36: Colorectal Flashcards
What are the following characteristics of diverticulosis?
- Percent of lower GI diverticular bleed that stops spontaneously
- Diagnosis
- Treatment
- Percent of lower GI diverticular bleed that stops spontaneously: 75% (recurs in 25%)
- Diagnosis: NGT (to rule out upper GI source), colonoscopy (diagnostic and therpeutic), Angiogram (1st step in management of massive bleed), tagged RBC scan (for intermittent bleeds that are hard to localize)
- Treatment: Colonoscopy (ligate bleeder), Angio with coil embolization, may need segmental colectomy or subtotal colectomy if bleeding is not localized or controlled.
[Diverticulosis is the most common cause of a lower GI bleed. It is caused by disrupted vasa rectum (resulting in arterial bleeding). Patients with recurrent diverticular bleeds should have resection of the area that has recurrent bleeding.]
What are the respective resolutions of the following imaging modalities as it pertains to detecting intrahepatic metastases?
- Conventional U/S
- Abdominal CT
- Abdominal MRI
- Intraoperative U/S
- Conventional U/S: 10 mm
- Abdominal CT: 5-10 mm
- Abdominal MRI: 5-10 mm (better than CT)
- Intraoperative U/S: 3-5 cm
[Intraoperative U/S is the best method of picking up intrahepatic metastases.]
Which is more sensitive to ischemia: Colon or small bowel?
Colon is more sensitive to ischemia secondary to decreased collaterals
Which 3 chemotherapy agents are used in colorectal cancer?
- 5-FU
- Leucovorin
- Oxaliplatin
[FOLFOX.]
What is the appropriate management for a patient with a sigmoid volvulus?
- If no evidence of gangrenous bowel or peritoneal signs then decompress with colonoscopy (80% reduce, 50% will recur), give bowel prep, and perform sigmoid colectomy during same admission
- If signs of gangrenous bowel or peritonitis are present then go straight to the OR
What are the following characteristics of GI bleeding?
- Length of time stool guaiac can remain positive after lower GI bleed
- Cause of azotemia after GI bleed
- Bleeding rate required for detection on arteriography
- Bleeding rate required for detection on tagged RBC scan
- Length of time stool guaiac can remain positive after lower GI bleed: 3 weeks
- Cause of azotemia after GI bleed: Production of urea from bacterial action on intraluminal blood (Increased BUN; also get elevated total bilirubin)
- Bleeding rate required for detection on arteriography: > 0.5 cc/min
- Bleeding rate required for detection on tagged RBC scan: > 0.1 cc/min
Which 3 characteristics of a colon polyp increase cancer risk?
- > 2cm
- Sessile
- Villous
What are the following characteristics of colonic angiodysplasia?
- Side that angiodysplasia most commonly occurs on
- Bleeding severity and risk of recurrence compared to diverticular bleeds
- Venous or arterial bleeding
- Percent of patients with angiodysplasia that have aortic stenosis
- Side that angiodysplasia most commonly occurs on: Right side
- Bleeding severity and risk of recurrence compared to diverticular bleeds: Less severe than diverticular bleeds but more likely to recur (80% compared to 25% for diverticular bleeds)
- Venous or arterial bleeding: Venous (Diverticular bleeds are arterial)
- Percent of patients with angiodysplasia that have aortic stenosis: 20%
[Soft signs of angiodysplasia on angiogram include tufts and slow emptying.]
What is the treatment for diversion colitis (stump pouchitis)?
Short-chain fatty acids
[UpToDate: Diversion colitis or diversion proctitis is a nonspecific inflammatory disorder that occurs in segments of the colon and rectum that are diverted from the fecal stream by surgery (eg, creation of a loop colostomy/ileostomy or an end colostomy/ileostomy with closure of the distal colon segment [eg, Hartmann’s procedure]).
Surgical reanastomosis is the treatment of choice in symptomatic patients with diversion colitis. Medical therapy (eg, short-chain fatty acid [SCFA] enemas, topical 5-aminisalicylic acid, and topical glucocorticoids) should be reserved for symptomatic patients who are not candidates for surgery or in whom diversion colitis cannot be distinguished from active distal inflammatory bowel disease (IBD).
