Colorectal cancer molecular classification using BRAF, KRAS, microsatellite instability and CIMP status: Prognostic implications and response to chemotherapy

668 Background: The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype’s response to chemotherapy. Methods: This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). Results: Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P < 0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P < 0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005). Conclusions: We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.

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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)

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.4118 ◽

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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Toward a Molecular Classification of Colorectal Cancer: The Role of Microsatellite Instability Status

Frontiers in Oncology ◽

10.3389/fonc.2013.00272 ◽

2013 ◽

Vol 3 ◽

Cited By ~ 19

Author(s):

Karl Heinimann

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Molecular Classification

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Adverse Prognostic Effect of Methylation in Colorectal Cancer Is Reversed by Microsatellite Instability

Journal of Clinical Oncology ◽

10.1200/jco.2003.03.123 ◽

2003 ◽

Vol 21 (20) ◽

pp. 3729-3736 ◽

Cited By ~ 147

Author(s):

Robyn Lynne Ward ◽

Kay Cheong ◽

Su-Lyn Ku ◽

Alan Meagher ◽

Terence O’Connor ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Methylation ◽

Microsatellite Instability ◽

Univariate Analysis ◽

Prognostic Significance ◽

Curative Surgery ◽

Fresh Tissue ◽

Vascular Space ◽

Response To Chemotherapy ◽

Vascular Space Invasion

Purpose: DNA methylation is an important biologic event in colorectal cancer and in some cases is associated with the development of microsatellite instability (MSI). In this study, we sought to determine the prognostic significance of DNA methylation, both in univariate analysis and in concert with other clinicopathologic factors known to influence outcome. Patients and Methods: Fresh tissue (625 cancers) was obtained from 605 individuals (age range, 29 to 99 years) undergoing curative surgery for colorectal cancer at one institution during a period of 8 years. Clinicopathologic details were recorded for all tumors, including stage, grade, type, vascular space invasion, and clinical follow-up to 5 years. Microsatellite status was assessed using standard markers. Methylation of p16 and hMLH1 promoters was determined by methylation-specific polymerase chain reaction (PCR), whereas methylation at methylated-in-tumor loci (MINT)1, MINT2, MINT12, and MINT31 loci were assessed by bisulfite-PCR. Results: Patients with microsatellite unstable tumors (12%) had better disease-specific survival than those with microsatellite stable (MSS) tumors (univariate analysis: hazard ratio [HR], 0.53; 95% CI, 0.27 to 1.0). Overall survival of individuals with MSS tumors was influenced by three independently significant factors: tumor stage (HR, 7.3; 95% CI, 5.1 to 10.4), heavy tumor methylation (HR, 2.1; 95% CI, 1.1 to 4.0), and vascular space invasion (HR, 1.9; 95% CI, 1.3 to 2.9). In MSS tumors, methylation at any single site was not independently predictive of survival. Neither methylation nor microsatellite status predicted a favorable response to chemotherapy. Conclusion: DNA methylation is associated with a worse outcome in colorectal cancer, but this adverse prognostic influence is lost in those methylated tumors showing MSI. The mechanisms of these events warrant additional investigation.

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Microsatellite instability in metastatic colorectal cancer: a review of pathology, response to chemotherapy and clinical outcome

Medical Oncology ◽

10.1007/s12032-011-0050-6 ◽

2011 ◽

Vol 29 (3) ◽

pp. 1796-1801 ◽

Cited By ~ 13

Author(s):

Kein-Leong Yim

Keyword(s):

Colorectal Cancer ◽

Clinical Outcome ◽

Microsatellite Instability ◽

Metastatic Colorectal Cancer ◽

Response To Chemotherapy

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Clinical implications of microsatellite instability in mucinous colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.657 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 657-657

Author(s):

Fergus Keane ◽

Darrell Martin ◽

Gregory D. Leonard ◽

Sean Hynes ◽

Margaret Sheehan

Keyword(s):

Colorectal Cancer ◽

Microsatellite Instability ◽

Who Classification ◽

Prognostic Significance ◽

Stage Ii ◽

Stage Iii ◽

Low Grade ◽

Tumor Type ◽

Response To Chemotherapy ◽

Microsatellite Stability

657 Background: Colorectal Cancer(CRC) is becoming increasingly recognised as a heterogeneous tumor type. Mucinous histological subtype is identified in 10-15% of CRCs, most commonly those with microsatellite instability (MSI), and has traditionally been associated with unfavorable outcomes and poor response to chemotherapy. In contrast, MSI is associated with relatively favourable pathological features and better outcomes, compared with CRCs with microsatellite stability (MSS), such that under the 2010 WHO classification, MSI mucinous CRC is considered low grade, while MSS mucinous CRC is classified as high grade. The aim of this study is to establish the significance of microsatellite stability status in non-metastatic mucinous colorectal cancer. Methods: Between 2010 and 2017, 69 patients with stage II or stage III mucinous colorectal cancer were identified. Microsatellite status was tested in all patients (MSS or MSI), and histological and clinical data, as well as recurrence rates, were assessed in both groups. MSI status was established using polymerase chain reaction(PCR) technique. Results: Sixty-nine patients with mucinous CRC were identified. The median age for the entire group was 73 years (range 32-87), no difference in gender was identified. 63%(n=43) and 37%(n=26) were stage II and stage III respectively at diagnosis. The majority of mucinous CRCs were right-sided (72%). 33% (n=23) were identified as microsatellite unstable (MSI). MSI status was associated with right sided tumours (78% right-sided vs 22% left-sided, p<0.05), older age at diagnosis (mean 76 years vs 68 years, p=0.01), and lower TNM staging at diagnosis (83% vs 52% diagnosed stage 2, p=0.007) compared with the MSS group. A lower disease recurrence rate was identified in the MSI group (4.3% vs 13% in MSS group) at median follow-up time of 33 months (range 8-93 months). Conclusions: In patients with mucinous colorectal cancer, MSI status is a useful marker of favourable histological and clinical features, and is associated with better outcomes. Our study supports the current 2010 WHO classification, and highlights the clinical and prognostic significance of MSI status in this patient cohort.

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Serrated colorectal cancer: Molecular classification, prognosis, and response to chemotherapy

World Journal of Gastroenterology ◽

10.3748/wjg.v22.i13.3516 ◽

2016 ◽

Vol 22 (13) ◽

pp. 3516 ◽

Cited By ~ 21

Author(s):

Oscar Murcia ◽

Miriam Juárez ◽

Eva Hernández-Illán ◽

Cecilia Egoavil ◽

Mar Giner-Calabuig ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Classification ◽

Response To Chemotherapy

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TUMOUR PATHOLOGY PREDICTS MICROSATELLITE INSTABILITY IN A POPULATION-BASED SERIES OF COLORECTAL CANCER CASES

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4807 ◽

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

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