Recent Insights into the Pathogenesis of Colorectal Cancer
Recent Insights into the Pathogenesis of Colorectal Cancer
Purpose of review Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the Western world, but our understanding of this disease is incomplete. The recent advent of new technologies has provided novel insights into the pathogenesis of CRC.
Recent findings Genome-wide association studies have recently linked CRC to 10 common genetic variants or single-nucleotide polymorphisms that map to chromosomes 8q23, 8q24, 10p14, 11q23, 14q22, 15q13, 16q22, 18q21, 19q13 and 20p1. However, the causal significance of these variants is not understood, and some are located in poorly characterized genomic regions or gene deserts. Recent studies indicate that the single-nucleotide polymorphism rs6983267, which maps to 8q24, serves as an enhancer of MYC expression by binding T cell factor 4 (TCF4) and influencing Wnt signaling. In addition, several microRNAs interact with genes such as K-RAS, APC, p53, PTEN, TCF4, COX-2, DNMT3a and DNMT3b. Germline hypermethylation of the DNA mismatch repair genes MLH1 and MSH2 may serve as predisposing events in some CRC patients.
Summary Recent studies have elucidated novel mechanisms involved in CRC, including the involvement of single-nucleotide polymorphisms not located within traditional genes, the role of microRNAs and epimutations in DNA mismatch repair genes. Interestingly, most of this progress has been made by understanding DNA that does not encode genes.
Colorectal cancer (CRC) is a common and deadly disease. The availability of tissues and cultured cells for analysis has provided opportunities for the elucidation of the cellular, genetic and molecular mechanisms involved in tumor initiation, progression and metastasis. CRCs arise through a multistep carcinogenic process in which genetic and epigenetic alterations accumulate sequentially. Although the genetic alterations occur in a stochastic fashion in individual cells, the defects accumulate in a nonrandom fashion in tumors because of growth or survival advantages conferred by rare mutations in the selected clones. Therefore, a key mechanistic component of initiation and progression in CRC is the occurrence of genomic and epigenetic instability, which increases the rate of accumulation of such alterations, which permits the adaptations characteristic of malignant tumors.
CRC is a disease that is largely influenced by lifestyle and dietary factors, and studies in recent years have begun to recognize the importance of single-nucleotide polymorphisms (SNPs) in genes that are involved in xenobiotic metabolism that might account for CRC risk in the context of certain environmental exposures. Until recently, it was impractical to explore the millions of SNPs in the human genome using candidate gene approaches. However, recent advances in technology permit genome-wide screening, and several candidate CRC susceptibility loci have been identified. Second, microRNAs (miRNAs) have emerged as important factors in human cancer, as these regulate the expression of approximately 30% of human genes. Identification of gene targets of miRNAs has been a daunting task; however, recent studies indicate that many miRNAs target key growth regulatory genes. Finally, germline hypermethylation of DNA mismatch repair (MMR) genes can be a factor in some proportion of patients who appear to have Lynch Syndrome, but do not have germline mutations in the suspected gene. In this review, we will review new concepts that have been uncovered in the past 2 years relevant to the pathogenesis of CRC, and will briefly discuss the opportunities and challenges that lie ahead.
Abstract and Introduction
Abstract
Purpose of review Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths in the Western world, but our understanding of this disease is incomplete. The recent advent of new technologies has provided novel insights into the pathogenesis of CRC.
Recent findings Genome-wide association studies have recently linked CRC to 10 common genetic variants or single-nucleotide polymorphisms that map to chromosomes 8q23, 8q24, 10p14, 11q23, 14q22, 15q13, 16q22, 18q21, 19q13 and 20p1. However, the causal significance of these variants is not understood, and some are located in poorly characterized genomic regions or gene deserts. Recent studies indicate that the single-nucleotide polymorphism rs6983267, which maps to 8q24, serves as an enhancer of MYC expression by binding T cell factor 4 (TCF4) and influencing Wnt signaling. In addition, several microRNAs interact with genes such as K-RAS, APC, p53, PTEN, TCF4, COX-2, DNMT3a and DNMT3b. Germline hypermethylation of the DNA mismatch repair genes MLH1 and MSH2 may serve as predisposing events in some CRC patients.
Summary Recent studies have elucidated novel mechanisms involved in CRC, including the involvement of single-nucleotide polymorphisms not located within traditional genes, the role of microRNAs and epimutations in DNA mismatch repair genes. Interestingly, most of this progress has been made by understanding DNA that does not encode genes.
Introduction
Colorectal cancer (CRC) is a common and deadly disease. The availability of tissues and cultured cells for analysis has provided opportunities for the elucidation of the cellular, genetic and molecular mechanisms involved in tumor initiation, progression and metastasis. CRCs arise through a multistep carcinogenic process in which genetic and epigenetic alterations accumulate sequentially. Although the genetic alterations occur in a stochastic fashion in individual cells, the defects accumulate in a nonrandom fashion in tumors because of growth or survival advantages conferred by rare mutations in the selected clones. Therefore, a key mechanistic component of initiation and progression in CRC is the occurrence of genomic and epigenetic instability, which increases the rate of accumulation of such alterations, which permits the adaptations characteristic of malignant tumors.
CRC is a disease that is largely influenced by lifestyle and dietary factors, and studies in recent years have begun to recognize the importance of single-nucleotide polymorphisms (SNPs) in genes that are involved in xenobiotic metabolism that might account for CRC risk in the context of certain environmental exposures. Until recently, it was impractical to explore the millions of SNPs in the human genome using candidate gene approaches. However, recent advances in technology permit genome-wide screening, and several candidate CRC susceptibility loci have been identified. Second, microRNAs (miRNAs) have emerged as important factors in human cancer, as these regulate the expression of approximately 30% of human genes. Identification of gene targets of miRNAs has been a daunting task; however, recent studies indicate that many miRNAs target key growth regulatory genes. Finally, germline hypermethylation of DNA mismatch repair (MMR) genes can be a factor in some proportion of patients who appear to have Lynch Syndrome, but do not have germline mutations in the suspected gene. In this review, we will review new concepts that have been uncovered in the past 2 years relevant to the pathogenesis of CRC, and will briefly discuss the opportunities and challenges that lie ahead.