SCFA enemas are used as initial therapy in patients with diversion colitis who are unable or unwilling to undergo surgery and in patients with known distal IBD in whom the diagnosis of diversion colitis is unclear. In patients with underlying IBD, we use SCFA enemas in combination with topical antiinflammatory drugs.]
What are the following characteristics of ulcerative colitis?
- Most common extraintestinal manifestation requiring total colectomy
- 2 extraintestinal manifestations of ulcerative colitis that do not improve with colectomy
- 3 extraintestinal manifestations of ulcerative colitis that do improve with colectomy
- 1 extraintestinal manifestation of ulcerative colitis that sometimes (50%) improves with colectomy
- Most common extraintestinal manifestation requiring total colectomy: Failure to thrive in children
- 2 extraintestinal manifestations of ulcerative colitis that do not improve with colectomy: Primary sclerosing cholangitis and ankylosing spondylitis
- 3 extraintestinal manifestations of ulcerative colitis that do improve with colectomy: Most ocular problems, arthritis, and anemia
- 1 extraintestinal manifestation of ulcerative colitis that sometimes (50%) improves with colectomy: Pyoderma gangrenosum
What is the 5-year survival of a colorectal cancer patient with resectable liver metastases?
35% 5-year survival
[If resection leaves adequate liver function.]
What is the main nutrient of colonocytes?
Short-chain fatty acids (SCFAs)
[UpToDate: SCFAs, predominantly acetate, propionate, and n-butyrate, are derived from anaerobic bacterial metabolism of unabsorbed dietary carbohydrates. They are absorbed from the lumen by a combination of simple diffusion and ion exchange and oxidized by colonocytes. In addition to supplying 70% of the fuel used by mucosal cells, luminal SCFAs have a number of other effects, including modulation of fluid and electrolyte transport, colonic motility, mucosal blood flow, and production of inflammatory cytokines. Other luminal nutrients for colonocytes, such as glutamine, may also play a role in the pathogenesis of diversion colitis.]
Do colon polyps have a left or right side predominance?
Left side predominance
Rectal cancer can metastasize directly to the spine via which plexus of vessels?
Batson’s plexus
[Colon cancer typically doesnt metastasize to bone.]
Most colorectal cancers in which region can be treated with primary anastamosis after resection without needing an ostomy?
Right-sided colorectal cancer
[Need 2cm margins.]
What percent of patients with colorectal cancer recur after surgical resection?
20%
[Recurrence usually occurs in the first year. 5% get another primary which is the main reason for surveillance colonoscopy. Follow-up colonoscopy is done at 1 year.]
What are the following characteristics of diverticulitis?
- Most common complication of diverticulitis
- Treatment for uncomplicated diverticulitis
- Treatment of complicated diverticulitis
- Treatment of right-sided diverticulitis
- Best diagnostic tool for suspected colovesicular fistula
- Most common complication of diverticulitis: Abscess formation
- Treatment for uncomplicated diverticulitis: Levofloxacin and flagyl, bowel rest for 3-4 days (treat mild cases as outpatient)
- Treatment of complicated diverticulitis: Resect all of sigmoid colon down to the superior rectum (distal margin should be normal rectum)
- Treatment of right-sided diverticulitis: Right hemicolectomy
- Best diagnostic tool for suspected colovesicular fistula: Cystoscopy
[Need follow-up colonoscopy after an episode of diverticulitis to rule out colorectal cancer.]
What are the criteria that make a low rectal T1 cancer eligible for transanal resection?
- < 4cm
- Negative margins (need 1 cm)
- Well differentiated
- No neurologic or vascular invasion
[If these criteria are not met, an APR or LAR are required. Low rectal T2 cancers or higher require an APR or LAR.]]
What is the role of chemotherapy in treating colorectal cancer?
