Although colorectal cancer (CRC) was among the first solid tumors to undergo molecular profiling, the clinical translation of this knowledge into effective therapies has been impeded by the startling level of complexity and heterogeneity revealed among these tumors. Despite the FDA’s approval of several new drugs in recent years, the success of these and other agents in development has been stifled by the complex nature of CRC. As a result, experts in the field assert that the path forward requires a paradigm shift toward integrative analyses that encompass multiple classes of genomic aberrations and consensus classification of CRC based on genomic data to facilitate more effective management of this disease.
Molecular Understanding of CRC
Every case of CRC is associated with genomic alterations that drive dysregulation of key signaling pathways involved in the hallmark processes that are essential to the transformation of a normal cell into a cancerous one.
Somatic Versus Hereditary
In the vast majority of cases, this results from the sporadic accumulation of somatic mutations over a patient’s lifetime. However, in approximately 5% of patients, CRC arises as part of an inherited syndrome that results from a germline mutation in a well-defined gene (hereditary
). A further 10%-30% of CRC cases are associated with increased familial risk depending upon the analysis, but have no identified germline mutation (Figure A)
Several subtypes of hereditary mutations have been characterized, and protocols have been developed for screening patients with CRC at risk for these syndromes or individuals from families with a known high-risk syndrome associated with CRC.
The most common inherited subtype is Lynch syndrome, often called hereditary non-polyposis CRC, which results from germline mutations in one of several mismatch repair (MMR) genes and is believed to occur in approximately 2% to 5% of all CRC cases. Familial adenomatous polyposis (FAP), believed to occur in about 1% of CRC cases, stems from mutations in the adenomatous polyposis coli (APC
Regardless of whether mutations present in CRC are inherited, the genomic instability that fosters cancer development can arise via several distinct pathways. Most common (about 70%-80% of cases) is the chromosomal instability
(CIN) pathway, in which there is an accumulation of numerical or structural alterations to the chromosomes. These tumors also harbor somatic mutations in a number of oncogenes and tumor suppressors that activate signaling pathways with a critical role in carcinogenesis.
In about 15% of cases, colorectal carcinogenesis results from insertions or deletions in the microsatellites, which are short stretches of repetitive DNA scattered throughout the genome.
This microsatellite instability
, which changes the length of the microsatellites, occurs predominantly because of defects in the MMR system. The MMR system is responsible for double checking the work of the DNA polymerase enzyme that synthesizes an identical copy of the DNA during cell replication. As a result of a malfunctioning MMR system, any errors introduced during replication cannot be corrected, impacting gene expression and function.
Adding another layer of complexity, a third pathway recently has been described, reflecting increased appreciation of the importance of epigenetic alterations to the genome. Epigenetics describes the regulatory mechanisms that affect gene expression without altering the DNA sequence, most commonly through the addition of methyl groups (methylation).
CpG islands are rare, short DNA sequences that contain an unusually high frequency of a cytosine being followed by a guanine; hence, CpG, a cytosine and guanine separated by only one phosphate. As a result of this pattern of base pairs, CpG islands have a tendency to be methylated. When methylated, CpG islands that are located within the promoter region of genes silence the expression of that gene, thus tightly regulating the gene’s methylation status. Aberrant methylation of CpG islands in the promoter region of tumor suppressor genes can promote tumorigenesis via the CpG Island Methylation Pathway (CIMP).
The CRC Genome
Several key genes involved in the carcinogenic process in CRC have been identified and include a number of well-known tumor suppressors and oncogenes (Figure B)
. The discovery of these driver genes has in some cases led to the development of drugs targeting the proteins encoded by these aberrant genes or components of the dysfunctional signaling pathways in which they play a role.