In the past decades, a number of genomic changes were found in colorectal adenoma and carcinoma, but the target genes are limited and molecular mechanism of adenoma to carcinoma progression is still unknown.
Previous studies found that 8q, 13q and 20q gains and 8p, 15q and 18q losses are linked with colorectal adenoma to carcinoma progression [4–9]. Our study narrowed down the gain regions to 13q13.1-q14.11, 13q21.1-q32.1, 13q32.2-q34 and 20q11.23-q12 and the loss regions to 18q11.2. Furthermore, gains of 7p21.3-p15.3 and 7q22.3-q32.1 and losses of 17p13.1-p11.2, 18p11.32-p11.21 were also found in both rectal adenoma and carcinoma.
Our study also showed that some genomic aberrations were present in rectal tumor but not in adenoma. They are gains of 1q and 6p21.33 and losses of 10p14-p11.21, 14q12-q21.1, 14q22.1-q24.3, 14q31.3-q32.1, 14q32.2-q32.32, 15q15.1-q21.1, 15q22.31 and 15q25.1-q25.2. These aberrations occurred at the later stages of rectal carcinogenesis, and may contribute the progression from adenoma to carcinoma.
Identifying the candidate targets underlying the genomic aberrations was important for understanding the mechanism of carcinogenesis. Carvalho et al. found that the overexpressions of C20orf24, AURKA, RNPC1, TH1L, ADRM1, C20orf20 and TCRL5 in carcinomas compared with adenomas were correlated with 20q gain . Habermann et al. showed that copy number changes of 7q, 8p, 8q, 13q, 18p, 18q, 20p and 20q deregulated the average expression levels of the genes on these chromosome arms . However, most of samples detected in these reports were colon cancer which had some different genomic aberrations compared with rectal cancer , expression-dysregulated genes in the carcinogenesis of rectum were still limited. By literature analyses, we selected 14 genes to compare their expression between in tumor and paracancerous tissues or between in rectal adenoma and carcinoma tissues. Of them, copy number and mRNA expression of EFNA1 increased from rectal adenoma to carcinoma, and C13orf27 and PMEPA1 with gains in both adenoma and carcinoma were overexpressed in rectal cancer tissues. These results revealed that copy number increase maybe the reason of expression up-regulation. Interestingly, both mRNA and protein expression of GPNMB was higher in cancer tissues than rectal adenoma tissues.
GPNMB is a type I transmembrane protein and overexpressed in several malignant human tissues relative to the corresponding normal tissues. Ectopic overexpression of GPNMB/osteoactivin can promote the metastasis and invasion of glioma, breast and hepatocellular carcinoma [14–17]. EFNA1 was overexpressed in hepatocellular carcinoma and can inhibit growth of malignant mesothelioma by phosphorylating EPHA2 [18, 19]. C13orf27 was overexpressed in rectal tumor in our study, but the function of C13orf27 was unknown. PMEPA1 was also identified in our study, which is mapped to 20q13.3 is a TGF-beta inducible gene and encodes a NEDD4 E3 ubiguitin ligase binding protein. PMEPA1 is over-expressed in prostate, breast, renal cell, stomach and rectal carcinomas [20–22]. But little is known about the function of PMEPA1, Further study should be conducted to investigate the roles of the above genes in human colorectal cancer.
Loss of 18q is a common event in colorectal cancer, and 18q deletion and loss of SMAD4 expression are associated with liver metastasis. In colorectal cancer, patients with reduced SMAD4 expression frequently presented an unfavorable survival because of liver metastasis [23–26]. High expression level of SMAD4 reflected significantly longer overall and disease-free survival time than low expression level . Bixiang et al. found that transgenic expression of SMAD4 can significantly reduce the oncogenic potential of MC38 and SW620 cells . Our study confirmed the decreased expression of SMAD4 in rectal cancer.
In summary, we identified EFNA1 (1q), C13orf27 (13q), PMEPA1 (20q), GPNMB (7q) as candidate driving genes of genomic aberrations in rectal cancer. Further study was needed to reveal the mechanisms by which these genes may be involved in the carcinogenesis of the rectum.