to dcc or other tumour suppressor candidates in the neighbouring areas. many reviews refuse to comment on dcc due to its history of conflicting information, stating that more study is required. chromosome 18 loh tends to occur in clusters. one major cluster is at 18q21, which agrees with the location of dcc. this cluster includes the marker d18s51, and is flanked by the d18s1109 and d18s68 loci. this segment spans 7.64cm, which is a relatively large section of dna that could easily encompass more than one tumour suppressor gene. a significant difference between dcc expression and 18q21 loh was detected in 1997. studies found that more tumours had reduced dcc expression than could be explained by loh or msi, indicating that another mechanism was at work. this observation was likely explained when epigenetic analysis was performed. epigenetics loss of dcc in colorectal cancer primarily occurs via chromosomal instability, with only a small percent having epigenetic silencing involved. epigenetic silencing of dcc by promoter hypermethylation has shown to be a significant factor in other cancer types. in head and neck squamous cell carcinoma, 77.3% of tumour samples presented dcc promoter hypermethylation versus 0.8% in non-cancerous saliva samples. similar results have been seen in breast cancer, acute lymphoblastic leukemia, and several others. use in pharmacogenetics dcc has found to be a useful prognostic marker for late stage colorectal carcinoma in some studies, but unhelpful in others. currently the american society of clinical oncology does not recommend using dcc as a marker due to insufficient classification data. a recent review of over two dozen 18q loh-survival studies concluded that there was a significant amount of inconsistency between the data sets. they concluded that loss of 18q remains a marker for poor prognosis, and that dcc status has the potential to define a group of patients who may benefit from specific treatment regimes. metastasis the increase in loss of heterozygosity percentages of chromosome 18q21 have long suggested that dcc may be involved in the progression of benign adenomas to malignant carcinomas. dcc has recently been found to suppress metastasis in an experimental environment, but a mechanism for this has not yet been proposed. pharmacology at this junction, dcc is not a pharmaceutical target. as dcc is not overexpressed in cancer and is present throughout the body, so it is not considered a good target for most types of cancer drugs. dcc is expressed at very low levels through most of the body but at higher levels in many areas of the brain, particularly in dopamine neurons. recently it has been shown that a sensitizing treatment regimen of amphetamines causes markedly increased levels of dcc and unc-5 expression on neuron cell bodies. this may indicate that netrin-1 receptors are involved in the lasting effects of exposure to stimulant drugs like amphetamine, and may have some therapeutic value in the field of drug tolerance. interactions deleted in colorectal cancer has been shown to interact with: appl1, androgen receptor, caspase 3, maz, ntn1 and ptk2. history dcc's biological role in cancer has had a long, controversial history. although dcc has been studied for many years, a significant amount of the data collected is contradictory and much of the focus has been on getting clear picture of the basics. when the genetic abnormalities that occur in advanced colorectal cancer were first identified, one of the most frequent events was found to be loss of heterozygosity (loh) of region 18q21. one of the first genes sequenced in this region was dcc, and it was subsequently analyzed for tumour suppressor activity. however, the lack of somatic dcc mutations made it seem likely that the nearby smad2 and smad4 genes were the reason for 18q21 loh. the fact that dcc heterozygotes had no increased rates of cancer, even when crossed with mice carrying apc mutations, solidified this viewpoint. the finding that dcc was a receptor for netrin-1 involved in axon guidance initially moved research away from dcc in cancer. it was later realized that dcc may be involved in directing cell motility, which has direct implications for metastatic cancer. the first direct evidence for dcc as a tumour suppressor gene was published in 1995. researchers found that addition of dcc to an immortalized cell line suppressed tumorigenicity rather definitively. however no mechanism for this suppression was obvious, and it took several years to propose one. nearly ten years after dcc was discovered, studies were published that showed that dcc was involved in apoptosis. instead of studying loss of dcc as was commonly done, the authors looked at human embryonic kidney cells transfected with dcc. they found an increase in apoptosis that corresponded to dcc expression, which was completely eliminated when netrin-1 was co-transfected or simply added to the media. when it was understood that dcc apoptosis may also be overcome by netrin-1 overexpression, colorectal cancers were assessed for netrin-1 overexpression, and a small but significant percent of these cancers were found to vastly overexpress the molecule.