Cancer Report

Cancer : Colon: Colorectal adenocarcinoma
Cancer Name Colon: Colorectal adenocarcinoma
Description Hereditary colorectal cancers can be broadly classified into three types:
  • 1- Familial adenomatous polyposis (FAP): characterized by the development of hundreds of polyps at a very early age, due to mutations in the APC gene.
  • 2- Attenuated familial adenomatous polyposis (AFAP): Fewer polyps, and later onset of cancer than FAP. The difference is due to extreme 5' mutations in APC gene.
  • 3-Hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome: develops without the polyps, due to germline mutations in genes intervening in the repair of DNA mismatches occurring during replication (mostly hMSH2 and hMLH1 on 2p16 and 3p21 respectively).
    Clinics and Pathology
    Disease Adenocarcinoma
    Etiology 75% colorectal cancers occur sporadically. 25% are associated with family history. 5-6% through genetic mutations. 85% arise from chromosomal instability, 15% due to microsatellite instability. Most arise from adenomatous polyps.
    History with ulcerative colitis, breast, uterine and ovarian cancers. Personal or familial history of colon cancer increases the risk (23% of all colorectal cancers).
    High fat diet, obesity, smoking may also increase the risk.
    Epidemiology Colorectal cancer is the third most frequent cancer in the world in both sexes and the third most frequent cause of cancer related deaths.
    Until age 50, men and women are susceptible at same levels, but after 50 years of age, men are more susceptible.
    Pathology Dukes's staging system, modified by Astler-Coller. Detection through colonoscopy, flexible sigmoidoscopy, barium enema, chest x-ray, faecal occult blood testing (FOBT).
    Treatment Surgery is the most common method.
  • For colon cancer, the tumour together with a small portion of the surrounding tissue is removed with the adjacent lymph nodes.
  • For rectal cancer, rectum is totally removed and replaced with colostomies.
    After surgery, micrometastasis can be experienced, which requires chemotherapy to destroy the metastatic cells (adjuvant chemotherapy). 5FU is the most frequently used drug. Radiotherapy may be used for rectal cancer, but it is not useful in colon cancer.
  • Prognosis Survival, although improving is not much more than 50% after 5 years, depending mainly of the stage of tumour growth at the time of diagnosis. Metastasis resulting from penetration of the tumor through the bowel wall of the colon is very common with lymph node involvement. Patients with early colon cancer can survive with surgery (more than 80%). For patients with metastasis, 5 year survival rate is less than 10%.
    Genetic alterations have been studied in relation to prognosis with contradictory results. Loss of heterozygosity (LOH) of chromosomes 18q and 17p and overexpression and mutation of the p53 gene result in poorer prognosis in primary cancer patients.
    Related Genes
    Gene Symbol CAV2
    Description From maunal review
    Gene Symbol CTNNB1
    Description From COSMIC, OMIM, cancer gene census of CGP
    Gene Symbol PTPRG
    Description From OMIM: "Wang et al. (2004) performed a mutational analysis of the tyrosine phosphatase gene superfamily in human cancers and identified 83 somatic mutations in 6 protein-tyrosine phosphatases (PTPRF, 179590; PTPRG; PTPRT, 608712; PTPN3, 176877; PTPN13, 600267; and PTPN14, 603155), affecting 26% of colorectal cancers and a smaller fraction of lung, breast, and gastric cancers."
    Gene Symbol CAV1
    Description From maunal review
    Gene Symbol FHIT
    Description From OMIM: "Ohta et al. (1996) identified a human gene, which they designated fragile histidine triad (FHIT). The FHIT gene, a member of the histidine triad gene family, encodes a protein similar to the aph1 gene in S. pombe. The gene is composed of 10 exons distributed over at least 500 kb, with three 5-prime untranslated exons centromeric to the renal carcinoma-associated 3p14.2 breakpoint, the remaining exons telomeric to this translocation breakpoint, and exon 5 within the homozygously deleted fragile region. Aberrant transcripts of the FHIT locus were found in approximately 50% of esophageal, stomach, and colon carcinomas."
