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.

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.

BRAF-V600E and microsatellite instability prediction through CA-19-9/CEA ratio in patients with colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15065-e15065
Author(s):  
Pashtoon Murtaza Kasi ◽  
Saivaishnavi Kamatham ◽  
Dorin Colibaseanu ◽  
Faisal Shahjehan ◽  
Amit Merchea
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Tumor Markers ◽  
Treatment Options ◽  
Braf V600e ◽  
P Value ◽  
Repair Deficiency ◽  
Compare And Contrast ◽  
Braf Mutant ◽  
Antigen Tumor

e15065 Background: Colorectal cancer (CRC) is a heterogeneous disease. Specifically for patients with BRAF-V600E mutations and/or mismatch repair deficiency or microsatellite instability-high (dMMR/MSI-High), there have been significant advances in terms of treatment options. Early identification of these subsets of patients has both prognostic and predictive value. We wanted to highlight an observation of utilizing 2 simple, rapid and universally available lab tests i.e. carbohydrate cancer antigen 19-9 and carcinoembryonic antigen tumor markers, the ratio (CA-19-9/CEA) of which can distinctly identify these patients. Methods: We included and analyzed the ratio of CA-19-9/CEA levels in patients with metastatic CRC at Mayo Clinic from December 2016 to February 2019, where both the results were available. Non-parametric tests were done to compare and contrast the differences in the median ratio and tumor marker levels. Results: BRAF-V600E mutant CRC patients had a discordantly profound elevation in CA-19-9 levels as opposed to the CEA levels. The median CA-19-9/CEA ratio was 20 (range: 0.3-167.3) in BRAF-V600E MSS patients as opposed to 4.40 (range: 0.003-216.2) in all other patients, p-value of 0.007 (Table). Similarly, the mean CA-19-9/CEA ratio for BRAF V600E MSS tumors was 57.15 (S.D.± 62.76) versus 10.5 (S.D.± 33.90) for all other types. Furthermore, this discordant elevation is not seen in BRAF-mutant MSI-High or any MSI-High patients (median CA-19-9/CEA ratio - 0.46). Conclusions: To date, this is the first report utilizing the ratio of tumor markers CA-19-9/CEA as predictive rather than just prognostic markers. It clearly identifies BRAF-V600E MSS and the MSI-High CRC patients from other subsets.[Table: see text]

scholarly journals Distinct BRAF (V600E) and KRAS Mutations in High Microsatellite Instability Sporadic Colorectal Cancer in African Americans

2009 ◽  
Vol 15 (4) ◽  
pp. 1155-1161 ◽  
Author(s):  
Krishan Kumar ◽  
Hassan Brim ◽  
Francis Giardiello ◽  
Duane T. Smoot ◽  
Mehdi Nouraie ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
African Americans ◽  
Microsatellite Instability ◽  
Braf V600e ◽  
Sporadic Colorectal Cancer ◽  
Kras Mutations

Su1080 Limited Diagnostic Value of Microsatellite Instability Associated Pathology Features in Colorectal Cancer

2013 ◽  
Vol 144 (5) ◽  
pp. S-394
Author(s):  
Paul G. van Putten ◽  
Margot G. van Lier ◽  
M. Hage ◽  
Katharina Biermann ◽  
R. van Rijssel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Diagnostic Value

scholarly journals Methylation in p14ARF is Frequently Observed in Colorectal Cancer with Low-level Microsatellite Instability

2009 ◽  
Vol 37 (4) ◽  
pp. 1038-1045 ◽  
Author(s):  
K Kominami ◽  
T Nagasaka ◽  
HM Cullings ◽  
N Hoshizima ◽  
H Sasamoto ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Gene Promoters ◽  
Braf Mutations ◽  
Low Level ◽  
Methylguanine Dna Methyltransferase ◽  
High Level

Colorectal cancer (CRC) can be classified as high-level microsatellite instability (MSI-H), low-level MSI (MSI-L) and microsatellite stable (MSS) depending on levels of MSI. MSI-H CRC relies on a distinct molecular pathway due to the mismatch repair (MMR) deficiency and shows methylation in multiple gene promoters. The genetic pathway leading to MSI-L is unknown, although higher levels of promoter methylation are observed in this group compared with MSS CRCs. This study explored how promoter methylation affects MSI phenotype, by analysing the methylation status of eight CRC-related promoters, MSI phenotype and KRAS/BRAF mutations in a series of 234 CRCs. Promoter methylation of p14ARF was significantly related to MSI-L CRC with KRAS mutation. The MSI-H phenotype was related to methylation of MLH1 as expected, while the MSS phenotype was related to methylation of p16INK4a and O6-methylguanine-DNA methyltransferase, although this was not statistically significant. Thus, promoter methylation of p14ARF could be a significant alteration leading to CRC with MSI-L.

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.

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