- Stage III and IV colon cancer –> Postop chemotherapy (no XRT)
- Stage II and III rectal cancer –> Pre-op chemo and XRT
- Stage IV rectal cancer –> Chemo and XRT +/- surgery (possibly just a colostomy, may choose to avoid APR in patients with metastatic disease.)
[UpToDate: In our view, patients with potentially resectable disease should undergo multivisceral resection rather than upfront chemoradiotherapy, if they are surgical candidates. Consensus-based guidelines from the National Comprehensive Cancer Network (NCCN) suggest that patients with locally unresectable colon cancer or who are medically inoperable be given chemotherapy for advanced disease.
For patients who have undergone potentially curative resection of a colon cancer, the goal of postoperative (adjuvant) chemotherapy is to eradicate micrometastases, thereby reducing the likelihood of disease recurrence and increasing the cure rate. The benefits of adjuvant chemotherapy have been most clearly demonstrated in patients with stage III (node-positive) disease, who have an approximately 30% reduction in the risk of disease recurrence and a 22% to 32% reduction in mortality with modern chemotherapy.
Most treatments involve a combination of several chemotherapy drugs, which are given intravenously, in a specific order on specific days. For patients with node-positive colon cancer, a six-month course of oxaliplatin-containing chemotherapy is generally recommended for most patients, although the benefits of oxaliplatin are controversial in the elderly.
Among patients with resected node-negative (stage II) disease, the benefits of chemotherapy are controversial, as is the relative benefit of an oxaliplatin as compared with a non-oxaliplatin-based regimen. Treatment decisions must be individualized.]
Which portions of the colon are retroperitoneal?
- Ascending colon
- Descending colon
- Sigmoid colon
[Transverse colon is intraperitoneal.]
[UpToDate: The colon and rectum occupy retroperitoneal and intraperitoneal spaces, in close approximation to solid organs. The ascending and descending colon are retroperitoneal, while the transverse colon, which extends from the hepatic flexure to the splenic flexure, is intraperitoneal. The sigmoid colon continues from the descending colon, ending where the teniae converge to form the rectum. The rectum is the distal continuation of the colon, measuring 12 to 15 cm in length. The rectum lies anterior to the three inferior sacral vertebrae, the coccyx, and sacral vessels, and is posterior to the bladder in men and the vagina in women. The anterior upper two-thirds of the rectum are located intraperitoneally and the remainder is extraperitoneal.
At what age does colonoscopy screening for colon cancer begin?
- Age 50 for normal risk
- Age 40 for intermediate risk or 10 years before youngest first degree relative with colon cancer diagnosis
Where does colorectal cancer fall on the list deaths caused by cancer?
2nd leading cause of cancer death
What are the following characteristics of inflammatory bowel disease?
- Most common location of perforation in ulcerative colitis
- Most common location of perforation in crohn’s disease
- Most common location of perforation in ulcerative colitis: Transverse colon
- Most common location of perforation in crohn’s disease: Distal ileum
What are the following characteristics of colon pathphysiology?
- Most likely location for colon perforation to occur in setting of obstruction
- # 1 cause of colonic obstruction
- # 2 cause of colonic obstruction
- Problem associated with pneumatosis intestinalis
- Problem associated with air in the portal system
- Most likely location for colon perforation to occur in setting of obstruction: Cecum (LePlace’s law: Tension = pressure x diameter)
- # 1 cause of colonic obstruction: Cancer
- # 2 cause of colonic obstruction: Diverticulitis
- Problem associated with pneumatosis intestinalis: Ischemia and dissection of air through areas of bowel wall
- Problem associated with air in the portal system: Significant infection or necrosis of the large or small bowel (often an ominous sign)
Injury to which nerve during an abdominal perineal resection (APR) can result in impotence and bladder dysfunction?
Pudendal nerves
What are the names of the following components of the colon?
- Inner nerve plexus
- Outer nerve plexus
- Mucus-secreting goblet cells
- Rectovesicular fascia in men, Rectovaginal fascia in women
- Rectosacral fascia
- Inner nerve plexus: Meissner’s (submucosal) plexus
- Outer nerve plexus: Auerbach’s (myenteric) plexus
- Mucus-secreting goblet cells: Crypts of Lieberkuhn
- Rectovesicular fascia in men, Rectovaginal fascia in women: Denonvilliers (anterior) fascia
- Rectosacral fascia: Waldeyer’s (posterior) fascia
How does the venous drainage differ between the superior, middle, and inferior rectal veins?
