|Classification and external resources|
Diagram of the lower gastrointestinal tract
|ICD-O:||M8140/3 (95% of cases)|
|eMedicine||med/413 med/1994 ped/3037|
Colorectal cancer (also known as colon cancer, rectal cancer, bowel cancer or colorectal adenocarcinoma) is a cancer from uncontrolled cell growth in the colon or rectum (parts of the large intestine), or in the appendix. Genetic analysis shows that essentially colon and rectal tumours are genetically the same cancer. Symptoms of colorectal cancer typically include rectal bleeding and anemia which are sometimes associated with weight loss and changes in bowel habits.
Most colorectal cancer occurs due to lifestyle and increasing age with only a minority of cases associated with underlying genetic disorders. It typically starts in the lining of the bowel and if left untreated, can grow into the muscle layers underneath, and then through the bowel wall. Screening is effective at decreasing the chance of dying from colorectal cancer and is recommended starting at the age of 50 and continuing until a person is 75 years old. Localized bowel cancer is usually diagnosed through sigmoidoscopy or colonoscopy.
Cancers that are confined within the wall of the colon are often curable with surgery while cancer that has spread widely around the body is usually not curable and management then focuses on extending the person's life via chemotherapy and improving quality of life. Colorectal cancer is the third most commonly diagnosed cancer in the world, but it is more common in developed countries. Around 60% of cases were diagnosed in the developed world. It is estimated that worldwide, in 2008, 1.23 million new cases of colorectal cancer were clinically diagnosed, and that it killed 608,000 people.
- 1 Signs and symptoms
- 2 Cause
- 3 Pathogenesis
- 4 Diagnosis
- 5 Prevention
- 6 Management
- 7 Prognosis
- 8 Epidemiology
- 9 Society and culture
- 10 Research
- 11 References
- 12 External links
Signs and symptoms
The symptoms and signs of colorectal cancer depend on the location of tumor in the bowel, and whether it has spread elsewhere in the body (metastasis). The classic warning signs include: worsening constipation, blood in the stool, decrease in stool calibre, loss of appetite, loss of weight, and nausea or vomiting in someone over 50 years old. While rectal bleeding or anemia are high-risk features in those over the age of 50, other commonly-described symptoms including weight loss and change in bowel habit are typically only concerning if associated with bleeding.
Greater than 75-95% of colon cancer occurs in people with little or no genetic risk. Other risk factors include older age, male gender, high intake of fat, alcohol or red meat, obesity, smoking and a lack of physical exercise. Approximately 10% of cases are linked to insufficient activity. The risk for alcohol appears to increase at greater than one drink per day.
Inflammatory bowel disease
People with inflammatory bowel disease (ulcerative colitis and Crohn's disease) are at increased risk of colon cancer. The risk is greater the longer a person has had the disease, and the worse the severity of inflammation. In these high risk groups both prevention with aspirin and regular colonoscopies are recommended. People with inflammatory bowel disease account for less than 2% of colon cancer cases yearly. In those with Crohn's disease 2% get colorectal cancer after 10 years, 8% after 20 years, and 18% after 30 years. In those with ulcerative colitis approximately 16% develop either a cancer precursor or cancer of the colon over 30 years.
Those with a family history in two or more first-degree relatives have a two to threefold greater risk of disease and this group accounts for about 20% of all cases. A number of genetic syndromes are also associated with higher rates of colorectal cancer. The most common of these is hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in about 3% of people with colorectal cancer. Other syndromes that are strongly associated include: Gardner syndrome, and familial adenomatous polyposis (FAP) in which cancer nearly always occurs and is the cause of 1% of cases.
Most deaths due to colon cancer are associated with metastatic disease. A gene that appears to contribute to the potential for metastatic disease, metastasis associated in colon cancer 1 (MACC1), has been isolated. It is a transcriptional factor that influences the expression of hepatocyte growth factor. This gene is associated with the proliferation, invasion and scattering of colon cancer cells in cell culture and tumor growth and metastasis in mice. It has also been associated with the response to treatment.
Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of the gastrointestinal tract, most frequently as a result of mutations in the Wnt signaling pathway that artificially increase signaling activity. The mutations can be inherited or are acquired, and most probably occur in the intestinal crypt stem cell.[not in citation given] The most commonly mutated gene in all colorectal cancer is the APC gene, which produces the APC protein. The APC protein is a "brake" on the accumulation of β-catenin protein; without APC, β-catenin accumulates to high levels and translocates (moves) into the nucleus, binds to DNA, and activates the transcription of genes that are normally important for stem cell renewal and differentiation but when inappropriately expressed at high levels can cause cancer. While APC is mutated in most colon cancers, some cancers have increased β-catenin because of mutations in β-catenin (CTNNB1) that block its degradation, or they have mutation(s) in other genes with function analogous to APC such as AXIN1, AXIN2, TCF7L2, or NKD1.
Beyond the defects in the Wnt-APC-beta-catenin signaling pathway, other mutations must occur for the cell to become cancerous. The p53 protein, produced by the TP53 gene, normally monitors cell division and kills cells if they have Wnt pathway defects. Eventually, a cell line acquires a mutation in the TP53 gene and transforms the tissue from an adenoma into an invasive carcinoma. (Sometimes the gene encoding p53 is not mutated, but another protective protein named BAX is.)
Other apoptotic proteins commonly deactivated in colorectal cancers are TGF-β and DCC (Deleted in Colorectal Cancer). TGF-β has a deactivating mutation in at least half of colorectal cancers. Sometimes TGF-β is not deactivated, but a downstream protein named SMAD is. DCC commonly has deletion of its chromosome segment in colorectal cancer.
