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Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer.

ABSTRACT: Sporadic colorectal cancer (CRC) is a somatic genetic disease in which pathogenesis is influenced by the local colonic environment and the patient's genetic background. Consolidating the knowledge of genetic and epigenetic events that occur with initiation, progression, and metastasis of sporadic CRC has identified some biomarkers that might be utilized to predict behavior and prognosis beyond staging, and inform treatment approaches. Modern next-generation sequencing of sporadic CRCs has confirmed prior identified genetic alterations and has classified new alterations. Each patient's CRC is genetically unique, propelled by 2-8 driver gene alterations that have accumulated within the CRC since initiation. Commonly observed alterations across sporadic CRCs have allowed classification into a (1) hypermutated group that includes defective DNA mismatch repair with microsatellite instability and POLE mutations in ?15%, containing multiple frameshifted genes and BRAF(V600E); (2) nonhypermutated group with multiple somatic copy number alterations and aneuploidy in ?85%, containing oncogenic activation of KRAS and PIK3CA and mutation and loss of heterozygosity of tumor suppressor genes, such as APC and TP53; (3) CpG island methylator phenotype CRCs in ?20% that overlap greatly with microsatellite instability CRCs and some nonhypermutated CRCs; and (4) elevated microsatellite alterations at selected tetranucleotide repeats in ?60% that associates with metastatic behavior in both hypermutated and nonhypermutated groups. Components from these classifications are now used as diagnostic, prognostic, and treatment biomarkers. Additional common biomarkers may come from genome-wide association studies and microRNAs among other sources, as well as from the unique alteration profile of an individual CRC to apply a precision medicine approach to care.

SUBMITTER: Carethers JM

PROVIDER: S-EPMC4589489 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer.

Carethers John M JM Jung Barbara H BH

Gastroenterology 20150726 5

Sporadic colorectal cancer (CRC) is a somatic genetic disease in which pathogenesis is influenced by the local colonic environment and the patient's genetic background. Consolidating the knowledge of genetic and epigenetic events that occur with initiation, progression, and metastasis of sporadic CRC has identified some biomarkers that might be utilized to predict behavior and prognosis beyond staging, and inform treatment approaches. Modern next-generation sequencing of sporadic CRCs has confir ...[more]

PMID: 26216840

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Project description:Sporadic early onset colorectal carcinoma (EOCRC) which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve identification of distinct sub-types of colorectal cancers (CRC) with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45-60 years were excluded to help define "young" and "old" groups. Thirty-nine cases of sporadic EOCRC (patients ≤ 45 years with microsatellite stable tumors) were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years) and to groups of patients with microsatellite instability. Each group was tested for TP53, KRAS, BRAF, PIK3CA mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013). Genetic studies also showed the absence of BRAF mutations (p = 0.022) and the methylator phenotype (p = 0.005) in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF) and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01). This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways including the TNFR1 pathway have been identified as potential biomarkers for both the diagnosis and treatment of this disease.

Dataset Information

Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer.

Publications

Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer.

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