- The superior and middle rectal veins drain into the IMV and eventually the portal vein
- The inferior rectal veins drain into the internal iliac veins and eventually the caval system
[Picture is misleading and suggests the middle and inferior veins drain in similar fashion.]
[UpToDate: The colon and rectum occupy retroperitoneal and intraperitoneal spaces, in close approximation to solid organs. The ascending and descending colon are retroperitoneal, while the transverse colon, which extends from the hepatic flexure to the splenic flexure, is intraperitoneal. The sigmoid colon continues from the descending colon, ending where the teniae converge to form the rectum. The rectum is the distal continuation of the colon, measuring 12 to 15 cm in length. The rectum lies anterior to the three inferior sacral vertebrae, the coccyx, and sacral vessels, and is posterior to the bladder in men and the vagina in women. The anterior upper two-thirds of the rectum are located intraperitoneally and the remainder is extraperitoneal.
The blood supply to the colon is derived from the superior (SMA) and inferior mesenteric arteries (IMA), and internal iliac artery. The SMA, ileocolic, right colic, and middle colic arteries supply the cecum, right colon, and first portion of the transverse colon respectively. The venous outflow generally follows the arterial supply. The transverse colon derives its blood supply from both the SMA and IMA. The watershed area between these vessels is at risk for ischemia. The descending and sigmoid colon are supplied by the left colic artery and the superior sigmoid artery, branches of the IMA. The rectum is supplied by the superior, middle rectal, and inferior rectal artery. Venous drainage from the rectum is from the superior rectal and middle rectal veins draining to the inferior mesenteric veins, and the inferior rectal veins draining to the internal pudendal veins.]
What are the 4 layers of the colon from the lumen outwards?
- Mucosa (columnar epithelium)
- Submucosa
- Muscularis propria
- Serosa
[The muscularis mucosa is the small interwoven inner muscle layer just below mucosa but above the basement membrane. The muscularis propria is the circular layer of muscle.]
What are the screening options for colon cancer?
- Colonoscopy every 10 years
- High-sensitivity fecal occult blood testing every 3 years and flexible sigmoidoscopy every 5 years
- High sensitivity fecal occult blood testing annually
[Need total colonoscopy to rule out synchronous lesions in patients with colorectal cancer.]
What is blood supply to the colon as it pertains to below?
- 3 vessels from SMA that supply the Ascending and proximal 2/3 of transverse colon
- 3 vessels from the IMA that supply the distal 1/3 of transverse colon, descending and sigmoid colon, and upper portion of rectum
- Vessel that connects the SMA to the IMA
- 3 vessels from SMA that supply the Ascending and proximal 2/3 of transverse colon:
- Ileocolic artery
- Right colic artery
- Middle colic artery
- 3 vessels from the IMA that supply the distal 1/3 of transverse colon, descending and sigmoid colon, and upper portion of rectum:
- Left colic artery
- Sigmoid artery
- Superior rectal artery
- Vessel that connects the SMA to the IMA: Arc of Riolan
What is needed to make a patient with colorectal cancer eligible for a low anterior resection (LAR) rather than an abdominal perineal resection (APR)?
2 cm margin from lavator ani muscles
[Risk of local recurrence is higher with rectal than with colon cancer in general.]
At what approximate distance from the anal verge are the following landmarks?
- Anal canal
- Rectum
- Rectosigmoid junction
- Anal canal: 0 to 5 cm
- Rectum: 5 to 15 cm
- Rectosigmoid junction: 15 to 18 cm
The external anal sphincter (puborectalis muscle) is under CNS (voluntary) control innervated by which nerve?
Inferior rectal branch of the internal pudendal nerve
[The external sphincter is the continuation of the levator ani muscle (striated muscle). The internal sphincter is the continuation of the muscularis propria and is composed of smooth muscle under involuntary control.]
