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      The Homeobox Gene MEIS1 Is Methylated in BRAF p.V600E Mutated Colon Tumors

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          Abstract

          Development of colorectal cancer (CRC) can occur both via gene mutations in tumor suppressor genes and oncogenes, as well as via epigenetic changes, including DNA methylation. Site-specific methylation in CRC regulates expression of tumor-associated genes. Right-sided colon tumors more frequently have BRAF p.V600E mutations and have higher methylation grades when compared to left-sided malignancies. The aim of this study was to identify DNA methylation changes associated with BRAF p.V600E mutation status. We performed methylation profiling of colon tumor DNA, isolated from frozen sections enriched for epithelial cells by macro-dissection, and from paired healthy tissue. Single gene analyses comparing BRAF p.V600E with BRAF wild type revealed MEIS1 as the most significant differentially methylated gene (log 2 fold change: 0.89, false discovery rate-adjusted P-value 2.8*10 -9). This finding was validated by methylation-specific PCR that was concordant with the microarray data. Additionally, validation in an independent cohort ( n=228) showed a significant association between BRAF p.V600E and MEIS1 methylation (OR: 13.0, 95% CI: 5.2 - 33.0, P<0.0001). MEIS1 methylation was associated with decreased MEIS1 gene expression in both patient samples and CRC cell lines. The same was true for gene expression of a truncated form of MEIS1, MEIS1 D27 , which misses exon 8 and has a proposed tumor suppression function. To trace the origin of MEIS1 promoter methylation, 14 colorectal tumors were flow-sorted. Four out of eight BRAF p.V600E tumor epithelial fractions (50%) showed MEIS1 promoter methylation, as well as three out of eight BRAF p.V600E stromal fractions (38%). Only one out of six BRAF wild type showed MEIS1 promoter methylation in both the epithelial tumor and stromal fractions (17%). In conclusion, BRAF p.V600E colon tumors showed significant MEIS1 promoter methylation, which was associated with decreased MEIS1 gene expression.

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          Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer.

          Lanlan Shen, Minoru Toyota, Yutaka Kondo … (2007)
          Colon cancer has been viewed as the result of progressive accumulation of genetic and epigenetic abnormalities. However, this view does not fully reflect the molecular heterogeneity of the disease. We have analyzed both genetic (mutations of BRAF, KRAS, and p53 and microsatellite instability) and epigenetic alterations (DNA methylation of 27 CpG island promoter regions) in 97 primary colorectal cancer patients. Two clustering analyses on the basis of either epigenetic profiling or a combination of genetic and epigenetic profiling were performed to identify subclasses with distinct molecular signatures. Unsupervised hierarchical clustering of the DNA methylation data identified three distinct groups of colon cancers named CpG island methylator phenotype (CIMP) 1, CIMP2, and CIMP negative. Genetically, these three groups correspond to very distinct profiles. CIMP1 are characterized by MSI (80%) and BRAF mutations (53%) and rare KRAS and p53 mutations (16% and 11%, respectively). CIMP2 is associated with 92% KRAS mutations and rare MSI, BRAF, or p53 mutations (0, 4, and 31% respectively). CIMP-negative cases have a high rate of p53 mutations (71%) and lower rates of MSI (12%) or mutations of BRAF (2%) or KRAS (33%). Clustering based on both genetic and epigenetic parameters also identifies three distinct (and homogeneous) groups that largely overlap with the previous classification. The three groups are independent of age, gender, or stage, but CIMP1 and 2 are more common in proximal tumors. Together, our integrated genetic and epigenetic analysis reveals that colon cancers correspond to three molecularly distinct subclasses of disease.
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            Predictive and prognostic roles of BRAF mutation in stage III colon cancer: results from intergroup trial CALGB 89803.

