Recent Insights into the Pathogenesis of Colorectal Cancer

Ajay Goel; Clement Richard Boland


Curr Opin Gastroenterol. 2012;26(1):47-52. 

In This Article

Epimutations and Colorectal Cancer

The paradigm for hereditary cancer syndromes has been to find a germline mutation in a coding region, splice site or promoter of the gene associated with that disease. Recent data suggest that some cases of the hereditary CRC syndrome, Lynch syndrome, are associated with epigenetic inactivation of the gene caused by promoter methylation. This has been seen in multiple family members, acting like a classic autosomal dominant disease. The theoretical problem is that epigenetic alterations (such as methylation) are thought to be 'erased' early in embryogenesis, which conflicts with the observation of vertical passage of the trait through a family. A novel explanation has been found for this.

MutL Homolog 1 Epimutations in Patients with Colorectal Cancer

Lynch syndrome is an autosomal dominant cancer syndrome characterized by early-onset CRCs and a variety of extracolonic tumors. This is caused by germline mutations in DNA MMR genes, most often MutL homolog 1 (MLH1) and MutS homolog 2 (MSH2), and less frequently MutS homolog 6 (MSH6) and postmeiotic segregation 2 (PMS2). The MLH1 gene can also be inactivated by methylation in sporadic CRCs, leading to a tumor that mimics Lynch syndrome, but this is not inherited. This acquired situation is strongly associated with the CpG island methylator phenotype.

In 2002, it was reported that MLH1 can be methylated in the peripheral blood as well as the tumor tissues of some CRC patients,[43] and subsequently, about 20 CRC patients have been reported with monoallelic MLH1 methylation in the tumor tissue and in DNA isolated from lymphocytes and other tissues.[44–46] However, it has been controversial whether these 'soma-wide' epimutations can be inherited, and the conventional wisdom is that, in contrast to genetic mutations, MLH1 epimutations are reversible between generations and are not inherited in a Mendelian fashion.[45,46]

Germline MutS Homolog 2 Epimutations in Colorectal Cancer Patients

Large genomic alterations of MSH2 are a frequent mechanism for its inactivation in Lynch syndrome patients because this gene is embedded in an archipelago of Alu sequences, which predisposes to internal homologous recombination and excisional deletion. Additionally, evidence for germline methylation was also reported for MSH2 in a few 'Lynch syndrome' families.[47,48••,49] These families had multiple affected members with features of Lynch syndrome, loss of the MSH2 and MSH6 proteins, but lacked germline mutations in either of these genes required for that diagnosis.[47,49] A Finnish study[50] recently demonstrated simultaneous large genomic deletions in MSH2 and germline epimutations in MLH1 in some proportion of mutation-negative suspected Lynch syndrome families. Interestingly, in contrast to MLH1, epimutations in MSH2 were documented to be stably inherited in multiple individuals across three generations, providing compelling evidence for Mendelian transmission of this epimutation.[47]

Molecular Mechanism for MutS Homolog 2 Epimutations

In a breakthrough study, a novel molecular explanation for germline MSH2 methylation was indentified. In this report, germline deletions at the 3′-end of the epithelial cell adhesion molecule (EpCAM) gene (formerly known as tumor-associated calcium signal transducer 1 or TACSTD1), which is located immediately upstream of MSH2 and expressed in the same direction, were identified in the epimutation carriers.[48••] The deletions in EpCAM included the termination signal, which abolished transcriptional termination of EpCAM and resulted in transcriptional read-through into MSH2. These fusion transcripts were significantly overexpressed in the epithelial tissues and correlated with extensive MSH2 methylation in these patients.[48••,51]

Our current understanding of the contribution of epimutations in MMR genes in CRC is in its infancy; however, these recent discoveries are provocative as identification of such epimutations has important implications for surveillance recommendations in affected families.


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