    Gene Symbol ALOX5
    Description "Exposure to cigarette smoke extract (CSE) was shown to enhance 5-LOX protein expression in the inflammation-associated colonic adenomas. The effects of CSE on colon cancer cells were mediated by 5-LOX DNA demethylation. In addition, an up-regulation of matrix metalloproteinase-2 (, MMP-2 ) and vascular endothelial growth factor (VEGF), key angiogenic factors for tumorigenesis, were also observed. These effects were reversed by treating the colon cancer cells with dual 5-LOX and COX-2 inhibitors."
    Gene Symbol APAF1
    Description "Gastro-intestinal tract cancers ( oesophagus cancer, gastric cancer, gallbladder cancer, ampulla of vater cancer, peritoneum cancer, vermiform appendix cancer,, colon cancer, rectal cancer , cancer of the anus). "
    Gene Symbol NQO1
    Description From maunal review:
    Gene Symbol MYC
    Description "amplification has been described in many types of tumour, including, breast ,, cervical and, colon cancers, as well as in squamous cell carcinomas of the head and neck,, myeloma , non-Hodgkin's lymphoma, gastric adenocarcinomas and, ovarian cancer"
    Gene Symbol ERBB2
    Description From COSMIC:
    Gene Symbol PMS1
    Description From OMIM, cancer gene census of CGP
    Gene Symbol CTNNA1
    Description From COSMIC:
    Gene Symbol MUTYH
    Description From cancer gene census of CGP:
    Gene Symbol MTHFR
    Description From OMIM: "Aberrant DNA methylation is a common feature of human neoplasia. Paz et al. (2002) studied interindividual inherited susceptibility to the epigenetic processes of CpG island hypermethylation and global genomic hypomethylation, which are observed simultaneously in cancer cells. They genotyped 233 patients with colorectal, breast, or lung tumors for 4 germline variants in 3 key genes involved in the metabolism of the methyl group. A positive association was found between aberrant methylation and the 677T allele. A second association of aberrant methylation was with homozygosity for the 2756G allele of methionine synthase (156570.0008)."
    Gene Symbol AXIN2
    Gene Symbol CDKN2A
    Description From COSMIC:
    Gene Symbol SMAD2
    Description From NCI, OMIM
    Gene Symbol FBXW7
    Description From cancer gene census of CGP:
    Gene Symbol STK11
    Description From COSMIC:
    Gene Symbol PTCH
    Description From COSMIC:
    Gene Symbol AATF
    Description From OMIM: "Di Padova et al. (2003) found that CHE1 expression was downregulated in several tumors, including colon and kidney carcinomas, compared with matched normal tissues. CHE1 overexpression inhibited proliferation in 2 colon carcinoma cell lines by activating the cyclin-dependent kinase inhibitor WAF1 (CDKN1A; 116899) in a p53 (190070)-dependent manner and by promoting growth arrest at the G1 phase of the cell cycle. CHE1 activated WAF1 by displacing histone deacetylase-1 (HDAC1; 601241) from the Sp1 (189906)-binding sites of the WAF1 promoter and accumulating histone H3 (see 601128) on these sites. Downregulation of CHE1 by interfering RNA inhibited WAF1 transactivation and increased cell proliferation. Di Padova et al. (2003) concluded that CHE1 is a general HDAC1 competitor."
    Gene Symbol MADH4
    Description From cancer gene census of CGP, OMIM, COSMIC and NCI
    Gene Symbol TOPORS
    Description From cancer gene census of CGP, COSMIC and NCI
    Gene Symbol WISP2
    Description From OMIM: "Pennica et al. (1998) cloned and characterized 3 genes downstream in the Wnt signaling pathway that are relevant to malignant transformation: WISP1 (603398), WISP2, and WISP3 (603400). The WISP2 cDNA encodes a 250-amino acid protein that is 73% identical to the mouse protein. The authors found that WISP2 RNA expression was reduced in 79% of human colon tumors, in contrast to WISP1 and WISP3, which were overexpressed in colon tumors."
