scholarly journals NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions

2021 ◽  
Author(s):  
Jung Ho Kim ◽  
Jeong Hoon Hong ◽  
Yoon-La Choi ◽  
Ji Ae Lee ◽  
Mi-kyoung Seo ◽  
...  
Keyword(s):  
Drug Targets ◽  
Cpg Island ◽  
Colorectal Carcinogenesis ◽  
Wild Type ◽  
Cpg Island Methylator Phenotype ◽  
Braf Mutations ◽  
Epithelial Tumor ◽  
Age Related ◽  
Serrated Lesions ◽  
Serrated Neoplasia Pathway

Background: NTRK fusions are emerging tissue-agnostic drug targets in malignancies including colorectal cancers (CRCs), but their detailed landscape in the context of various colorectal carcinogenesis pathways remains to be investigated. Methods: Pan-TRK expression was assessed by immunohistochemistry in retrospectively collected colorectal epithelial tumor tissues, including 441 CRCs (133 microsatellite instability-high (MSI-high) and 308 microsatellite stable (MSS)) and 565 premalignant colorectal lesions (300 serrated lesions and 265 conventional adenomas). TRK-positive cases were subjected to next-generation sequencing and/or fluorescence in situ hybridization to confirm NTRK rearrangements. Results: TRK positivity was not observed in any of the MSS CRCs, conventional adenomas, traditional serrated adenomas, or hyperplastic polyps, whereas TRK positivity was observed in 11 of 58 (19%) sporadic MSI-high CRCs, 4 of 23 (17%) sessile serrated lesions with dysplasia (SSLDs), and 5 of 132 (4%) SSLs. The 11 TRK-positive MSI-high CRCs commonly harbored CpG island methylator phenotype-high (CIMP-high), MLH1 methylation, KRAS/BRAF wild-type, and NTRK1 or NTRK3 fusion (TPM3-NTRK1, TPR-NTRK1, LMNA-NTRK1, SFPQ-NTRK1, ETV6-NTRK3, or EML4-NTRK3). Both NTRK1 or NTRK3 rearrangement and KRAS/BRAF wild-type were detected in all nine TRK-positive SSL(D)s, seven of which demonstrated MSS and/or CIMP-low. TRK overexpression and early dysplastic changes are occasionally co-localized in the crypt base area of SSLs. Age-related occurrence patterns suggest that the progression interval from NTRK-rearranged SSLs to CRCs may be shorter than from BRAF-mutated SSLs to CRCs. Conclusion: NTRK-rearranged colorectal tumors develop exclusively through the serrated neoplasia pathway and can be initiated from non-dysplastic SSLs without KRAS/BRAF mutations prior to full occurrence of MSI-high/CIMP-high.

Clinicopathologic Characteristics, CpG Island Methylator Phenotype, and BRAF Mutations in Microsatellite-Stable Colorectal Cancers Without Chromosomal Instability

2008 ◽  
Vol 132 (6) ◽  
pp. 958-964
Author(s):  
Sanjay Kakar ◽  
Guoren Deng ◽  
Vaibhav Sahai ◽  
Koji Matsuzaki ◽  
Hirofumi Tanaka ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Braf Mutation ◽  
Chromosomal Instability ◽  
Cpg Island ◽  
Adverse Outcomes ◽  
Colorectal Carcinogenesis ◽  
Cpg Island Methylator Phenotype ◽  
Braf Mutations ◽  
Methylator Phenotype

Abstract Context.—The 2 chief pathways implicated in colorectal carcinogenesis, microsatellite instability and chromosomal instability, are not present in 20% to 37% of cases. Objective.—To determine whether the CpG island methylator phenotype (CIMP) pathway, characterized by simultaneous methylation of several known tumor suppressor genes, is the principal underlying mechanism in cases without chromosomal or microsatellite instability, and to determine the significance of CIMP pathway and BRAF mutations in microsatellite-stable (MSS) cases. Design.—Clinicopathologic features and chromosomal instability status by loss of heterozygosity analysis were determined in 83 cases of colorectal cancer in which microsatellite instability, CIMP status, BRAF mutations, and KRAS mutations were previously known. Results.—Microsatellite instability was present in 14 cases (17%). Of the 69 MSS cases (83%), chromosomal instability manifested by LOH involving at least one locus was observed in 53 cases (64%). Hence, 16 (19%) of 83 colorectal cancer cases showed neither microsatellite instability nor chromosomal instability. These cases had a low incidence of CIMP (3/16; 19%) and BRAF mutation (1/16; 6%). The 5-year survival in these cases was significantly better compared with MSS cases with chromosomal instability (80% vs 54%, P = .02). BRAF mutations were identified in 10 MSS cases (15%). BRAF mutation in MSS cases correlated significantly with high-level chromosomal instability (P = .009) and poor 5-year survival (0% vs 70%, P < .001). Conclusions.—CIMP does not appear to play a key role in colorectal cancer without microsatellite instability and chromosomal instability. These cases have a better survival, probably related to absence of significant chromosomal instability. BRAF mutations in MSS cases are associated with high levels of chromosomal instability that are likely responsible for the adverse outcomes in these cases.