Some genes are oncogenes - they are overexpressed in colorectal cancer. For example, genes encoding the proteins KRAS, RAF, and PI3K, which normally stimulate the cell to divide in response to growth factors, can acquire mutations that result in over-activation of cell proliferation. The chronological order of mutations is sometimes important, with a primary KRAS mutation generally leading to a self-limiting hyperplastic or borderline lesion, but if occurring after a previous APC mutation it often progresses to cancer. PTEN, a tumor suppressor, normally inhibits PI3K, but can sometimes become mutated and deactivated.
Comprehensive, genome-scale analysis has revealed that colorectal carcinomas are clearly separable into hypermutated and non-hypermutated tumor types. In addition to the oncogenic and inactivating mutations described for the genes above, non-hypermutated samples also contain mutated CTNNB1, FAM123B, SOX9, ATM, and ARID1A. Progressing through a distinct set of genetic events, hypermutated tumors display mutated forms of ACVR2A, TGFBR2, MSH3, MSH6, SLC9A9, TCF7L2, and BRAF. The common theme among these genes, across both tumor types, is their involvement in WNT and TGF-β signaling pathways, which in turn results in increased activity of MYC, a central player in colorectal cancer.
The term “field cancerization” was first used in 1953 to describe an area or “field” of epithelium that has been preconditioned by (at that time) largely unknown processes so as to predispose it towards development of cancer. Since then, the terms “field cancerization”, “field carcinogenesis”, “field defect”, and “field effect” have been used to describe pre-malignant or pre-neoplastic tissue in which new cancers are likely to arise.
However, in most cancer research, as pointed out by Rubin “The vast majority of studies in cancer research has been done on well-defined tumors in vivo, or on discrete neoplastic foci in vitro. Yet there is evidence that more than 80% of the somatic mutations found in mutator phenotype human colorectal tumors occur before the onset of terminal clonal expansion…” Similarly, Vogelstein et al. point out that more than half of somatic mutations identified in tumors occurred in a pre-neoplastic phase (in a field defect), during growth of apparently normal cells. Likewise, epigenetic alterations present in tumors may have occurred in pre-neoplastic field defects.
Epigenetic alterations are much more frequent in colon cancer than genetic (mutational) alterations. As described by Vogelstein et al., an average cancer of the colon has only 1 or 2 oncogene mutations and 1 to 5 tumor suppressor mutations (together designated “driver mutations”), with about 60 further “passenger” mutations. The oncogenes and tumor suppressor genes are well studied and are described below under Pathogenesis.
However, by comparison, epigenetic alterations in colon cancers are frequent and affect hundreds of genes. For instance, there are types of small RNAs called microRNAs that are about 22 nucleotides long. These microRNAs (or miRNAs) do not code for proteins, but they can “target” protein coding genes and reduce their expression. Expression of these miRNAs can be epigenetically altered. As one example, the epigenetic alteration consisting of CpG island methylation of the DNA sequence encoding miR-137 reduces its expression, and this is a frequent early epigenetic event in colorectal carcinogenesis, occurring in 81% of colon cancers and in 14% of the normal appearing colonic mucosa adjacent to the cancers. The altered adjacent tissues associated with these cancers are called field defects. Silencing of miR-137 can affect expression of about 500 genes, the targets of this miRNA.
Changes in the level of miR-137 expression result in changed mRNA expression of the target genes by 2 to 20-fold and corresponding, though often smaller, changes in expression of the protein products of the genes. Other microRNAs, with likely comparable numbers of target genes, are even more frequently epigenetically altered in colonic field defects and in the colon cancers that arise from them. These include miR-124a, miR-34b/c and miR-342 which are silenced by CpG island methylation of their encoding DNA sequences in primary tumors at rates of 99%, 93% and 86%, respectively, and in the adjacent normal appearing mucosa at rates of 59%, 26% and 56%, respectively.
In addition to epigenetic alteration of expression of miRNAs, other common types of epigenetic alterations in cancers that change gene expression levels include direct hypermethylation or hypomethlyation of CpG islands of protein-encoding genes and alterations in histones and chromosomal architecture that influence gene expression. As an example, 147 hypermethylations and 27 hypomethylations of protein coding genes were frequently associated with colorectal cancers. Of the hypermethylated genes, 10 were hypermethylated in 100% of colon cancers, and many others were hypermethylated in more than 50% of colon cancers. In addition, 11 hypermethylations and 96 hypomethyaltions of miRNAs were also associated with colorectal cancers.
As summarized in the articles Carcinogenesis and Neoplasm, for sporadic cancers in general, a deficiency in DNA repair is occasionally due to a mutation in a DNA repair gene, but is much more frequently due to epigenetic alterations that reduce or silence expression of DNA repair genes.
Diagnosis of colorectal cancer is via tumor biopsy typically done during colonoscopy or sigmoidoscopy, depending on the location of the lesion. The extent of the disease is then usually determined by a CT scan of the chest, abdomen and pelvis. There are other potential imaging test such as PET and MRI which may be used in certain cases. Colon cancer staging is done next and based on the TNM system which is determined by how much the initial tumor has spread, if and where lymph nodes are involved, and if and how many metastases there are.
The histology of the tumor is usually reported from the analysis of tissue taken from a biopsy or surgery. A pathology report will usually contain a description of cell type and grade. The most common colon cancer cell type is adenocarcinoma which accounts for 95% of cases. Other, rarer types include lymphoma and squamous cell carcinoma.
