New insights into the molecular pathogenesis of colorectal cancer

Abstract

Although there have been tremendous advances in the management of colorectal cancer (CRC), there is still a need for improved therapeutic approaches. On a molecular genetic level, CRC is one of the best-understood solid malignancies, and these insights can serve as a foundation for the design of novel targeted therapies. We present new genetic and epigenetic pathways that highlight the heterogeneous mechanisms in CRC pathogenesis, including the roles of the MYH DNA repair gene and of aberrant DNA hypermethylation and imprinting. We then describe some of the successful targeted therapies that inhibit COX2, EGFR, and VEGF as well as potential new targets that have been revealed by studies of molecular genetics.

Figure 1

Key mechanisms involved in colorectal carcinogenesis. The top half depicts key mutations that are required for progression along the adenoma–carcinoma axis in the chromosomal instability (CIN) pathway. One of the major mutational targets of MUTYH is the APC gene, the so-called gatekeeper to the adenoma–carcinoma axis. Progression along this axis is accompanied by corresponding mutations in genes such as KRAS and TP53. The bottom half depicts some of the key mutations in the microsatellite instability (MSI) pathway, MLH1, MSH2, and MSH6. The DNA mismatch repair gene MLH1 can be inactivated either by a mutation or by promoter hypermethylation, which typically occurs in the context of the CpG island methylator phenotype (CIMP). BRAF mutations and MLH1 hypermethylation are associated with an alternative form of polyp—serrated polyps. Abbreviations: LOH—loss of heterozygosity; APC—Adenomatous Polyposis Coli; COX2—cyclooxygenase 2; MLH1—mutL homolog 1; MSH2—mutS homolog 2; MSH6—mutS homolog 6; MYH—mutY homolog.

Figure 2

DNA methylation of promoter CpG islands results in transcriptional silencing of key tumor suppressor genes, such as MLH1. DNA methyltransferases can transfer methyl groups from the carrier S-adenosine-methionine (SAM) to CpG dinucleotides. This is balanced by DNA demethylases that remove methyl groups from these CpG sequences. The mechanisms that regulate these two enzymatic processes are still unknown. Silencing of key tumor suppressor genes can lead to the formation of colorectal cancer.

Figure 3

Loss of imprinting of the maternal insulin-like growth factor II (IGF2) allele predisposes to colorectal cancer. Imprinting of the maternal (M) allele (designated by the (*) in (a)) results in transcription of only the paternal (P) copy of IGF2. The imprinted region is indicated by the yellow oval. Loss of imprinting of the maternal allele (b) results in transcription from both the maternal and paternal copies of IGF2. This is associated with an increased risk for the development of colorectal cancer.