scholarly journals Effects of Somatic Methylation in Colonic Polyps on Risk of Developing Metachronous Advanced Colorectal Lesions

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 246
Author(s):  
Oscar Murcia ◽  
Alejandro Martínez-Roca ◽  
Miriam Juárez ◽  
Mar Giner-Calabuig ◽  
Miren Alustiza ◽  
...  
Keyword(s):  
Cpg Island ◽  
Risk Estimation ◽  
Colonic Polyps ◽  
Cpg Island Methylator Phenotype ◽  
Polyp Size ◽  
Serrated Lesions ◽  
Amplification Technique ◽  
Methylator Phenotype ◽  
The Relationship ◽  
Dependent Probe

The utility of molecular markers for predicting the risk of metachronous advanced colorectal lesions (MACLs) remains poorly investigated. We examined the relationship between somatic hypermethylation in polyps at baseline and the risk of developing MACL. This retrospective cohort study included 281 consecutive patients with colonic polyps who were enrolled between 2007 and 2009 and followed-up until 2014. MACLs were defined as adenomas of >10 mm, high-grade dysplasia, or with a villous component; and serrated lesions of >10 mm or with dysplasia. In total, 595 polyps were removed at baseline colonoscopy and analyzed for pathological characteristics and CpG island methylator phenotype (CIMP) using the MS-MLPA (Methylation-Specific -- Multiplex Ligation-dependent Probe Amplification) technique. Forty-five patients (16.0%) showed at least one CIMP+ polyp. MACL risk was higher in patients with CIMP+ polyps (odds ratio (OR), 4.50; 95% CI, 1.78–11.4; p = 0.002). Patients with CIMP+ polyps also exhibited shorter time to MACL development (33.8 months vs. 50.1 months; p < 0.001), even with adjustment for polyp size and number (OR, 2.40; 95% CI, 1.33–4.34). Adding CIMP analysis improved the sensitivity (57.0% to 70.9%), negative predictive value (71.1% to 77.3%), and overall accuracy (49.8% to 52.0%) for MACL risk estimation. These results highlight that CIMP may be a useful marker for endoscopic surveillance.

scholarly journals Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer

2006 ◽  
Vol 120 (3) ◽  
pp. 656-663 ◽  
Author(s):  
Martha L. Slattery ◽  
Karen Curtin ◽  
Carol Sweeney ◽  
Theodore R. Levin ◽  
John Potter ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cpg Island ◽  
Lifestyle Factor ◽  
Cpg Island Methylator Phenotype ◽  
Braf Mutations ◽  
Methylator Phenotype ◽  
Diet And Lifestyle

scholarly journals Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival

2017 ◽  
Vol 35 (24) ◽  
pp. 2806-2813 ◽  
Author(s):  
Xinwei Hua ◽  
Amanda I. Phipps ◽  
Andrea N. Burnett-Hartman ◽  
Scott V. Adams ◽  
Sheetal Hardikar ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Kras Mutation ◽  
Cpg Island ◽  
The United States ◽  
Wild Type ◽  
Cpg Island Methylator Phenotype ◽  
Mutation Status ◽  
Anti Inflammatory ◽  
Kras Mutation Status

Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia. Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up. Survival outcomes were completed through linkage to national death registries. BRAF- and KRAS-mutation status, microsatellite instability, and CpG island methylator phenotype were also evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for overall survival (OS) and CRC-specific survival. Results After a median of 10.8 years of follow-up since diagnosis, 381 deaths (100 as a result of CRC) were observed. Compared with nonusers, postdiagnostic aspirin-only users had more favorable OS (HR, 0.75; 95% CI, 0.59 to 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 to 0.71), especially among those who initiated aspirin use (OS: HR, 0.64; 95% CI, 0.47 to 0.86; CRC-specific survival: HR, 0.40; 95% CI, 0.20 to 0.80). The association between any NSAID use after diagnosis and OS differed significantly by KRAS-mutation status ( Pinteraction = .01). Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 to 0.80) but not among those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 to 1.96). Conclusion Among long-term CRC survivors, regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors.