Cancers on the right side (ascending colon and cecum) tend to be exophytic, that is, the tumour grows outwards from one location in the bowel wall. This very rarely causes obstruction of feces, and presents with symptoms such as anemia. Left-sided tumours tend to be circumferential, and can obstruct the bowel much like a napkin ring which can present with thinner calibre stools.
Adenocarcinoma is a malignant epithelial tumor, originating from glandular epithelium of the colorectal mucosa. It invades the wall, infiltrating the muscularis mucosae, the submucosa and thence the muscularis propria. Tumor cells describe irregular tubular structures, harboring pluristratification, multiple lumens, reduced stroma ("back to back" aspect). Sometimes, tumor cells are discohesive and secrete mucus, which invades the interstitium producing large pools of mucus/colloid (optically "empty" spaces) - mucinous (colloid) adenocarcinoma, poorly differentiated. If the mucus remains inside the tumor cell, it pushes the nucleus at the periphery - "signet-ring cell." Depending on glandular architecture, cellular pleomorphism, and mucosecretion of the predominant pattern, adenocarcinoma may present three degrees of differentiation: well, moderately, and poorly differentiated.
Most colorectal cancer tumors are thought to be cyclooxygenase-2 (COX-2) positive. This enzyme is generally not found in healthy colon tissue, but is thought to fuel abnormal cell growth.
PET/CT of a staging exam of colon carcinoma. Besides the primary tumor a lot of lesions can be seen. On cursor position: lung nodule.
Precancer — Tubular adenoma (left of image), a type of colonic polyp and a precursor of colorectal cancer. Normal colorectal mucosa is seen on the right.
Precancer — Colorectal villous adenoma.
The colon cancer staging can be made according to the TNM staging system from the WHO organization, the UICC and the AJCC. The Astler-Coller classification (1954) or the Dukes classification (1932) are now less used.
Tumor budding in colorectal cancer is loosely defined by the presence of individual cells and small clusters of tumor cells at the invasive front of carcinomas. It has been postulated to represent an epithelial–mesenchymal transition (EMT). Tumor budding is a well-established independent adverse prognostic factor in colorectal carcinoma that may allow for stratification of patients into risk categories more meaningful than those defined by TNM staging, and also potentially guide treatment decisions, especially in T1 and T3 N0 (Stage II, Dukes’ B) colorectal carcinoma. Unfortunately, its universal acceptance as a reportable factor has been held back by a lack of definitional uniformity with respect to both qualitative and quantitative aspects of tumor budding.
Current dietary recommendations to prevent colorectal cancer include increasing the consumption of whole grains, fruits and vegetables, and reducing the intake of red meat. The evidence for fiber and fruits and vegetables however is poor. Physical activity can moderately reduce the risk of colorectal cancer.
Aspirin and celecoxib appear to decrease the risk of colorectal cancer in those at high risk. However it is not recommended in those at average risk. There is tentative evidence for calcium supplementation but it is not sufficient to make a recommendation. Vitamin D intake and blood levels are associated with a lower risk of colon cancer.
More than 80% of colorectal cancers arise from adenomatous polyps making this cancer amenable to screening. Diagnosis of cases of colorectal cancer through screening tends to occur 2–3 years before diagnosis of cases with symptoms. Screening has the potential to reduce colorectal cancer deaths by 60%.
Medical societies recommend screening between the age of 50 and 75 years with sigmoidoscopy every 5 years and colonoscopy every 10 years. For those at high risk, screenings usually begin at around 40. For people with average risk who have had a high-quality colonoscopy with normal results, the American Gastroenterological Association does not recommend any type of screening in the 10 years following the colonoscopy. For people over 75 or those with a life expectancy of less than 10 years, screening is not recommended.
The three main screening tests are fecal occult blood testing, flexible sigmoidoscopy and colonoscopy. Of the three, only sigmoidoscopy cannot screen the right side of the colon where 42% of malignancies are found. Virtual colonoscopy via a CT scan appears as good as standard colonoscopy for detecting cancers and large adenomas but is expensive, associated with radiation exposure, and cannot remove any detected abnormal growths like standard colonoscopy can.
Fecal occult blood testing (FOBT) of the stool is typically recommended every two years and can be either guaiac based or immunochemical. Annual FOBT screening results in a 16% relative reduction in colorectal cancer mortality, but no difference in all-cause mortality. Immunochemical tests are highly accurate and do not require dietary or medication changes before testing.
The M2-PK test identifies an enzyme in colorectal cancers and polyps rather than blood in the stool. It does not require any special preparation prior to testing. M2-PK is sensitive for colorectal cancer and polyps and is able to detect bleeding and non-bleeding colorectal cancer and polyps. In the event of a positive result people would be asked to undergo further examination e.g. colonoscopy.
The treatment of colorectal cancer can be aimed at curation or palliation. The decision on which aim to adopt depends on various factors, including the patient's health and preferences, as well as the stage of the tumour. When colorectal cancer is caught early, surgery can be curative. However, when it is detected at later stages for which (metastases are present), this is less likely and treatment is often directed at palliation, to relieve symptoms caused by the tumour and keep the person as comfortable as possible.
For people with localized cancer, the preferred treatment is complete surgical removal with adequate margins, with the attempt of achieving a cure. This can either be done by an open laparotomy or sometimes laparoscopically. If there are only a few metastases in the liver or lungs they may also be removed. Sometimes chemotherapy is used before surgery to shrink the cancer before attempting to remove it. The two most common sites of recurrence of colorectal cancer is in the liver and lungs.