            Shuji Ogino, Kaori Shima, Jeffrey A. Meyerhardt … (2012)
            Alterations in the RAS-RAF-MAP2K (MEK)-MAPK signaling pathway are major drivers in colorectal carcinogenesis. In colorectal cancer, BRAF mutation is associated with microsatellite instability (MSI), and typically predicts inferior prognosis. We examined the effect of BRAF mutation on survival and treatment efficacy in patients with stage III colon cancer. We assessed status of BRAF c.1799T>A (p.V600E) mutation and MSI in 506 stage III colon cancer patients enrolled in a randomized adjuvant chemotherapy trial [5-fluorouracil and leucovorin (FU/LV) vs. irinotecan (CPT11), FU and LV (IFL); CALGB 89803]. Cox proportional hazards model was used to assess the prognostic role of BRAF mutation, adjusting for clinical features, adjuvant chemotherapy arm, and MSI status. Compared with 431 BRAF wild-type patients, 75 BRAF-mutated patients experienced significantly worse overall survival [OS; log-rank P = 0.015; multivariate HR = 1.66; 95% CI: 1.05-2.63]. By assessing combined status of BRAF and MSI, it seemed that BRAF-mutated MSS (microsatellite stable) tumor was an unfavorable subtype, whereas BRAF wild-type MSI-high tumor was a favorable subtype, and BRAF-mutated MSI-high tumor and BRAF wild-type MSS tumor were intermediate subtypes. Among patients with BRAF-mutated tumors, a nonsignificant trend toward improved OS was observed for IFL versus FU/LV arm (multivariate HR = 0.52; 95% CI: 0.25-1.10). Among patients with BRAF wild-type cancer, IFL conferred no suggestion of benefit beyond FU/LV alone (multivariate HR = 1.02; 95% CI: 0.72-1.46). BRAF mutation is associated with inferior survival in stage III colon cancer. Additional studies are necessary to assess whether there is any predictive role of BRAF mutation for irinotecan-based therapy.
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              Morphology of sporadic colorectal cancer with DNA replication errors.

              Janet A. Young, C V A Wynter, Ellen L Simms … (1998)
              Up to 15% of colorectal cancers are characterised by DNA microsatellite instability (MIN), shown by the presence of DNA replication errors (RERs). To identify pathological features that are discriminating for colorectal cancer (CRC) showing extensive MIN. A prospective series of 303 patients with CRC and no family history of either familial adenomatous polyposis or hereditary non-polyposis colorectal cancer. DNA was extracted from fresh tissue samples and the presence of MIN was studied at nine loci that included TGF beta RII, IGFIIR, and BAX. The 61 cases showing RERs were compared with 63 RER negative cases with respect to a comprehensive set of clinical and pathological variables. Predictive utility of the variables was tested by decision tree analysis. Twenty seven patients with CRC showed extensive RERs (three loci or more) (RER+) and 34 had limited RERs only (28 = one locus; 6 = two loci) (RER+/-), yielding a bimodal distribution. RER+ cancers differed from RER- and RER+/-) cases. Tumour type (adenocarcinoma, mucinous carcinoma, and undifferentiated carcinoma) (p = 0.001), tumour infiltrating lymphocytes (p = 0.001), and anatomical site (p = 0.001) were the most significant of the discriminating variables. Algorithms developed by decision tree analysis allowed cases to be assigned to RER+ versus RER- and +/- status with a global sensitivity of 81.5%, specificity of 96%, and overall accuracy of 93%. Pathological examination of CRC allows assignment of RER+ status; assignment is specific and relatively sensitive. Conversely RER- and RER+/- CRC are indistinguishable.
              Article 0 comments Cited 66 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Amanda Ewart Toland: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 7 November 2013
                Volume: 8
                Issue: 11
                Electronic Location Identifier: e79898
                Affiliations
                [1 ]Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
                [2 ]Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
                [3 ]Department of Medical Statistics, Leiden University Medical Center, Leiden, The Netherlands
                [4 ]Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands
                [5 ]Department of Pediatric Oncology, Erasmus MC, Sophia Children’s Hospital, Rotterdam, The Netherlands
                [6 ]Netherlands Bioinformatics Center, Nijmegen, The Netherlands
                Ohio State University Medical Center, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AAD AB EHvR HM TvW JMB. Performed the experiments: AAD AB EHvR MS. Analyzed the data: AAD AB EHvR MS MF TvW JMB. Contributed reagents/materials/analysis tools: AFS ECMZ PJKK HM. Wrote the manuscript: AAD TvW JMB.

                Article
                Publisher ID: PONE-D-13-26371
                DOI: 10.1371/journal.pone.0079898
                PMC ID: 3820613
                PubMed ID: 24244575
                SO-VID: cef881ff-77fa-4918-a9d5-f55117b9eced
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 25 June 2013
                Date accepted : 26 September 2013
                Funding
                This work was supported by the Centre for Medical Systems Biology, a Centre of Excellence supported by the Netherlands Genomics Initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article

                ScienceOpen disciplines: Uncategorized
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