Evaluation of the CpG island methylator phenotype as a predictive biomarker for adjuvant oxaliplatin-based chemotherapy in colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 592-592
Author(s):  
Stacey Shiovitz ◽  
Chen Wu ◽  
Ming Yu ◽  
Georgia Gourgioti ◽  
Georgia Raptou ◽  
...  
Keyword(s):  
Treatment Response ◽  
Cpg Island ◽  
Univariate Analysis ◽  
Disease Free Survival ◽  
Predictive Biomarker ◽  
Primary Objective ◽  
Tnm Stage ◽  
Cpg Island Methylator Phenotype ◽  
Braf Mutations ◽  
Methylator Phenotype

592 Background: The CpG island methylator phenotype (CIMP) has previously been shown to be a predictive biomarker for 5-fluorouracil (5-FU)/leucovorin (LV)/irinotecan (IFL) adjuvant chemotherapy in stage III colon cancer patients. It is unknown if CIMP serves as a biomarker for standard-of-care oxaliplatin-based adjuvant therapy. Methods: HE6C05 randomized 441 patients with stage II/III colorectal adenocarcinoma to adjuvant oxaliplatin with either capecitabine (XELOX) or 5-FU/LV (mFOLFOX6) between November 2005 and January 2008. The primary objective was disease-free survival (DFS); overall survival (OS) was a secondary objective. The study closed early due to poor accrual with last follow-up in November 2013. Isolated DNA from 293 tumor samples was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. Cox univariate and multivariate models were used to assess the effects of CIMP on DFS and OS, accounting for interactions with TNM stage; site (right vs. left); KRAS, BRAF, and mismatch repair (MMR) status; tumor T-cell ratio (CD3/CD8); and treatment arm. Results: Of the tumor samples available for CIMP analysis, 28 (9.6%) were CIMP-positive. The CIMP-positive tumors were more likely to be right-sided and have BRAF mutations (chi-square, p<0.001). In the univariate analysis, no significant differences in DFS or OS were observed between individuals with CIMP-positive vs. negative tumors (OS hazard ratio 1.27, Wald’s p=0.55). In addition, CIMP had no predictive value for response to the treatments administered in the two arms of the trial (XELOX vs. mFOLFOX6). In the multivariate model, only TNM stage and primary site were associated with survival outcome (Wald’s p=0.0002 and p=0.006, respectively); CIMP did not improve treatment response prediction. Conclusions: In this exploratory analysis, unlike what we have seen with IFL, CIMP does not appear to serve as a predictive biomarker for treatment response to oxaliplatin-based therapy. CIMP analysis in an irinotecan vs. oxaliplatin trial may offer additional insight.

scholarly journals P.051 5-hydroxymethylcytosine profiling identifies differential targeting in IDH1 mutant versus IDH1 wild-type high-grade gliomas

2018 ◽  
Vol 45 (s2) ◽  
pp. S29-S29
Author(s):  
W Glowacka ◽  
H Jain ◽  
M Okura ◽  
A Maimaitiming ◽  
R Nejad ◽  
...  
Keyword(s):  
Gene Expression ◽  
Target Genes ◽  
Cpg Island ◽  
High Grade ◽  
Spearman Correlation ◽  
Wild Type ◽  
Cpg Island Methylator Phenotype ◽  
B Values ◽  
Active Demethylation ◽  
Methylator Phenotype

Background: Gliomas demonstrate epigenetic dysregulation highlighted by the Glioma CpG-Island Methylator Phenotype (G-CIMP) seen in IDH1 mutant tumors. IDH1 mutation perturbs the balance between 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) by inhibiting TET-mediated active demethylation. The role 5hmC plays in IDH1 mutant tumors remains poorly understood. Methods: We profiled 5hmC in high grade IDH1 mutant (n = 12) and wild-type (n = 9) tumors on the Illumina MethylationEPIC Beadchip. We examined regions with high 5hmC abundance (top 1% probes), and differentially hydroxymethylated regions (DHMR). 5hmC profiles were correlated with gene expression. Results: Mean 5hmC b-values were 4.6%% and 3.8% for IDH1 mutant and wild-type tumors, respectively. Top 1% and DHMR probes demonstrated increased 5hmC among IDH1 mutants. 5hmC enriched for enhancer and super-enhancers. Among G-CIMP target genes, 22/50 were hydroxymethylated in our IDH1 mutant cohort, suggesting that 5hmC contributes to their overall methylation. Gene expression was associated with gene body 5hmC. 48 genes differentially expressed between IDH1 cohorts showed a positive Spearman correlation between 5hmC and gene expression, in particular for genes upregulated in IDH1 mutants. Conclusions: Locus-specific gain of 5hmC, targeting regulatory regions and associated with over-expressed genes, suggests a significant role for 5hmC in IDH1 mutant HGG.

scholarly journals Association of Smoking, CpG Island Methylator Phenotype, and V600E BRAF Mutations in Colon Cancer