If cancer has entered the lymph nodes, adding the chemotherapy agents fluorouracil or capecitabine increases life expectancy. If the lymph nodes do not contain cancer, the benefits of chemotherapy are controversial. If the cancer is widely metastatic or unresectable, treatment is then palliative. Typically in this setting, a number of different chemotherapy medications may be used. Chemotherapy drugs for this condition may include capecitabine, fluorouracil, irinotecan, leucovorin, oxaliplatin and UFT. Another type of agent that is sometimes used are the epidermal growth factor receptor inhibitors.
While a combination of radiation and chemotherapy may be useful for rectal cancer, its use in colon cancer is not routine due to the sensitivity of the bowels to radiation. Just as for chemotherapy, radiotherapy can be used in the neoadjuvant and adjuvant setting for some stages of rectal cancer.
In people with incurable colorectal cancer, palliative care can be considered for improving quality of life. Surgical options may include non-curative surgical removal of some of the cancer tissue, bypassing part of the intestines, or stent placement. These procedures can be considered to improve symptoms and reduce complications such as bleeding from the tumor, abdominal pain and intestinal obstruction. Non-operative methods of symptomatic treatment include radiation therapy to decrease tumor size as well as pain medications.
Survival is directly related to detection and the type of cancer involved, but overall is poor for symptomatic cancers, as they are typically quite advanced. Survival rates for early stage detection is about 5 times that of late stage cancers. For example, patients with a tumor that has not breached the muscularis mucosa (TNM stage Tis, N0, M0) have an average 5-year survival of 100%, while those with an invasive cancer, i.e. T1 (within the submucosal layer) or T2 (within the muscular layer) cancer have an average 5-year survival of approximately 90%. Those with a more invasive tumor, yet without node involvement (T3-4, N0, M0) have an average 5-year survival of approximately 70%. Patients with positive regional lymph nodes (any T, N1-3, M0) have an average 5-year survival of approximately 40%, while those with distant metastases (any T, any N, M1) have an average 5-year survival of approximately 5%.
According to the American Cancer Society statistics in 2006, over 20% of patients present with metastatic (stage IV) colorectal cancer at the time of diagnosis, and up to 25% of this group will have isolated liver metastasis that is potentially resectable. Lesions which undergo curative resection have demonstrated 5-year survival outcomes now exceeding 50%.
The aims of follow-up are to diagnose, in the earliest possible stage, any metastasis or tumors that develop later, but did not originate from the original cancer (metachronous lesions).
The U.S. National Comprehensive Cancer Network and American Society of Clinical Oncology provide guidelines for the follow-up of colon cancer. A medical history and physical examination are recommended every 3 to 6 months for 2 years, then every 6 months for 5 years. Carcinoembryonic antigen blood level measurements follow the same timing, but are only advised for patients with T2 or greater lesions who are candidates for intervention. A CT-scan of the chest, abdomen and pelvis can be considered annually for the first 3 years for patients who are at high risk of recurrence (for example, patients who had poorly differentiated tumors or venous or lymphatic invasion) and are candidates for curative surgery (with the aim to cure). A colonoscopy can be done after 1 year, except if it could not be done during the initial staging because of an obstructing mass, in which case it should be performed after 3 to 6 months. If a villous polyp, a polyp >1 centimeter or high grade dysplasia is found, it can be repeated after 3 years, then every 5 years. For other abnormalities, the colonoscopy can be repeated after 1 year.
Routine PET or ultrasound scanning, chest X-rays, complete blood count or liver function tests are not recommended. These guidelines are based on recent meta-analyses showing intensive surveillance and close follow-up can reduce the 5-year mortality rate from 37% to 30%.
Globally more than 1 million people get colorectal cancer every year resulting in about 715,000 deaths as of 2010 up from 490,000 in 1990. As of 2008 it is the second most common cause of cancer in women and the third most common in men with it being the fourth most common cause of cancer death after lung, stomach, and liver cancer. It is more common in developed than developing countries. Globally incidences vary 10-fold with highest rates in the Australia, New Zealand, Europe and the US and lowest rates in Africa and South-Central Asia.
Based on rates from 2007-2009, 4.96% of US men and women born today will be diagnosed with colorectal cancer during their lifetime. From 2005-2009, the median age at diagnosis for cancer of the colon and rectum in the US was 69 years of age. Approximately 0.1% were diagnosed under age 20; 1.1% between 20 and 34; 4.0% between 35 and 44; 13.4% between 45 and 54; 20.4% between 55 and 64; 24.0% between 65 and 74; 25.0% between 75 and 84; and 12.0% 85+ years of age. Rates are higher among males (54 per 100,000 c.f. 40 per 100,000 for females).
Society and culture
In the United States, March is colorectal cancer awareness month.
- Corazon Aquino, former president of the Philippines
- Pope John Paul II
- Ronald Reagan
- Harold Wilson, former Prime Minister of the United Kingdom
- Robin Gibb, musician and member of the Bee Gees
- Humayun Ahmed, Bengali writer and film maker
- J.B.S. Haldane, Geneticist; polymath, popular science author.
- Cancer Genome Atlas Network (19 July 2012). "Comprehensive molecular characterization of human colon and rectal cancer". Nature 487 (7407): 330–337. Bibcode:2012Natur.487..330T. doi:10.1038/nature11252. PMC 3401966. PMID 22810696.
- Colorectal Cancer Incidence, Mortality and Prevalence Worldwide in 2008 — Summary. Available from: Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. (2010) GLOBOCAN 2008 v2.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Lyon, France: International Agency for Research on Cancer. Accessed on 11 Oct 2012.
