Colon Cancer

Pathogenesis of Colorectal Ca (familial vs. sporadic):

• Knudsen’s “two- hit” hypothesis of carcinogenesis: two mutations are needs to induce carcinogenesis
• in familial ca syndromes, one hit is a germline mutation (present in every cell) and the second is a somatic mutation
• in sporadic cancers, both mutations are somatic, which is less common (however, colorectal ca occurs in about 5% of the population)
• a series of mutations causes the progression from normal mucosa to adenoma to carcinoma (in approx 15 yrs)
• Tumor suppressor genes (dysregulated growth occurs when both copies are mutated):

  o    APC gene normally regulates colonocyte growth; mutations in the APC gene tend to occur early in the process of colon carcinogenesis and are the cause of most cases of familial adenomatous polyposis syndrome (FAP)—tends to occur early in the sequence of normal mucosaàadenoma

  o    p53 is another tumor suppressor gene that is involved in >70% of colon cancers; facilitates cell repair and initiates apoptosis (these mutations often occur late in the sequence from adenomaàcarcinoma)

• Oncogenes (promote cell growth and replication, one mutation is oncogenic):

o    Ras gene mutations occur in 50% of sporadic colon ca, but do not appear to be involved in most hereditary cancers

o    myc is another oncogene implicated in sporadic colon ca

• Mismatch Repair genes (assist in the repair of errors that may occur in DNA replication):

  o    Results in microsatellite instability

  o    Causes rapidly accelerated ademoma to carcinoma sequence

  o    Implicated in hereditary nonpolyposis colorectal ca (HNPCC) and approx 15% of sporadic colon ca (MLH1 in HNPCC and MLH2 in sporadic cc)

  o    MYH is a base excision repair gene which plays a role in autosomal recessive FAP

Epidemiology/Risk factors for Colon Ca:

• 1/20 persons in the US will develop colorectal ca in their lifetime
• 3rd most common cancer (behind prostate/breast and lung) and 3rd most common cause of cancer death in the US in both sexes
• Affects men and women equally
• Incidence is highest in African Americans and often have more advanced disease at diagnosis
• Environmental factors:

  o    diets high in fruit/veg/fiber have been associated with fewer colon cancers c/w a diet that is high in fat and red meat

  o    high intake of calcium, folate and selenium also associated w decreased risk

  o    obesity and sedentary lifestyle also associated w development of adenomas and reduced survival in colon ca

  o    smoking and etoh : increased risk of polypsàcancer and decreased survival

   

Colorectal Cancer Screening:

FAP: annual flex sig beginning at age 10 or 12 yrs; colectomy should be considered when polyposis is detected (in attenuated FAP, annual colonoscopy is required as many polyps will only present in the proximal colon) + upper endoscopy every 1-3 yrs, starting at age 25-35

HNPCC: colonoscopy every 1-2 yrs starting at age 20-25 (or 10 yrs earlier than age of diagnosis for youngest affected family member).  Annual colo after age 40. Consider prophylactic hysterectomy and salpingo-oophorectomy.  Also includes annual screening renal US and urine cytology.

IBD: pts with UC and Chron’s disease have increased risk for colon ca (proportional to duration if disease, extent of colon involvement and coexistence of sclerosing cholangitis).  Screening colonoscopy should be initiated in patients who have had the disease for >8 yrs.  If dysplasia is detected, colectomy should be considered.

Average risk (no family hx of adenomatous polyps or colon ca): starting at age 50; frequency depends of the modality of screening:

• Screening is feasible b/c on average the process of polypàcancer takes 10-15 yrs
• Most screening strategies result in cost-effectiveness ratios of 10-25K per year of life saved
• FOBT (or FIT) requires annual testing with 2 samples collected from 2 separate, spontaneously passed stools (no red meat, asa and certain fruit/veg must be eliminated from diet prior to testing)—if done correctly can reduce colorectal-ca related mortality by 33%
• DRE-obtained FOBT is not acceptable (reduces efficacy five-fold)
• Flexible sigmoidoscopy decreases cancer mortality by 45%; should be performed every 5 yrs if no adenomas detected
• combined FOBT and flex sig increases the detection rate of colon ca to 76%
• Colonoscopy can be diagnostic and therapeutic; studies have found a reduced incidence of colorectal ca of 66-90% but there have been no RCTs that show a reduction in cancer-related mortality (although can likely extrapolate the flex sig data)
• Barium enema no longer recommended for screening
• CT colonography? sensitivity of polyp detection is cariable, radiation exposure, surveillance interval unclear
• Fecal DNA testing? sensitivity varies, no studies demonstrate a mortality benefit

 

(Victoria Kelly MD, 8/31/10)