2006 ◽  
Vol 98 (23) ◽  
pp. 1731-1738 ◽  
Author(s):  
Wade S. Samowitz ◽  
Hans Albertsen ◽  
Carol Sweeney ◽  
Jennifer Herrick ◽  
Bette J. Caan ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cpg Island ◽  
Cpg Island Methylator Phenotype ◽  
Braf Mutations ◽  
Methylator Phenotype

scholarly journals Molecular Subtypes of Colorectal Cancer and Their Clinicopathologic Features, With an Emphasis on the Serrated Neoplasia Pathway

2016 ◽  
Vol 140 (5) ◽  
pp. 406-412 ◽  
Author(s):  
Jeong Mo Bae ◽  
Jung Ho Kim ◽  
Gyeong Hoon Kang
Keyword(s):  
Colorectal Cancer ◽  
Complex Disease ◽  
Molecular Subtypes ◽  
Cpg Island ◽  
Colorectal Cancers ◽  
Cpg Island Methylator Phenotype ◽  
Molecular Features ◽  
Methylator Phenotype ◽  
Serrated Neoplasia Pathway ◽  
Molecular Carcinogenesis

Context.—Colorectal cancer is a heterogeneous disease entity with 3 molecular carcinogenesis pathways and 2 morphologic multistep pathways. Right-sided colon cancers and left-sided colon and rectal cancers exhibit differences in their incidence rates according to geographic region, age, and sex. A linear tendency toward increasing frequencies of microsatellite instability–high or CpG island methylator phenotype–high cancers in subsites along the bowel from the rectum to the cecum or the ascending colon accounts for the differences in tumor phenotypes associated with these subsites. The molecular subtypes of colorectal cancers exhibit different responses to adjuvant therapy, which might be responsible for differences in subtype-specific survival. Objectives.—To review the clinicopathologic and molecular features of the molecular subtypes of colorectal cancer generated by combined CpG island methylator phenotype and microsatellite statuses, to integrate these features with the most recent findings in the context of the prognostic implications of molecular subtypes, and to emphasize the necessity of developing molecular markers that enable the identification of adenocarcinomas involving the serrated neoplasia pathway. Data Sources.—Based on the authors' own experimental data and a review of the pertinent literature. Conclusions.—Because colorectal cancers arise from 2 different morphologic multistep carcinogenesis pathways with varying contributions from 3 different molecular carcinogenesis pathways, colorectal cancer is a heterogeneous and complex disease. Thus, molecular subtyping of colorectal cancers is an important approach to characterizing their heterogeneity with respect to not only prognosis and therapeutic response but also biology and natural history.

Four Molecular Subtypes of Colorectal Cancer and Their Precursor Lesions

2011 ◽  
Vol 135 (6) ◽  
pp. 698-703
Author(s):  
Gyeong Hoon Kang
Keyword(s):  
Molecular Subtypes ◽  
Cpg Island ◽  
Colorectal Carcinogenesis ◽  
Colorectal Cancers ◽  
Precursor Lesions ◽  
Cpg Island Methylator Phenotype ◽  
Molecular Features ◽  
Epigenetic Instability ◽  
Geographic Differences ◽  
Methylator Phenotype

Abstract Context.—In addition to chromosomal instability and microsatellite instability (MSI), a third pathway, epigenetic instability, has been implicated in progression to colorectal carcinogenesis. CpG island methylator phenotype (CIMP) refers to a subset of colorectal cancers (CRCs) that occur through the epigenetic instability pathway and that are characterized by widespread hypermethylation of promoter CpG island loci, resulting in the inactivation of several tumor suppressor genes or tumor-related genes. Colorectal cancers can be classified into 4 molecular subtypes according to their CIMP and MSI statuses: CIMP+/MSI+, CIMP+/MSI−, CIMP−/MSI+, and CIMP−/MSI−. There are differences between Western (United States and European Union) and Eastern (Korea and China) populations in the number of CRCs that are MSI+, and in the number of MSI+ CRCs that are CIMP+. Objective.—To review the clinicopathologic and molecular features of the 4 molecular subtypes of CRCs and their precursor lesions, and to emphasize geographic differences in CRCs between Eastern and Western populations. Data Sources.—This article is based on the author's own experimental data and a literature review of relevant articles indexed in PubMed (US National Library of Medicine). Conclusion.—The 4 molecular subtypes of CRC that are defined by their CIMP and MSI statuses are characterized by their own distinct clinicopathologic and molecular features and precursor lesions. In particular, the clinicopathologic features of MSI+ CRCs differ depending on the CIMP status. Further understanding of the heterogeneity in CRC molecular pathways may help to explain the diverse morphologic features of CRCs.

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