- al.], edited by Tadataka Yamada ; associate editors, David H. Alpers ... [et (2008). Principles of clinical gastroenterology. Chichester, West Sussex: Wiley-Blackwell. p. 381. ISBN 978-1-4051-6910-3.
- Astin M, Griffin, T, Neal, RD, Rose, P, Hamilton, W (May 2011). "The diagnostic value of symptoms for colorectal cancer in primary care: a systematic review". The British journal of general practice : the journal of the Royal College of General Practitioners 61 (586): 231–43. doi:10.3399/bjgp11X572427. PMC 3080228. PMID 21619747.
- Adelstein BA, Macaskill, P, Chan, SF, Katelaris, PH, Irwig, L (2011). "Most bowel cancer symptoms do not indicate colorectal cancer and polyps: a systematic review". BMC gastroenterology 11: 65. doi:10.1186/1471-230X-11-65. PMC 3120795. PMID 21624112.
- Watson AJ, Collins, PD (2011). "Colon cancer: a civilization disorder". Digestive diseases (Basel, Switzerland) 29 (2): 222–8. doi:10.1159/000323926. PMID 21734388.
- Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, Starling N (2010). "Colorectal cancer". Lancet 375 (9719): 1030–47. doi:10.1016/S0140-6736(10)60353-4. PMID 20304247.
- Lee, I-Min; Shiroma, Eric J; Lobelo, Felipe; Puska, Pekka; Blair, Steven N; Katzmarzyk, Peter T (1 July 2012). "Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy". The Lancet 380 (9838): 219–29. doi:10.1016/S0140-6736(12)61031-9. PMC 3645500. PMID 22818936.
- Fedirko V, Tramacere, I, Bagnardi, V, Rota, M, Scotti, L, Islami, F, Negri, E, Straif, K, Romieu, I, La Vecchia, C, Boffetta, P, Jenab, M (Sep 2011). "Alcohol drinking and colorectal cancer risk: an overall and dose-response meta-analysis of published studies". Annals of Oncology 22 (9): 1958–72. doi:10.1093/annonc/mdq653. PMID 21307158.
- Jawad N, Direkze, N, Leedham, SJ (2011). "Inflammatory bowel disease and colon cancer". Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer. Recent Results in Cancer Research 185: 99–115. doi:10.1007/978-3-642-03503-6_6. ISBN 978-3-642-03502-9. PMID 21822822.
- Xie J, Itzkowitz, SH (2008). "Cancer in inflammatory bowel disease". World journal of gastroenterology : WJG 14 (3): 378–89. doi:10.3748/wjg.14.378. PMC 2679126. PMID 18200660.
- Triantafillidis JK, Nasioulas, G, Kosmidis, PA (Jul 2009). "Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies". Anticancer research 29 (7): 2727–37. PMID 19596953.
- Juhn E, Khachemoune, A (2010). "Gardner syndrome: skin manifestations, differential diagnosis and management". American journal of clinical dermatology 11 (2): 117–22. doi:10.2165/11311180-000000000-00000. PMID 20141232.
- Half E, Bercovich, D, Rozen, P (2009). "Familial adenomatous polyposis". Orphanet journal of rare diseases 4: 22. doi:10.1186/1750-1172-4-22. PMC 2772987. PMID 19822006.
- Stein, Ulrike; Walther, Wolfgang; Arlt, Franziska; Schwabe, Holger; Smith, Janice; Fichtner, Iduna; Birchmeier, Walter; Schlag, Peter M (2008). "MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis". Nature Medicine 15 (1): 59–67. doi:10.1038/nm.1889. PMID 19098908.
- Stein U (2013) MACC1 - a novel target for solid cancers. Expert Opin Ther Targets
- Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M (1993). "Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis". Nature 363 (6429): 558–61. doi:10.1038/363558a0. PMID 8505985.
- Srikumar Chakravarthi, Baba Krishnan, Malathy Madhavan (1999). "Apoptosis and expression of p53 in colorectal neoplasms". Indian J Med Res 86 (7): 95–102.
- Markowitz SD, Bertagnolli MM (December 2009). "Molecular Origins of Cancer: Molecular Basis of Colorectal Cancer". N. Engl. J. Med. 361 (25): 2449–60. doi:10.1056/NEJMra0804588. PMC 2843693. PMID 20018966.
- Mehlen P, Fearon ER (August 2004). "Role of the dependence receptor DCC in colorectal cancer pathogenesis". J. Clin. Oncol. 22 (16): 3420–8. doi:10.1200/JCO.2004.02.019. PMID 15310786.
- Vogelstein, B; Kinzler, KW (2004). "Cancer genes and the pathways they control". Nature Medicine 10 (8): 789–99. doi:10.1038/nm1087. PMID 15286780.
- Muzny, DM.; Bainbridge, MN.; Chang, K.; Dinh, HH.; Drummond, JA.; Fowler, G.; Kovar, CL.; Lewis, LR.; Morgan, MB.; Newsham, Irene F.; Reid, Jeffrey G.; Santibanez, Jireh; Shinbrot, Eve; Trevino, Lisa R.; Wu, Yuan-Qing; Wang, Min; Gunaratne, Preethi; Donehower, Lawrence A.; Creighton, Chad J.; Wheeler, David A.; Gibbs, Richard A.; Lawrence, Michael S.; Voet, Douglas; Jing, Rui; Cibulskis, Kristian; Sivachenko, Andrey; Stojanov, Petar; McKenna, Aaron; Lander, Eric S.; Gabriel, Stacey (Jul 2012). "Comprehensive molecular characterization of human colon and rectal cancer". Nature 487 (7407): 330–7. doi:10.1038/nature11252. PMC 3401966. PMID 22810696.
