EP.FRI.181 Beyond the adenoma- carcinoma sequence. A review of the morphogenetic basis of colorectal cancer

Abstract Introduction Looking beyond the adenoma carcinoma sequence researchers have discovered alternate morpho-genetic routes, and tumour biomarkers in colorectal cancer. This has caused a paradigm shift in the management, resulting in improved diagnosis, prevention, and delivery of tailored treatment aiming at specific molecular pathways. Aims, Methods This review summarises Methods PubMed, Google Scholar, NLM searches based on aims and key words were conducted. Further, academically and clinically relevant searches were made if more information was required. When required, references of articles were also retrieved. Results The two main theories regarding the morphological origins of colorectal cancer are the adenoma carcinoma sequence and the De-novo origins. The underlying genetic models are the (i) chromosomal instability pathway (CIN), (ii) the microsatellite instability pathway (MSI) and (iii) the CpG Island methylator phenotype (CIMP) pathways. Though unique, the pathways communicate with each other. The genetic fingerprinting of colorectal cancers has an impact on their tailored management and consequently a through grounding in the basics are essential for those in gastrointestinal subspecialties. Conclusions Two morphologically distinct pathways and three unique genetic mechanisms have been described. There are significant interactions between them. Behaviours of sporadic and inherited colorectal cancer, their treatment and prognosis depend on our understanding of these mechanisms and the availability of targeted therapies to assist surgical resection.

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943 Beyond the Adenoma Carcinoma Sequence

British Journal of Surgery ◽

10.1093/bjs/znab259.821 ◽

2021 ◽

Vol 108 (Supplement_6) ◽

Author(s):

S Daniel ◽

S Iype

Keyword(s):

Colorectal Cancer ◽

Paradigm Shift ◽

Chromosomal Instability ◽

De Novo ◽

Cpg Island ◽

Cpg Island Methylator Phenotype ◽

Genetic Fingerprinting ◽

Tailored Treatment ◽

Genetic Mechanisms ◽

Methylator Phenotype

Abstract Introduction Looking beyond the adenoma carcinoma sequence researchers have discovered alternate morpho-genetic routes, and tumour biomarkers in colorectal cancer. This has caused a paradigm shift in the management, resulting in improved diagnosis, prevention, and delivery of tailored treatment aiming at specific molecular pathways. Aim This review summarises Method PubMed, Google Scholar, NLM searches based on aims and key words were conducted. Further, academically, and clinically relevant searches were made if more information was required. When required, references of articles were also retrieved. Results The two main theories regarding the morphological origins of colorectal cancer are the adenoma carcinoma sequence and the De-novo origins. The underlying genetic models are the (i) chromosomal instability pathway (CIN), (ii) the microsatellite instability pathway (MSI) and (iii) the CpG Island methylator phenotype (CIMP) pathways. Though unique, the pathways communicate with each other. The genetic fingerprinting of colorectal cancers has an impact on their tailored management and consequently a through grounding in the basics are essential for those in gastrointestinal subspecialties. Conclusions Two morphologically distinct pathways and three unique genetic mechanisms have been described. There are significant interactions between them. Behaviours of sporadic and inherited colorectal cancer, their treatment and prognosis depend on our understanding of these mechanisms and the availability of targeted therapies to assist surgical resection.

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JC Virus T-Antigen in Colorectal Cancer Is Associated with p53 Expression and Chromosomal Instability, Independent of CpG Island Methylator Phenotype

Neoplasia ◽

10.1593/neo.81188 ◽

2009 ◽

Vol 11 (1) ◽

pp. 87-95 ◽

Cited By ~ 40

Author(s):

Katsuhiko Nosho ◽

Kaori Shima ◽

Shoko Kure ◽

Natsumi Irahara ◽

Yoshifumi Baba ◽

...

Keyword(s):

Colorectal Cancer ◽

Chromosomal Instability ◽

Jc Virus ◽

Cpg Island ◽

T Antigen ◽

Cpg Island Methylator Phenotype ◽

P53 Expression ◽

Methylator Phenotype

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Genetics, Cytogenetics, and Epigenetics of Colorectal Cancer

Journal of Biomedicine and Biotechnology ◽

10.1155/2011/792362 ◽

2011 ◽

Vol 2011 ◽

pp. 1-19 ◽

Cited By ~ 117

Author(s):

Lucia Migliore ◽

Francesca Migheli ◽

Roberto Spisni ◽

Fabio Coppedè

Keyword(s):

Colorectal Cancer ◽

Chromosomal Instability ◽

Cpg Island ◽

Methylation Pattern ◽

Structural Rearrangements ◽

Cpg Island Methylator Phenotype ◽

Multiple Tumor ◽

History Of ◽

Methylator Phenotype ◽

Instability Phenotype

Most of the colorectal cancer (CRC) cases are sporadic, only 25% of the patients have a family history of the disease, and major genes causing syndromes predisposing to CRC only account for 5-6% of the total cases. The following subtypes can be recognized: MIN (microsatellite instability), CIN (chromosomal instability), and CIMP (CpG island methylator phenotype). CIN occurs in 80–85% of CRC. Chromosomal instability proceeds through two major mechanisms, missegregation that results in aneuploidy through the gain or loss of whole chromosomes, and unbalanced structural rearrangements that lead to the loss and/or gain of chromosomal regions. The loss of heterozygosity that occur in the first phases of the CRC cancerogenesis (in particular for the genes on 18q) as well as the alteration of methylation pattern of multiple key genes can drive the development of colorectal cancer by facilitating the acquisition of multiple tumor-associated mutations and the instability phenotype.

