Chemotherapy ◽  
Embedded Blocks

4118 Background: Microsatellite instability (MSI) is present in 10–20% of patients (pts) with non-hereditary colorectal cancer (CRC) and is generally associated with improved overall survival. The effect of chemotherapy in such pts is uncertain, and most data are derived from early stage CRC. Therefore the outcome of treatment in relation to presence or absence of MSI was studied in pts with non- hereditary advanced CRC. Methods: Data were collected from previously untreated advanced CRC pts randomized between 1st line capecitabine (Cap), 2nd line irinotecan (Iri), and 3rd line Cap + oxaliplatin (CapOx) vs 1st line CapIri and 2nd line CapOx. Formalin-fixed, paraffin embedded blocks of primary tumors and normal tissue were collected and tissue microarrays were made. Expression of the mismatch repair proteins MLH1, MSH2, MSH6 and PMS2 was examined by immunohistochemistry. Additionally MSI analysis and hypermethylation of the MLH1-promoter were performed. Pts with a tumor showing MSI caused by hypermethylation of the MLH1-promoter were included to study the correlation between MSI status and response to 1st line treatment and overall survival. Results: MSI caused by hypermethylation of the MLH1-promoter was found in 14 (3%) of 512 eligible pts. In 461 evaluable pts, disease control (CR+PR+SD=4 months) in 12 pts with MSI was 58% [95% CI 28%- 85%] and in 449 without MSI 83% [95% CI 79%-86%, p= 0.03].The median OS in pts with MSI was 7 months [95% CI 4–17] and in pts without MSI 18 months [95% CI 16–19, log rank p=0.08]. Conclusions: MSI in advanced non-hereditary CRC is very rare, and predicts a significantly worse outcome in terms of response to chemotherapy with a trend towards a decreased OS. No significant financial relationships to disclose.

Microsatellite instability and promoter hypermethylation in colorectal cancer in India

Tumor Biology ◽  
2014 ◽  
Vol 35 (5) ◽  
pp. 4347-4355 ◽  
Author(s):  
V. V. Ravi Kanth ◽  
Sandeep Bhalsing ◽  
M. Sasikala ◽  
G. V. Rao ◽  
R. Pradeep ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Promoter Hypermethylation

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

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.

Low Microsatellite Instability Is Associated With Poor Prognosis in Stage C Colon Cancer

2005 ◽  
Vol 23 (10) ◽  
pp. 2318-2324 ◽  
Author(s):  
Maija R.J. Kohonen-Corish ◽  
Joseph J. Daniel ◽  
Charles Chan ◽  
Betty P.C. Lin ◽  
Sun Young Kwun ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Protein Expression ◽  
Microsatellite Instability ◽  
Dna Methyltransferase ◽  
Prognostic Significance ◽  
Promoter Hypermethylation ◽  
Prognostic Indicator ◽  
Study Cohort ◽  
Distinct Subgroup

Purpose The significance of low microsatellite instability (MSI-L) in colorectal cancer is poorly understood. No clear biologic distinction has been found between MSI-L and microsatellite stable (MSS) colorectal cancer, and these two phenotypes are usually combined when analyzed against the well-defined high MSI (MSI-H) phenotype. Evidence is emerging that an O6-methylguanine DNA methyltransferase (MGMT) gene defect is associated with MSI-L. Therefore, to further define this phenotype, we undertook a detailed analysis of the prognostic significance of MSI-L and loss of MGMT expression in colon cancer. Patients and Methods The study cohort was 183 patients with clinicopathologic stage C colon cancer who had not received adjuvant therapy. We analyzed MSI status, MGMT, and mismatch repair protein expression, as well as MGMT and p16 promoter hypermethylation. Results We showed that MSI-L defines a group of patients with poorer survival (P = .026) than MSS patients, and that MSI-L was an independent prognostic indicator (P = .005) in stage C colon cancer. Loss of MGMT protein expression was associated with the MSI-L phenotype but was not a prognostic factor for overall survival in colon cancer. p16 methylation was significantly less frequent in MSI-L than in MSI-H and MSS tumors and was not associated with survival. Conclusion MSI-L characterizes a distinct subgroup of stage C colon cancer patients, including the MSI-L subset of proximal colon cancer, who have a poorer outcome. Neither the MGMT defect nor p16 methylation are likely to contribute to the worse prognosis of the MSI-L phenotype.