- Slaughter, DP; Southwick, HW; Smejkal, W (1953). "Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin". Cancer 6 (5): 963–8. doi:10.1002/1097-0142(195309)6:5<963::AID-CNCR2820060515>3.0.CO;2-Q. PMID 13094644.
- Giovannucci, E; Ogino, S (Sep 21, 2005). "DNA methylation, field effects, and colorectal cancer.". Journal of the National Cancer Institute 97 (18): 1317–9. doi:10.1093/jnci/dji305. PMID 16174847.
- Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer
- Bernstein, C; Bernstein, H; Payne, CM; Dvorak, K; Garewal, H (2008). "Field defects in progression to gastrointestinal tract cancers". Cancer letters 260 (1–2): 1–10. doi:10.1016/j.canlet.2007.11.027. PMC 2744582. PMID 18164807.
- Nguyen, H; Loustaunau, C; Facista, A; Ramsey, L; Hassounah, N; Taylor, H; Krouse, R; Payne, CM; Tsikitis, VL; Goldschmid, S; Banerjee, B; Perini, RF; Bernstein, C (2010). "Deficient Pms2, ERCC1, Ku86, CcOI in field defects during progression to colon cancer". Journal of visualized experiments : JoVE (41): 1931. doi:10.3791/1931. PMC 3149991. PMID 20689513. The 28 minute video in this article is best watched by clicking on "Download video file" under the image in the abstract at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3149991/
- Rubin, H (2011). "Fields and field cancerization: The preneoplastic origins of cancer: Asymptomatic hyperplastic fields are precursors of neoplasia, and their progression to tumors can be tracked by saturation density in culture". BioEssays : news and reviews in molecular, cellular and developmental biology 33 (3): 224–31. doi:10.1002/bies.201000067. PMID 21254148.
- Tsao, JL; Yatabe, Y; Salovaara, R; Järvinen, HJ; Mecklin, JP; Aaltonen, LA; Tavaré, S; Shibata, D (2000). "Genetic reconstruction of individual colorectal tumor histories". Proceedings of the National Academy of Sciences of the United States of America 97 (3): 1236–41. doi:10.1073/pnas.97.3.1236. PMC 15581. PMID 10655514.
- Vogelstein, B; Papadopoulos, N; Velculescu, VE; Zhou, S; Diaz Jr, LA; Kinzler, KW (2013). "Cancer genome landscapes". Science 339 (6127): 1546–58. doi:10.1126/science.1235122. PMC 3749880. PMID 23539594.
- Balaguer F, Link A, Lozano JJ, et al. (August 2010). "Epigenetic silencing of miR-137 is an early event in colorectal carcinogenesis". Cancer Res. 70 (16): 6609–18. doi:10.1158/0008-5472.CAN-10-0622. PMC 2922409. PMID 20682795.
- Deng, G; Kakar, S; Kim, YS (2011). "MicroRNA-124a and microRNA-34b/c are frequently methylated in all histological types of colorectal cancer and polyps, and in the adjacent normal mucosa". Oncology letters 2 (1): 175–180. doi:10.3892/ol.2010.222. PMC 3412539. PMID 22870149.
- Grady, WM; Parkin, RK; Mitchell, PS; Lee, JH; Kim, YH; Tsuchiya, KD; Washington, MK; Paraskeva, C; Willson, JK; Kaz, AM; Kroh, EM; Allen, A; Fritz, BR; Markowitz, SD; Tewari, M (2008). "Epigenetic silencing of the intronic microRNA hsa-miR-342 and its host gene EVL in colorectal cancer". Oncogene 27 (27): 3880–8. doi:10.1038/onc.2008.10. PMID 18264139.
- Kanwal, R; Gupta, S (2012). "Epigenetic modifications in cancer". Clinical genetics 81 (4): 303–11. doi:10.1111/j.1399-0004.2011.01809.x. PMC 3590802. PMID 22082348.
- Baldassarre, G; Battista, S; Belletti, B; Thakur, S; Pentimalli, F; Trapasso, F; Fedele, M; Pierantoni, G; Croce, CM; Fusco, A (2003). "Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma". Molecular and Cellular Biology 23 (7): 2225–38. doi:10.1128/MCB.23.7.2225-2238.2003. PMC 150734. PMID 12640109.
- Schnekenburger, M; Diederich, M (2012). "Epigenetics Offer New Horizons for Colorectal Cancer Prevention". Current colorectal cancer reports 8 (1): 66–81. doi:10.1007/s11888-011-0116-z. PMC 3277709. PMID 22389639.
- Jacinto FV, Esteller M (July 2007). "Mutator pathways unleashed by epigenetic silencing in human cancer". Mutagenesis 22 (4): 247–53. doi:10.1093/mutage/gem009. PMID 17412712. http://mutage.oxfordjournals.org/content/22/4/247.long
- Lahtz C, Pfeifer GP (February 2011). "Epigenetic changes of DNA repair genes in cancer". J Mol Cell Biol 3 (1): 51–8. doi:10.1093/jmcb/mjq053. PMC 3030973. PMID 21278452. http://jmcb.oxfordjournals.org/content/3/1/51.long
- Bernstein C, Nfonsam V, Prasad AR, Bernstein H (March 2013). "Epigenetic field defects in progression to cancer". World J Gastrointest Oncol 5 (3): 43–9. doi:10.4251/wjgo.v5.i3.43. PMC 3648662. PMID 23671730. http://www.wjgnet.com/1948-5204/full/v5/i3/43.htm
- Pathology atlas
- Mitrovic, B.; Schaeffer, D. F.; Riddell, R. H.; Kirsch, R. (2012). "Tumor budding in colorectal carcinoma: Time to take notice". Modern Pathology 25 (10): 1315. doi:10.1038/modpathol.2012.94. PMID 22790014.