From where do the following rectal arteries originate?
- Superior rectal artery
- Middle rectal artery
- Inferior rectal artery
- Superior rectal artery: Inferior mesenteric artery
- Middle rectal artery: Internal iliac artery
- Inferior rectal artery: Internal pudendal artery (branch of internal iliac artery)
[The lateral stalks during low anterior resection or abdominoperineal resection contain the middle rectal arteries.]
What is the treatment for infectious pouchitis of an ileal pouch-anal anastomosis?
Metronidazole
[UpToDate: Pouchitis is an inflammatory condition of the ileal pouch reservoir of an ileal pouch-anal anastomosis. Pouchitis is classified based on the duration of symptoms (acute versus chronic), response to antibiotics (antibiotic-responsive versus antibiotic-dependent versus antibiotic-refractory), the frequency of flares (infrequent versus relapsing), and the etiology (idiopathic versus secondary).
First-line therapy for acute pouchitis consists of treatment with ciprofloxacin (1000 mg daily in divided doses for 14 days). Other antibiotics that have been used to treat acute pouchitis include metronidazole (1000 to 2000 mg daily, in divided doses for 14 days) and tinidazole (1000 mg daily in divided doses for 14 days). In a systematic review that included four randomized trials evaluating five agents for treatment of acute pouchitis, ciprofloxacin was more effective at inducing remission as compared with metronidazole. Rifaximin was not more effective than placebo, while budesonide enemas and metronidazole were similarly effective for inducing remission of acute pouchitis.
In patients with chronic pouchitis, we begin with fecal coliform culture and sensitivity testing to identify effective antimicrobial agents. In patients with chronic antibiotic-refractory pouchitis, secondary factors associated with an antibiotic-refractory course should be sought and treated.
For patients who respond to initial treatment but have relapsing symptoms at least three times within one year, or within one month of discontinuation of antibiotics, we suggest using maintenance therapy with probiotic VSL#3 (6 to 9 g/day) or chronic low-dose antibiotics (Grade 2C).]
What is the treatment for abdominal actinomycosis?
- Penicillin or tetracycline
- Drainage of any abscess
[Pathology shows yellow-white sulfur granules.]
[UpToDate: Actinomycosis is an uncommon, chronic granulomatous disease caused by filamentous, gram-positive, anaerobic bacteria. Actinomyces israelii is the major human pathogen. Actinomycosis has a worldwide distribution, affects mostly middle-aged individuals, and is two to four times more common in men.
Actinomycetes are commensal inhabitants of the oral cavity and intestinal tract but acquire pathogenicity through invasion of breached or necrotic tissue. As the infection progresses, granulomatous tissue, extensive reactive fibrosis and necrosis, abscesses, draining sinuses, and fistulas are formed.
Actinomycosis is a difficult disease to diagnose preoperatively by virtue of its rarity, nonspecific symptoms, and imitation of more common conditions such as malignancy, Crohn’s disease, and tuberculosis. It has been estimated that fewer than 10% of cases are diagnosed preoperatively. As a result, a high index of suspicion is required in patients presenting with constitutional or nonspecific abdominal symptoms and an abdominal mass. The disease is characterized by a chronic, indolent course with symptoms such as fatigue, fever, weight loss, and abdominal pain. Physical findings may include a palpable mass, visible sinus tracts, or fistulas.
Radiologic findings are nonspecific in abdominal actinomycosis. Computed tomography (CT) is the most useful imaging modality; it determines the location and extent of disease, occasionally contributes to an accurate preoperative diagnosis through fine-needle aspiration, and is used for monitoring the radiologic response to treatment on follow-up exams. CT may show the infiltrative nature of the disease with disruption of tissue planes and demonstrate one or more solid masses with focal low-attenuation areas or cystic masses with thickened walls
A definitive diagnosis is usually based upon histologic identification of actinomycotic sulfur granules and/or culture of Actinomyces. The preferred specimen for culture is pus. Sulfur granules represent colonies of Actinomyces and are characterized by a zone of granulation tissue surrounding one or more oval eosinophilic granules. Beaded or filamentous, non–acid-fast, gram-positive bacilli radiate from these granules. Actinomyces are indistinguishable from Nocardia on Gram stain, but only the latter are positive on modified acid-fast staining. An anaerobic environment is required for isolation of the organism.
