Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6092784 | Gastroenterology | 2015 | 40 Pages |
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 2â8 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 â¼15%, containing multiple frameshifted genes and BRAFV600E; (2) nonhypermutated group with multiple somatic copy number alterations and aneuploidy in â¼85%, 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 â¼20% that overlap greatly with microsatellite instability CRCs and some nonhypermutated CRCs; and (4) elevated microsatellite alterations at selected tetranucleotide repeats in â¼60% 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.
Keywords
EGFR15-PGDHPI3KMMR5-FUMSI-Hcyclo-oxygenase-2TGFCIMPmRNAACFPGE2MIRCOX-215-hydroxyprostaglandin dehydrogenaseMAPKCpG island methylator phenotypemessenger RNAloss of heterozygosityMicrosatellite instabilityGenomic instabilityChromosomal instabilitytransforming growth factormismatch repairCinRISCColorectal cancerphosphatidylinositide 3-kinase5-fluorouracilLOHRNA-Induced Silencing ComplexMicroRNAmitogen-activated protein kinaseProstaglandin E2Single nucleotide polymorphismSNPCRCEpithelial growth factor receptor
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Authors
John M. Carethers, Barbara H. Jung,