Phenotypic analogy to mice with homozygous inactivation of Ntn1 encoding the secreted axonal guidance protein netrin1, or Dcc encoding its receptor Deleted in Colorectal Cancer led us to perform sequence analysis of NTN1 and DCC in all the patients.No pathogenic mutations were found.
These findings indicate that the loss of one chromosome 18 is an important mechanism producing allelic deletion of the DCC gene in colorectal carcinomas.
Combined analysis of data obtained from individuals of either Kazakh or Russian decent showed a significant association with increased CRC risk in the following genotypes: DCC (32008376G/G and G/A versus A/A; OR = 3.45, 95 % confidence interval (95 %CI) = 1.75-6.81, χ (2) = 14.07, p < 0.0002), MLH1 (-93G/G versus G/A and A/A; OR = 1.45, 95 %CI = 1.02-2.07, χ (2) = 4.21, p < 0.04), TP53 (Pro72Pro; OR = 3.80, 95 %CI = 2.46-5.88, χ (2) = 61.27, p < 0.0001), combination GSTT1 deletions with heterozygotes versus normal homozygotes (OR = 1.43, 95 %CI = 1.00-2.04, χ (2) = 3.90, p < 0.05), and GSTM1 deletions (OR = 1.83, 95 %CI = 1.28-2.63, χ (2) = 11.04, p < .001).
In order to examine whether the deletion of the putative cell adhesion molecule DCC is related to the level of GJIC, which might, in turn, be important in human colorectal cancers, we compared levels of expression of the DCC gene with the GJIC capacity of a panel of human colorectal adenocarcinoma cell lines isolated from different stages of tumor progression.
The data recorded in our series differ from other authors' data in three respects: a high incidence of pseudodiploid chromosome number, rearrangements of chromosome 19 and 15, and involvement of DCC gene in the development of gastric cancer, as well as in colorectal cancer as previously reported.
In addition, all 4 specimens of colorectal cancer with liver metastasis showed the decreased expression level of DCC mRNA, suggesting that functional loss of DCC in cancerous tissues may play an important role in metastatic events.
A polymorphic change (Arg to Gly) at DCC codon 201 is related to advanced colorectal carcinoma and increases in the tumors with absent DCC protein expression.
It was subsequently shown that somatic mutations of these genes (APC, mismatch repair genes, TP53, KRAS, and DCC) also occur in sporadic colorectal cancer.
In contrast, distinct MIN-tumor-associated DNA amplifications were detected for E2F5 (8p22-q21.3), GARP (11q13.5-q14), ATM (11q22.3), KAL (Xp22.3), and XIST (Xq13.2) as well as DNA deletions for RAF1 (3p25), DCC (18q21.3), and KEN (21q tel). aCGH revealed distinct DNA copy number changes of oncogenes and tumor suppressor genes in CIN- and MIN-type sporadic colorectal carcinomas.
Whether or not the deleted in colorectal cancer (DCC) gene is implicated in metastases or in predicting prognosis in patients with colorectal cancer has not previously been substantiated.
While the DCC gene was expressed in most normal tissues, including colonic mucosa, its expression was greatly reduced or absent in most colorectal carcinomas tested.
Data are insufficient to recommend the routine use of p53, ras, thymidine synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, microsatellite instability, 18q loss of heterozygosity, or deleted in colon cancer (DCC) protein in the management of patients with colorectal cancer.
We previously used microcell-mediated chromosome transfer (MMCT) into the CRC cell line SW620 to map a approximately 7.7-Mb colorectal cancer-suppressor region (CRCSR) at 8p22-23.1.
These results suggest that the DCC gene is included in the allelic deletion on chromosome 18q, and that the progression of colorectal carcinoma from early stage to advanced stage accompanies the inactivation of the DCC gene through LOH and other mechanisms.
Since allelic loss of genes involved in the development of colorectal cancer could serve as prognostic markers, we examined the correlation between loss of markers linked to the hMSH2/hMSH6 (2p21-16.3), hMLH1 (3p21.3), APC (5q21-22), p53 (17p13.1) and DCC (18q21.3) loci and survival in a series of 64 consecutively collected colorectal cancers.
Well-known genetic bases for the carcinogenesis of CRC include chromosomal changes characteristic of the chromosomal instability pathway which correlates with specific and well-defined genetic alterations (such as APC, K-RAS, DCC and p53) and genomic instability characteristics for the mutator pathway focused on KRAS and BRAF mutations.
However, thus far few studies have analyzed the impact of numerical abnormalities of chromosomes 17 and 18, which carry the p53 and DCC plus SHAD4/DPC4 genes involved in colorectal cancer, on the clinical and biological behaviors of the disease.
Alterations of DCC gene were analyzed in stage-matched two panels of 30 RER+ and 30 RER- colorectal cancers using semiquantitative reverse transcription-PCR and PCR-LOH analyses.