Many patients undergo resection before the diagnosis has been established. Initial medical treatment is reasonable in patients in whom the diagnosis is established prior to surgery. Penicillin is the preferred choice. Initial intravenous therapy is required for larger lesions with abdominal abscesses or draining sinus tracts. The recommended dose is penicillin G 10 to 20 million units per day divided every four to six hours for four to six weeks, followed by oral penicillin (2 to 4 g per day) or amoxicillin for 6 to 12 months.]
What is the lymphatic drainage from the following regions of the rectum?
- Superior rectum
- Middle rectum
- Inferior rectum
- Superior rectum: Drains into IMA nodal lymphatics
- Middle rectum: Drains into IMA nodal lymphatics
- Inferior rectum: Drains into IMA nodal lymphatics and the internal iliac nodal lymphatics
At what approximate distance from the anal verge are the following landmarks?
- Dentate line
- Anorectal ring
- Lower 1/3 of rectum (range from start to finish)
- Middle 1/3 of rectum (range from start to finish)
- Upper 1/3 of rectum (range from start to finish)
- Dentate line: 2 cm
- Anorectal ring: 4 cm
- Lower 1/3 of rectum (range from start to finish): 4-8 cm
- Middle 1/3 of rectum (range from start to finish): 8-12 cm
- Upper 1/3 of rectum (range from start to finish): 12-16 cm
What is the treatment of Ogilvie’s syndrome?
- Check and replace electrolytes (especially K)
- Discontinue drugs that slow the gut (I.E. narcotics)
- Nasogastric decompression
- If colon > 10cm in diameter (high risk of perforation) then decompress with colonoscopy and neostigmine (cecostomy if that fails)
[UpToDate: Acute colonic pseudo-obstruction (Ogilvie’s syndrome) is a disorder characterized by acute dilatation of the colon in the absence of an anatomic lesion that obstructs the flow of intestinal contents.
The precise mechanism by which colonic dilation occurs in patients with acute colonic pseudo-obstruction is unknown. The association with trauma, spinal anesthesia, and pharmacologic agents suggests an impairment of the autonomic nervous system. Interruption of the parasympathetic fibers from S2 to S4 leaves an atonic distal colon and a functional proximal obstruction. However, there is no proposed mechanism to explain colonic dilation in those patients without obvious involvement of the parasympathetic nerves.
In patients with acute colonic pseudo-obstruction, increasing colonic diameter accelerates the rise in tension on the colonic wall, increasing the risk of colonic ischemia and perforation. The risk of colonic perforation increases when cecal diameter exceeds 10 to 12 cm and when the distention has been present for greater than six days. The duration of dilation is probably more important than the absolute diameter of the colon.
Initial management of acute colonic pseudo-obstruction is usually conservative in patients without significant abdominal pain, extreme (>12 cm) colonic distension, or signs of peritonitis and those who have one or more potential factors that are reversible.
In patients with cecal diameter >12 cm and in patients who have failed 24 to 48 hours of conservative therapy, we use pharmacologic therapy with neostigmine.
In patients who fail or who have contraindications to neostigmine, we perform colonoscopic decompression. In patients whose acute colonic pseudo-obstruction may be precipitated by opiates, we administer subcutaneous methylnaltrexone, prior to percutaneous or surgical decompression.
Percutaneous colostomy should be reserved for patients who fail endoscopic decompression and are not surgical candidates. We reserve surgical decompression for patients who fail endoscopic and pharmacologic therapy or have evidence of perforation or peritonitis.]
What are the 4 main gene mutations that lead to colon cancer?