    Gene Symbol SOCS1
    Description From OMIM: "Hanada et al. (2006) found that Socs1 -/- transgenic mice in which Socs1 expression was restored in T and B cells spontaneously developed colorectal carcinoma with nuclear Ctnnb (CTNNB1; 116806) accumulation and p53 (TP53; 191170) mutations at 6 months of age. Treatment with anti-Ifng prevented tumor development, and cancer did not develop in mice lacking both Ifng and Socs1. Immunohistopathologic and Western blot analyses showed hyperactivation of Stat1 and induction of the carcinogenesis-related enzymes Cox2 (PTGS2; 600262) and iNos (NOS2A; 163730) in Socs1 -/- transgenic mice. Hanada et al. (2006) proposed that SOCS1 is an antioncogene that prevents chronic inflammation-mediated carcinogenesis, a mechanism estimated to be responsible for 20% of human cancers, by regulation of the IFNG/ STAT1 pathways."
    Gene Symbol PTENP1
    Description From COSMIC:
    Gene Symbol BRAF
    Description From COSMIC, cancer gene census of CGP
    Gene Symbol TCN2
    Description From Genecards database: GCd
    Gene Symbol CDKN1B
    Gene Symbol RAF1
    Gene Symbol MSH2
    Description From cancer gene census of CGP:
    Gene Symbol K-RAS
    Description From COSMIC, cancer gene census of CGP
    Gene Symbol SRC
    Description From COSMIC:
    Gene Symbol EPHA7
    Gene Symbol MSH6
    Description From cancer gene census of CGP: "Mutations in four mismatch repair genes MSH2, MLH1, MSH6, and PMS2, have been convincingly linked to susceptibility of hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome. Of the 500 different HNPCC-associated MMR gene mutations known, approximately 10% are associated with mutations in the MSH6 gene."
    Gene Symbol PMS2
    Description From cancer gene census of CGP, OMIM: "Hendriks et al. (2006) analyzed the PMS2 gene in 112 patients from MLH1-, MSH2- and MSH6-negative HNPCC-like families and in 775 tumors from patients with familial colorectal cancer. They identified 4 genomic rearrangements and 3 truncating point mutations (600259.0008-600259.0010). The pattern of inheritance was autosomal dominant, and mutations segregated with disease. The most common cancer was colorectal carcinoma, followed by endometrial and ovarian carcinomas. The phenotype was milder compared to that of families with MLH1 or MSH2 mutations
    Gene Symbol REG-IV
    Description From OMIM: "Using Northern blot analysis, Violette et al. (2003) demonstrated high levels of REG4 mRNA in 4 of 6 drug-resistant human colorectal cancer cell lines, but very little or no REG4 mRNA is 2 drug-sensitive cell lines"
    Gene Symbol FAP
    Description from NCI: "Hereditary colorectal cancer has 2 well-described forms: familial adenomatous polyposis (FAP, including an attenuated form of polyposis [AFAP]), due to germline mutations in the APC gene,[45-52] and hereditary nonpolyposis colorectal cancer (HNPCC), which is caused by germline mutations in DNA mismatch repair genes.[53-56] Many other families exhibit aggregation of colorectal cancer and/or adenomas, but with no apparent association with an identifiable hereditary syndrome, and are known collectively as familial colorectal cancer (FCC).[2]"
    Gene Symbol CBLC
    Description From OMIM: "By searching an EST database for sequences similar to CBL, followed by screening a kidney cDNA library and oligo capping to extend the 5-prime sequence, Kim et al. (1999) cloned CBLC. Northern blot analysis detected a 2.0-kb transcript highly expressed in colon and small intestine. Expression was also observed in pancreas, placenta, liver, kidney, and prostate, but not in brain, testis, and lymphoid tissues. Minor transcripts of 4.0 and 6.0 kb were also detected in several tissues. Western blot analysis found that endogenous CBLC migrated with an apparent molecular mass of 52 kD in colon carcinoma cell lines."
