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The rectum adenocarcinoma proteomeColorectal cancer is the third most common cancer in the world and the fifth leading cause of cancer-related mortality. Environmental factors, including meat consumption, have been identified as important risk factors. The overall mortality is approximately 50%. The surgical stage at diagnosis is the most important factor for predicting prognosis and the survival rate varies greatly depending on the stage. The 5-year survival rate is more than 90% for stage I and less than 10% for stage IV. Most colorectal cancer cases are detected at an advanced stage. Bleeding and hematochezia are two of the most common symptoms associated with rectal lesions. Colorectal cancer is considered to originate from normal colon epithelium that develops into precursor lesions termed adenomas that subsequently may progress to invasive colorectal adenocarcinomas with metastatic potential. Colorectal cancer is divided into two subtypes, colon adenocarcinomas (COAD) and rectum adenocarcinomas (READ), depending on the site of the tumor. Here, we explore the rectum adenocarcinoma proteome using TCGA transcriptomics data and antibody-based protein data. 878 genes are suggested as prognostic based on transcriptomics data from 88 patients; 242 genes are associated with unfavorable prognosis and 638 genes are associated with favorable prognosis. TCGA data analysisIn this metadata study, we used data from TCGA where transcriptomics data was available from 88 patients in total, 39 females and 49 males. A majority of the patients (70 patients) were still alive at the time of data collection. The stage distribution was stage i) 10 patients, stage ii) 25 patients, stage iii) 32 patients, stage iv) 12 patients and 9 patients with missing stage information. Unfavorable prognostic genes in rectum adenocarcinomaFor unfavorable genes, higher relative expression levels at diagnosis give significantly lower overall survival for the patients. There are 242 genes associated with an unfavorable prognosis in rectum adenocarcinoma, among these potential prognostic genes there is 1 gene that was validated in a separate study. In Table 1, the top 20 most significant genes related to an unfavorable prognosis are listed. CD63 is a gene associated with unfavorable prognosis in rectum adenocarcinoma. The best separation is achieved by an expression cutoff at 677 TPM which divides the patients into two groups with 0% 5-year survival for patients with high expression versus 57% for patients with low expression, p-value: 4.97e-5. Immunohistochemical staining using an antibody targeting CD63 (HPA010088) shows a differential expression pattern in rectum adenocarcinoma samples.
p<0.001
Table 1. The 20 genes with highest significance associated with an unfavorable prognosis in rectum adenocarcinoma.
Favorable prognostic genes in rectum adenocarcinomaFor favorable genes, higher relative expression levels at diagnosis give significantly higher overall survival for the patients. There are 638 genes associated with a favorable prognosis in rectum adenocarcinoma, among these potential prognostic genes there are 8 genes that were validated in a separate study. In Table 2, the top 20 most significant genes related to a favorable prognosis are listed. ZSCAN16 is a gene associated with a favorable prognosis in rectum adenocarcinoma. The best separation is achieved by an expression cutoff at 5.7 TPM which divides the patients into two groups with 66% 5-year survival for patients with high expression versus 0% for patients with low expression, p-value: 7.84e-7. Immunohistochemical staining using an antibody targeting ZSCAN16 (HPA007290) shows a differential expression pattern in rectum adenocarcinoma samples.
p<0.001
Table 2. The 20 genes with highest significance associated with a favorable prognosis in rectum adenocarcinoma.
The rectum adenocarcinoma transcriptomeThe transcriptome analysis shows that 66% (n=13338) of all human genes (n=20162) are expressed in rectum adenocarcinoma. All genes were classified according to the rectum adenocarcinoma-specific expression into one of five different categories, based on the ratio between mRNA levels in rectum adenocarcinoma compared to the mRNA levels in the other 16 analyzed cancer tissues.
Figure 1. The distribution of all genes across the five categories based on transcript abundance in rectum adenocarcinoma as well as in all other cancer tissues. 175 genes show some level of elevated expression in rectum adenocarcinoma compared to other cancers (Figure 1). The elevated category is further subdivided into three categories as shown in Table 3. Table 3. The number of genes in the subdivided categories of elevated expression in rectum adenocarcinoma.
Additional informationAppropriate diagnosis and staging are crucial for determining the best choice of treatment. The surgical stage represents a classification system based on the extent and depth of tumor growth. Stage I colorectal cancer shows invasive growth into the anatomical layers of the the large intestine, but the tumor has not spread beyond the tissue of origin. Stage II colorectal cancer shows extended growth through the outer layer of the large intestine (peritoneum) and may have extended into nearby organs, but has not spread to any lymph node. Stage III colorectal cancer has spread to nearby lymph nodes but not yet metastasized to distant sites in the body. Finally, in Stage IV colorectal cancer the tumor has spread to distant organs such as the liver, lungs, or other sites. The Dukes classification is an older and less complicated staging system that predates the TNM system, and translates so that Duke A= Stage I, Duke B= Stage II, Duke C= Stage III and Dukes D= Stage IV. Early colorectal cancer, where tumor spread is restricted to large intestine, is treated surgically and chemotherapy is used for more advanced stages where the tumor has spread to other organs. Anti-EGFR treatment is one recently introduced therapy. Epidermal growth factor receptor (EGFR) is commonly expressed in colorectal tumors and monoclonal antibodies inhibiting EGFR demonstrate clinical efficacy in patients with tumors that do not harbor downstream activating KRAS mutations. Today KRAS mutation status is analyzed routinely before starting anti-EGFR treatment. The vast majority of colorectal cancer are adenocarcinomas, with less than 10% of the cancers being distinguished by an abundant secretion of mucin. The tumors are classified according to the degree of morphological differentiation into well, moderately and poorly differentiated. About 80% are well or moderately differentiated with a growth pattern consisting of tumor cells that form irregular glandular structures present at different layers of the bowel wall. Poorly differentiated colorectal cancer show no, or only slight, glandular formation. Generally poor differentiation is associated with poor prognosis, however there is no firmly established system for measuring the grade of differentiation. Therefore, treatment decisions are based on the surgical stage and not morphological features. Apart from adenocarcinomas, endocrine tumors can also arise within the colorectal mucosa. Squamous and adenosquamous tumors are exceedingly rare. In addition to microscopical examination of biopsies, immunohistochemistry can be used to determine the colorectal origin of a metastasis or to visualize the spread of tumor cells in surrounding tissues. Tumors of colorectal origin are immunoreactive toward cytokeratin 20, CDX-2, SATB2 and cadherin-17. Chromogranin-A antibodies can be used to distinguish endocrine tumors in the bowel from adenocarcinomas. Relevant links and publications Uhlen M et al., A pathology atlas of the human cancer transcriptome. Science. (2017) |
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The Human Protein Atlas project is funded