- Searke, David (2006). Cancer Epidemiology and Prevention (3 ed.). Oxford University Press. p. 809. ISBN 9780199747979.
- Rennert, Gad (2007). Cancer Prevention. Springer. p. 179. ISBN 9783540376965.
- Campos FG, Logullo Waitzberg, AG, Kiss, DR, Waitzberg, DL, Habr-Gama, A, Gama-Rodrigues, J (Jan 2005). "Diet and colorectal cancer: current evidence for etiology and prevention". Nutricion hospitalaria : organo oficial de la Sociedad Espanola de Nutricion Parenteral y Enteral 20 (1): 18–25. PMID 15762416.
- Doyle VC, Logullo Waitzberg, AG, Kiss, DR, Waitzberg, DL, Habr-Gama, A, Gama-Rodrigues, J (May 2007). "Nutrition and colorectal cancer risk: a literature review". Gastroenterology nursing : the official journal of the Society of Gastroenterology Nurses and Associates 30 (3): 178–82; quiz 182–3. doi:10.1097/01.SGA.0000278165.05435.c0. PMID 17568255.
- Harriss DJ, Atkinson, G, Batterham, A, George, K, Cable, NT, Reilly, T, Haboubi, N, Renehan, AG, Colorectal Cancer, Lifestyle, Exercise And Research, Group (Sep 2009). "Lifestyle factors and colorectal cancer risk (2): a systematic review and meta-analysis of associations with leisure-time physical activity". Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland 11 (7): 689–701. doi:10.1111/j.1463-1318.2009.01767.x. PMID 19207713.
- Cooper K, Squires, H, Carroll, C, Papaioannou, D, Booth, A, Logan, RF, Maguire, C, Hind, D, Tappenden, P (Jun 2010). "Chemoprevention of colorectal cancer: systematic review and economic evaluation". Health technology assessment (Winchester, England) 14 (32): 1–206. doi:10.3310/hta14320. PMID 20594533.
- Agency for Healthcare Research and Quality. "Aspirin or Nonsteroidal Anti-inflammatory Drugs for the Primary Prevention of Colorectal Cancer". United States Department of Health & Human Services. "2010/2011"
- Weingarten MA, Zalmanovici, A, Yaphe, J (2008). "Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps". In Weingarten, Michael Asher MA. Cochrane database of systematic reviews (Online) (1): CD003548. doi:10.1002/14651858.CD003548.pub4. PMID 18254022.
- Ma Y, Zhang, P, Wang, F, Yang, J, Liu, Z, Qin, H (2011). "Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies". Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29 (28): 3775–82. doi:10.1200/JCO.2011.35.7566. PMID 21876081.
- Yin L, Grandi, N, Raum, E, Haug, U, Arndt, V, Brenner, H (Jul 2011). "Meta-analysis: Serum vitamin D and colorectal adenoma risk". Preventive medicine 53 (1–2): 10–6. doi:10.1016/j.ypmed.2011.05.013. PMID 21672549.
- He J, Efron, JE (2011). "Screening for colorectal cancer". Advances in surgery 45: 31–44. doi:10.1016/j.yasu.2011.03.006. PMID 21954677.
- "Screening for Colorectal Cancer". U.S. Preventive Services Task Force. 2008.
- American Gastroenterological Association. "Five Things Physicians and Patients Should Question". Choosing Wisely: an initiative of the ABIM Foundation (American Gastroenterological Association). Retrieved August 17, 2012.
- Winawer, S; Fletcher, R; Rex, D; Bond, J; Burt, R; Ferrucci, J; Ganiats, T; Levin, T; Woolf, S; Johnson, D; Kirk, L; Litin, S; Simmang, C; Gastrointestinal Consortium, Panel (February 2003). "Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence". Gastroenterology 124 (2): 544–60. doi:10.1053/gast.2003.50044. PMID 12557158.
- Qaseem A, Denberg TD, Hopkins RH Jr, et al. (2012). "Screening for Colorectal Cancer: A Guidance Statement From the American College of Physicians". Annals of Internal Medicine 156 (5): 378–386. doi:10.7326/0003-4819-156-5-201203060-00010. PMID 22393133.
- Siegel RL, Ward EM, Jemal A (Mar 2012). "Trends in Colorectal Cancer Incidence Rates in the United States by Tumor Location and Stage, 1992–2008". Cancer Epidemiology, Biomarkers & Prevention 21 (3): 411–6. doi:10.1158/1055-9965.EPI-11-1020. PMID 22219318. Retrieved September 16, 2012.
- Hewitson, P; Glasziou, P; Watson, E; Towler, B; Irwig, L (June 2008). "Cochrane systematic review of colorectal cancer screening using the fecal occult blood test (hemoccult): an update". The American journal of gastroenterology 103 (6): 1541–9. doi:10.1111/j.1572-0241.2008.01875.x. PMID 18479499.
- Lee, Jeffrey K.; Liles, Elizabeth G.; Bent, Stephen; Levin, Theodore R.; Corley, Douglas A. (4 February 2014). "Accuracy of Fecal Immunochemical Tests for Colorectal Cancer". Annals of Internal Medicine 160 (3): 171–181. doi:10.7326/M13-1484.
