Table 2.
Tumor-Suppressor Genes and Oncogenes Commonly Associated with Colorectal Cancer.*
| Affected Gene | Frequency % |
Nature of Defect | Comments |
|---|---|---|---|
| APC | 85 | Activation of Wnt signaling due to inability to degrade the β-catenin oncoprotein41,42 | Germ-line mutation in familial adenomatous polyposis; somatic inactivation found in 85% of sporadic colorectal cancers43 |
| MLH1, MSH2, MSH6 | 15–25 | DNA single-nucleotide mismatch-repair defect permitting the accumulation of oncogenic mutations and tumor-suppressor loss10-14,31,35 | Germ-line mutation in hereditary nonpolyposis colorectal cancer30; epigenetic silencing causes loss of tumor MLH1 protein expression |
| TP53 | 35–55 | Encoding a protein responsible for cell-cycle regulation44,45; inactivating missense mutations paired with loss of heterozygosity at 17p | Germ-line mutation in Li–Fraumeni syndrome46 |
| TGFBR2 | 25–30 | Receptor responsible for signaling pathways mediating growth arrest and apoptosis; inactivated by frameshift mutation in polyA repeat within TGFBR2 coding sequence in patients with mismatch-repair defects47 or by inactivating mutation of kinase domain48,49 | Mutation present in >90% of tumors with microsatellite instability and 15% of microsatellite stable colon cancers50 |
| SMAD4 | 10–35 | Critical components of transforming growth factor β pathway signaling, along with related proteins SMAD2 and SMAD3; SMAD4 and SMAD2 are located on chromosome 18q, a frequent site of loss of heterozygosity in colorectal cancers; inactivated by homozygous deletion or mutation51,52 | Germ-line mutations in familial juvenile polyposis, with a risk of colorectal cancer as high as 60% over three to four decades53 |
| KRAS | 35–45 | Encoding the KRAS G-protein, with constitutive activation resulting in activation of both the PI3K–PDK1–PKB and RAF–MEK–ERK1/2 signaling pathways, thereby promoting cell survival and apoptosis suppression54,55 | Germ-line mutation in the cardiofaciocutaneous syndrome56 |
| BRAF V600E | 8–12 | Activating mutation in the BRAF serine–threonine kinase, a downstream mediator of signaling through the RAF–MEK–ERK1/2 pathway, which mimics the biologic consequences of KRAS mutation38,57 | Associated with hyperplastic polyposis, with increased incidence in serrated adenomas58,59; like KRAS, germ-line mutation in the cardiofaciocutaneous syndrome56 |
| PTEN | 10–15 | Promotion of the activation of PI3K pathway signaling through loss of function by inactivating mutation, resulting in cell-survival signaling and apoptosis suppression | Germ-line mutation in Cowden's syndrome, which carries a high risk of breast cancer, with 10% increased risk of colorectal cancer; possible role in maintenance of chromosomal stability60-62 |
*
ERK denotes extracellular signal–regulated kinase, MAPK mitogen-activated protein kinase, MEK MAPK kinase, PDK1 pyruvate dehydrogenase kinase isozyme 1, PI3K phosphatidylinositol 3-kinase, and PKB protein kinase B.