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Characterization of Chilean patients with sporadic colorectal cancer according to the three main carcinogenic pathways: Microsatellite instability, CpG island methylator phenotype and Chromosomal instability

Tumor Biology ◽

10.1177/1010428320938492 ◽

2020 ◽

Vol 42 (7) ◽

pp. 101042832093849 ◽

Cited By ~ 1

Author(s):

Ana María Wielandt ◽

Claudia Hurtado ◽

Mauricio Moreno C ◽

Cynthia Villarroel ◽

Magdalena Castro ◽

...

Keyword(s):

Colorectal Cancer ◽

Latin American ◽

Chromosomal Instability ◽

Cpg Island ◽

Sporadic Colorectal Cancer ◽

Cpg Island Methylator Phenotype ◽

Kras Mutations ◽

Group 3 ◽

Methylator Phenotype ◽

Chilean Population

Molecular classification of colorectal cancer is difficult to implement in clinical settings where hundreds of genes are involved, and resources are limited. This study aims to characterize the molecular subtypes of patients with sporadic colorectal cancer based on the three main carcinogenic pathways microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN) in a Chilean population. Although several reports have characterized colorectal cancer, most do not represent Latin-American populations. Our study includes 103 colorectal cancer patients who underwent surgery, without neoadjuvant treatment, in a private hospital between 2008 and 2017. MSI, CIN, and CIMP status were assessed. Frequent mutations in KRAS, BRAF, and PIK3CA genes were analyzed by Sanger sequencing, and statistical analysis was performed by Fisher’s exact and/or chi-square test. Survival curves were estimated with Kaplan–Meier and log-rank test. Based on our observations, we can classify the tumors in four subgroups, Group 1: MSI-high tumors (15%) are located in the right colon, occur at older age, and 60% show a BRAF mutation; Group 2: CIN-high tumors (38%) are in the left colon, and 26% have KRAS mutations. Group 3: [MSI/CIN/CIMP]-low/negative tumors (30%) are left-sided, and 39% have KRAS mutations; Group 4: CIMP-high tumors (15%) were more frequent in men and left side colon, with 27% KRAS and 7% presented BRAF mutations. Three percent of patients could not be classified. We found that CIMP-high was associated with a worse prognosis, both in MSI-high and MSI stable patients (p = 0.0452). Group 3 (Low/negative tumors) tend to have better overall survival compared with MSI-high, CIMP-high, and CIN-high tumors. This study contributes to understanding the heterogeneity of tumors in the Chilean population being one of the few characterizations performed in Latin-America. Given the limited resources of these countries, these results allow to improve molecular characterization in Latin-American colorectal cancer populations and confirm the possibility of using the three main carcinogenic pathways to define therapeutic strategies.

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

Archives of Pathology & Laboratory Medicine ◽

10.5858/2008-132-958-cccimp ◽

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.

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Comprehensive analysis of the MLH1 promoter region in 480 patients with colorectal cancer and 1150 controls reveals new variants including one with a heritable constitutional MLH1 epimutation

Journal of Medical Genetics ◽

10.1136/jmedgenet-2017-104744 ◽

2018 ◽

Vol 55 (4) ◽

pp. 240-248 ◽

Cited By ~ 13

Author(s):

Monika Morak ◽

Ayseguel Ibisler ◽

Gisela Keller ◽

Ellen Jessen ◽

Andreas Laner ◽

...

Keyword(s):

Colorectal Cancer ◽

Promoter Methylation ◽

Transcriptional Repression ◽

De Novo ◽

Cpg Island ◽

Promoter Sequence ◽

Cpg Island Methylator Phenotype ◽

Allele Specific ◽

Methylator Phenotype

BackgroundGermline defects in MLH1, MSH2, MSH6 and PMS2 predisposing for Lynch syndrome (LS) are mainly based on sequence changes, whereas a constitutional epimutation of MLH1(CEM) is exceptionally rare. This abnormal MLH1 promoter methylation is not hereditary when arising de novo, whereas a stably heritable and variant-induced CEM was described for one single allele. We searched for MLH1 promoter variants causing a germline or somatic methylation induction or transcriptional repression.MethodsWe analysed the MLH1 promoter sequence in five different patient groups with colorectal cancer (CRC) (n=480) composed of patients with i) CEM (n=16), ii) unsolved loss of MLH1 expression in CRC (n=37), iii) CpG-island methylator-phenotype CRC (n=102), iv) patients with LS (n=83) and v) MLH1-proficient CRC (n=242) as controls. 1150 patients with non-LS tumours also served as controls to correctly judge the results.ResultsWe detected 10 rare MLH1 promoter variants. One novel, complex MLH1 variant c.-63_-58delins18 is present in a patient with CRC with CEM and his sister, both showing a complete allele-specific promoter methylation and transcriptional silencing. The other nine promoter variants detected in 17 individuals were not associated with methylation. For four of these, a normal, biallelic MLH1 expression was found in the patients' cDNA.ConclusionWe report the second promoter variant stably inducing a hereditary CEM. Concerning the classification of promoter variants, we discuss contradictory results from the literature for two variants, describe classification discrepancies between existing rules for five variants, suggest the (re-)classification of five promoter variants to (likely) benign and regard four variants as functionally unclear.

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