- Tonus, C; Sellinger, M; Koss, K; Neupert, G (2012). "Faecal pyruvate kinase isoenzyme type M2 for colorectal cancer screening: A meta-analysis". World journal of gastroenterology : WJG 18 (30): 4004–11. doi:10.3748/wjg.v18.i30.4004. PMC 3419997. PMID 22912551.
- Stein A, Atanackovic, D, Bokemeyer, C (Sep 2011). "Current standards and new trends in the primary treatment of colorectal cancer". European journal of cancer (Oxford, England : 1990). 47 Suppl 3: S312–4. doi:10.1016/S0959-8049(11)70183-6. PMID 21943995.
- "Chemotherapy of metastatic colorectal cancer". Prescrire Int 19 (109): 219–24. October 2010. PMID 21180382.
- Shaib, W; Mahajan, R; El-Rayes, B (2013). "Markers of resistance to anti-EGFR therapy in colorectal cancer". Journal of gastrointestinal oncology 4 (3): 308–18. doi:10.3978/j.issn.2078-6891.2013.029. PMC 3712296. PMID 23997942.
- authors, editors, Vincent T. DeVita, Jr., Theodore S. Lawrence, Steven A. Rosenberg ; associate scientific advisors, Robert A. Weinberg, Ronald A. DePinho ; with 421 contributing (2008). DeVita, Hellman, and Rosenberg's cancer : principles & practice of oncology (8th ed.). Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins. p. 1258. ISBN 978-0-7817-7207-5.
- Wasserberg N, Kaufman HS (December 2007). "Palliation of colorectal cancer". Surg Oncol 16 (4): 299–310. doi:10.1016/j.suronc.2007.08.008. PMID 17913495.
- Amersi F, Stamos MJ, Ko CY (July 2004). "Palliative care for colorectal cancer". Surg. Oncol. Clin. N. Am. 13 (3): 467–77. doi:10.1016/j.soc.2004.03.002. PMID 15236729.
- Box 3-1, Page 107 in: Elizabeth D Agabegi; Agabegi, Steven S. (2008). Step-Up to Medicine (Step-Up Series). Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-7153-6.
- [dead link]
- Simmonds PC, Primrose JN, Colquitt JL, Garden OJ, Poston GJ, Rees M (April 2006). "Surgical resection of hepatic metastases from colorectal cancer: A systematic review of published studies". Br. J. Cancer 94 (7): 982–99. doi:10.1038/sj.bjc.6603033. PMC 2361241. PMID 16538219.
- NCCN Clinical Practice Guidelines in Oncology - Colon Cancer (version 1, 2008: September 19, 2007).
- Desch CE, Benson AB 3rd, Somerfield MR, et al.; American Society of Clinical Oncology (2005). "Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline". J Clin Oncol 23 (33): 8512–9. doi:10.1200/JCO.2005.04.0063. PMID 16260687.
- Jeffery M, Hickey BE, Hider PN (2002). "Follow-up strategies for patients treated for non-metastatic colorectal cancer". In Jeffery, Mark. Cochrane Database Syst Rev (1): CD002200. doi:10.1002/14651858.CD002200. PMID 11869629.
- Renehan AG, Egger M, Saunders MP, O'Dwyer ST (2002). "Impact on survival of intensive follow up after curative resection for colorectal cancer: systematic review and meta-analysis of randomised trials". BMJ 324 (7341): 831–8. doi:10.1136/bmj.324.7341.813. PMC 100789. PMID 11934773.
- Figueredo A, Rumble RB, Maroun J, et al.; Gastrointestinal Cancer Disease Site Group of Cancer Care Ontario's Program in Evidence-based Care (2003). "Follow-up of patients with curatively resected colorectal cancer: a practice guideline". BMC Cancer 3: 26. doi:10.1186/1471-2407-3-26. PMC 270033. PMID 14529575.
- "WHO Disease and injury country estimates". World Health Organization. 2009. Retrieved November 11, 2009.
- Lozano, R (December 15, 2012). "Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010". Lancet 380 (9859): 2095–128. doi:10.1016/S0140-6736(12)61728-0. PMID 23245604.
- Jemal A, Bray, F, Center, MM, Ferlay, J, Ward, E, Forman, D (2011). "Global cancer statistics". CA: a cancer journal for clinicians 61 (2): 69–90. doi:10.3322/caac.20107. PMID 21296855.
- WHO (February 2010). "Cancer". World Health Organization. Retrieved January 5, 2011.
- Merika E, Saif, MW, Katz, A, Syrigos, K, Morse, M (Sep 2010). "Review. Colon cancer vaccines: an update". In vivo (Athens, Greece) 24 (5): 607–28. PMID 20952724.
- Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). "SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations)". National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, 2012.
- [dead link]
- "Pope John Paul II". ABC News Online.
- "Reagan turns 90". BBC News: Americas. 6 February 2001.
- Daily Mail
- Klein, Sarah (2012-04-23). "12 Famous Faces Touched By Colorectal Cancer". Huffington Post.
- "Humayun Ahmed dies". Bdnews24.com. 2012-07-19. Retrieved July 19, 2012.
- Krishna Dronamraju (May 2010). "J.B.S. Haldane's Last Years: His Life and Work in India [1957-1964]". Genetics Society of America 185 (1): 5–10. doi:10.1534/genetics.110.116632. PMC 2870975. PMID 20516291.
|Wikimedia Commons has media related to Colorectal cancer.|