    Gene Symbol ERCC1
    Gene Symbol SMO
    Description From COSMIC:
    Gene Symbol CDH1
    Description From COSMIC, OMIM
    Gene Symbol BRCA2
    Description From COSMIC:
    Gene Symbol EP300
    Description From cancer gene census of CGP:
    Gene Symbol ARHA
    Gene Symbol KLF5
    Description "Down-regulation of KLF5 may be an early event in intestinal tumorigenesis. Expression of KLF5 in non-transformed intestinal epithelial cells enhances cell growth; however, KLF5 inhibits cell growth in colon cancer cell lines. Another group found that all-trans retinoic acid inhibits intestinal epithelial cell growth in vitro through inhibiting KLF5 expression. At the same time, lipopolysaccharide (LPS) induces proinflammatory response in intestinal epithelial cells through inducing KLF5 expression. These findings suggest that KLF5 may play an important but yet to be identified role in intestinal and colon cancer."
    Gene Symbol ITGAV
    Description Cancer Metastasis Rev 2003 Mar;22(1):103-15:
    Gene Symbol HSPH1
    Gene Symbol PIK3CA
    Description From COSMIC, cancer gene census of CGP
    Gene Symbol RB1
    Description From COSMIC:
    Gene Symbol DCC
    Description from NCI: "The transition from normal epithelium to adenoma to carcinoma is associated with acquired molecular events.This tumor progression model was deduced from comparison of genetic alterations seen in normal colon epithelium, adenomas of progressively larger size, and malignancies. At least 5 to 7 major deleterious molecular alterations may occur when a normal epithelial cell progresses in a clonal fashion to carcinoma. There are at least 2 major pathways by which these molecular events can lead to colorectal cancer. About 85% of colorectal cancers are due to events that result in chromosomal instability (CIN) and the remaining 15% are due to events that result in microsatellite instability (MSI or MIN, also known as replication error [RER]).The spectrum of somatic mutations contributing to the pathogenesis of colorectal cancer is likely to be far more extensive than previously appreciated. A comprehensive study that sequenced more than 13,000 genes in a series of colorectal cancers found that tumors accumulate an average of approximately 90 mutant genes. Sixty-nine genes were highlighted as relevant to the pathogenesis of colorectal cancer, and individual colorectal cancers harbored an average of 9 mutant genes per tumor. In addition, each tumor studied had a distinct mutational gene signature. Key changes in CIN cancers include widespread alterations in chromosome number (aneuploidy) and detectable losses at the molecular level of portions of chromosome 5q, chromosome 18q, and chromosome 17p; and mutation of the KRAS oncogene. The important genes involved in these chromosome losses are APC(5q), DCC/MADH2/MADH4(18q), and TP53(17p), and chromosome losses are associated with instability at the molecular and chromosomal level."
    Gene Symbol MLH1
    Description From cancer gene census of CGP:
    Gene Symbol VRK1
    Gene Symbol MAPRE1
    Description "Truncation of the Adenomatous Polyposis Coli (APC) protein is seen in, Familial Adenomatous Polyposis (FAP) as well as most sporadic colon cancers. EB1 binds to the APC C-terminus, so its binding is lost in most truncations. Also lost are other APC binding partners including the transcription factor, beta-catenin . The role of APC as a tumor suppressor is thought to be through the beta-catenin pathway. Some evidence in the mouse suggests that this is true.
    However, there is increasing evidence that connections between APC and the cytoskeleton are important in cell migration, which could have an important role in colon cancer. One Italian FAP family has been reported in which APC is truncated distal to the beta-catenin binding site but including the EB1 binding site. There is no direct evidence of EB1 mutation in colon cancer, and a single report found no evidence of somatic mutations by reverse transcriptase single-strand conformational polymorphism (SSCP) analysis in 21 sporadic colorectal cancers and seven colorectal adenomas."