- APC
- DCC
- p53
- k-ras
[UpToDate: A multistep process of specific genetic changes is thought to drive the transformation from normal colonic epithelium to an invasive cancer. Single, specific germline mutations underlie the common inherited syndromes (eg, adenomatous polyposis coli [APC], Lynch syndrome), while sporadic cancers result from the stepwise accumulation of multiple somatic mutations. Mutations in the APC gene occur early, while others, such as mutations of the TP53 suppressor gene, generally occur late in the process.
- Perhaps the most critical gene in the early development of CRC is the APC tumor suppressor gene. Somatic mutations in both alleles are present in 80% of sporadic CRCs, and a single germline mutation in this gene is responsible for familial adenomatous polyposis (FAP), a dominantly inherited syndrome characterized by the development of hundreds to thousands of colorectal polyps by the second or third decade of life. A germline APC mutation is also thought to contribute to the development of familial CRC in Ashkenazi Jews. A thymine to adenine transversion at nucleotide 3920 in the APC gene that resulted in a substitution of lysine for isoleucine at codon 1307 (I1307K) is found in 6% of all persons of Ashkenazi Jewish descent but in a higher frequency of Ashkenazi Jews with both a personal and family history of CRC (28%). This mutation was previously thought to represent a polymorphism.
- In 1989, a candidate gene termed the “deleted in colorectal carcinoma” (DCC) gene was identified at 18q21, and point mutations in the DCC gene have been identified in CRCs. Gene mutations presumably lead to a loss of expression of the DCC protein, which is thought to have a role in cell-cell or cell-matrix interactions. DCC is normally expressed in many tissues, including the colonic mucosa, although its normal function has been difficult to elucidate because of its large size and the lack of expression in CRCs. Loss of DCC expression may have prognostic value, particularly in patients with early stage CRC. Five-year survival rates seem to be worse for patients with stage II (node-negative (table 3)) CRCs that lack DCC expression compared with those that express it. For patients with DCC-negative stage II disease, prognosis more closely approximates that of patients with more advanced stage III (node-positive) disease.
- The TP53 gene on chromosome 17p is the most commonly mutated gene in human cancer. In approximately 50% to 70% of CRCs, TP53 inactivation occurs by a mutation of one allele followed by loss of the remaining wild type gene. 17p sequences are lost in as many as 75% of CRCs, while they are rarely lost in adenomas and aberrant crypt foci, suggesting that loss of p53 function represents a relatively late event in colorectal tumorigenesis. In keeping with this hypothesis, a large international study of 3583 CRCs found an increase in the frequency of TP53 mutations with advancing disease stage. The normal “wild-type” TP53 gene produces a DNA-binding protein p53 that acts as a transcriptional activator of growth inhibitory genes. Wild-type p53 may be particularly critical when cells are under stress. Normally, cells arrest their growth in response to DNA damaging agents and other stressors (eg, hypoxia) via induction/activation of p53. Once activated, p53 induces a variety of growth-limiting responses, including cell cycle arrest (in order to facilitate DNA repair), apoptosis, senescence, and differentiation. p53 produces these responses largely by altering the expression of a number of target genes, at least 20 of which have been described as being under transcriptional control of p53. Because of its central role in preventing the propagation of cells with DNA damage, p53 has been referred to as the “guardian of the genome”
- The RAS oncogene exists as three cellular variants, HRAS, KRAS, and NRAS. Although all three oncogenes, when mutated, have the ability to transform normal cells, KRAS is the most frequently mutated in human CRC. The importance of RAS to colorectal tumorigenesis is underscored by the finding that CRC cells in which a mutated RAS gene has been removed or replaced lose their ability to form tumors in nude mice. The RAS oncogenes encode a family of small proteins with homology to G-proteins that regulate cellular signal transduction by acting as a one-way switch for the transmission of extracellular growth signals to the nucleus. These proteins normally cycle between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. RAS mutations, typically point mutations, leave the protein resistant to GTP hydrolysis by GTPase, resulting in a constitutively active GTP-bound protein and a continuous growth stimulus. Data from animal models suggest that RAS mutations may contribute to colorectal tumorigenesis by activating cancer stem cells that have already been activated by adenomatous polyposis coli (APC) mutations.]