Improved Microsatellite Instability detection in colorectal cancer patients by a combination of fourteen markers especially DNMT3a, DCD, and MT1X

2021 ◽  
pp. 1-13
Author(s):  
Ali Khaligh ◽  
Mohammad Sadegh Fazeli ◽  
Habibollah Mahmoodzadeh ◽  
Amirhosein Mehrtash ◽  
Setareh Kompanian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Promoter Methylation ◽  
Detection Rate ◽  
Diagnostic Value ◽  
Braf V600e ◽  
Melting Curve Analysis ◽  
P Value ◽  
Marker Panel ◽  
Mlh1 Promoter

BACKGROUND: Microsatellite instability (MSI) results from genetic and epigenetic changes. Studying Microsatellite instability can help in treatment and categorization of colorectal cancer (CRC) patients. OBJECTIVES: We aimed to investigate whether 14 genomic markers consisting of BAT-62, BAT-60, BAT-59a, BAT-56a, BAT-56b, DCD, RIOX, RNF, FOXP, ACVR, CASP2, HSP110, MT1X, and DNMT3a can increase the detection rate of MSI in CRC. METHODS: Samples were stratified by pentaplex panel (Promega) and 14 markers using multiplex PCR and fragment analysis. In MSI+ samples, to identify the pattern of BRAF V600E mutation and MLH1 promoter methylation, ARMS-scorpion, and Methylation-Specific High-Resolution Melting Curve analysis, were applied respectively. RESULTS: Totally, 35 MSI+ cases identified by 14 marker panel. Only 18 cases of them were detected by both panels which are pentaplex and 14 marker. On the other hand, 17 new MSI+ cases just were identified by 14 markers panel. The highest diagnostic value among 14 markers is related to three makers, namely DCD, MT1X, and DNMT3a. In MSI+ cases, the rate of MLH1 promoter methylation was insignificant, (P value = 0.3979) while the rate of observed BRAFV600E mutation was significantly higher (P value = 0.0002). CONCLUSION: Fourteen marker panel showed higher sensitivity in comparison with the pentaplex panel increasing the detection rate of MSI+ cases up to 1.94 fold. Three markers namely DNMT3a, DCD, and MT1X of 14 marker panel were the best among them showing excellent diagnostic value. A combination of these markers showed 100% sensitivity and specificity in the studied group. In contrary to the markers in the pentaplex panel, these markers had the ability to detect MSI without any bias for the clinicopathological features. These markers will help to identify more end-stage MSI+ tumors which are located distal colon.

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

Evaluation of microsatellite instability, hMLH1 expression and hMLH1 promoter hypermethylation in defining the phenotype of colorectal cancer: a study from CALGB 9865

2003 ◽  
Vol 124 (4) ◽  
pp. A364
Author(s):  
Christian N. Arnold ◽  
Ajay Goel ◽  
Carolyn Compton ◽  
Victoria Marcus ◽  
Donna Niedzwiecki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Promoter Hypermethylation

scholarly journals Additional loss of MSH2 and MSH6 expression in sporadic deficient mismatch repair colorectal cancer due to MLH1 promoter hypermethylation

2019 ◽  
Vol 72 (6) ◽  
pp. 443-447 ◽  
Author(s):  
Alice Westwood ◽  
Amy Glover ◽  
Gordon Hutchins ◽  
Caroline Young ◽  
Scarlet Brockmoeller ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Mismatch Repair ◽  
Promoter Hypermethylation ◽  
Clinical Genetics ◽  
Patient Anxiety ◽  
Braf Mutations ◽  
Mlh1 Promoter ◽  
The Uk ◽  
Unusual Phenotype ◽  
Deficient Mismatch Repair

Colorectal cancer (CRC) is common with 3% of cases associated with germline mutations in the mismatch repair pathway characteristic of Lynch syndrome (LS). The UK National Institute for Health and Care Excellence recommends screening for LS in all patients newly diagnosed with CRC, irrespective of age. The Yorkshire Cancer Research Bowel Cancer Improvement Programme includes a regional LS screening service for all new diagnoses of CRC. In the first 829 cases screened, 80 cases showed deficient mismatch repair (dMMR) including four cases showing areas with loss of expression of all four mismatch repair proteins by immunohistochemistry. The cases demonstrated diffuse MLH1 loss associated with BRAF mutations and MLH1 promoter hypermethylation in keeping with sporadic dMMR, with presumed additional double hit mutations in MSH2+/−MSH6 rather than underlying LS. Recognition and accurate interpretation of this unusual phenotype is important to prevent unnecessary referrals to clinical genetics and associated patient anxiety.

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