    Gene Symbol EGFR
    Description From COSMIC:
    Gene Symbol MAP2K4
    Description From cancer gene census of CGP:
    Gene Symbol N-RAS
    Description From COSMIC:
    Gene Symbol MMP19
    Description From manual review:
    Gene Symbol CHFR
    Description From OMIM: "Toyota et al. (2003) analyzed the pattern of CHFR expression in a number of human cancer cell lines and primary tumors. They found CpG methylation-dependent silencing of CHFR expression in 45% of cancer cell lines, 40% of primary colorectal cancers, 53% of colorectal adenomas, and 30% of primary head and neck cancers. Expression of CHFR was precisely correlated with both CpG methylation and deacetylation of histones H3 and H4 in the CpG-rich regulatory region. Cells with CHFR methylation had an intrinsically high mitotic index when treated with microtubule inhibitor. This means that cells in which CHFR was epigenetically inactivated constituted loss-of-function alleles for mitotic checkpoint control. Taken together, these findings shed light on the pathway by which the mitotic checkpoint is bypassed in cancer cells and suggest that inactivation of checkpoint genes is much more widespread than previously suspected."
    Gene Symbol P53
    Description From manual review: "Glioblastoma is the most malignant astrocytic tumor and is preferentially located in the cerebral hemisphere. It may develop from a less malignant precursor lesion such as diffuse astrocytoma or anaplastic astrocytoma, or may develop de novo (secondary glioblastoma and primary glioblastoma respectively). Secondary glioblastoma are more frequent in younger patients and have a better prognosis."
    Gene Symbol PTPN11
    Description From COSMIC:
    Gene Symbol MMP2
    Description "Elevated expression of MMP-2, along with MMP-9 is usually seen in invasive and highly tumorigenic cancers such as, colorectal tumors , gastric carcinoma, pancreatic carcinoma,, breast cancer ,, oral cancer , melanoma,, malignant gliomas ,, Chondrosarcoma , gastrointestinal adenocarcinoma. Levels are also increased in malignant, astrocytomas , carcinomatous meningitis, and brain metastases."
    Gene Symbol APC
    Description From COSMIC, manual review, cancer gene census of CGP Somatic mutation of the APC gene is found in the majority of colorectal adenocarcinomas. Sporadic colorectal cancer is the third most frequent cancer in the world.
    Gene Symbol CES2
    Description From maunal review
    Gene Symbol HRAS
    Description From OMIM: "In 2 of 38 urinary tract tumors, Fujita et al. (1985) detected HRAS oncogenes by transfection, cloned the oncogene in biologically active form, and showed that it contained single base changes at codon 61 leading to substitutions of arginine and leucine, respectively, for glutamine at this position. In 1 tumor, a 40-fold amplification of KRAS was found. In the cell lines isolated from a single colon cancer, Greenhalgh and Kinsella (1985) found a point mutation in codon 12 of HRAS leading to an amino acid change in the gene product. The authors cited experience with KRAS involvement in 3 colon cancers and NRAS involvement in 1, while some 34 other colon cancers failed to demonstrate HRAS activation at codon 12. "
    Gene Symbol WISP3
    Cytogenetics Morphological There are two types of colorectal cancers, according to the ploidy:
  • Aneuploid tumours showing numerous allelic losses; Aneuploidy, loss and rearrangements of chromosome 1p (about 70%), 5q (55%, loss of APC), 15q, 18q (65%, loss of DCC), 17p (80%, TP53), and 17q (30%); and abnormalities in 7q(25%) and 8p (55%). Reciprocal translocation t(5;10)(q22;q25), inv(5)(q22-q31.3).
  • Diploid tumours without frequent allelic losses.
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