A 32-year-old man presents to the ED with a 2-month history of alternating diarrhea and constipation, rectal bleeding, a 20-lb weight loss, and worsening fatigue. What are the most common genetic mutations that could have led to the development of this patient's colon cancer?
Mutations may cause activation of oncogenes (K-ras) and/or inactivation of tumor suppressor genes (APC, deleted in colo rectal carcinoma [DCC] , p53). Colorectal carcinoma is thought to develop from adenomatous polyps by accumulation of these mutations in what has come to be known as the adenomacarcinoma sequence. The APC gene is a tumor suppressor gene. Mutations in both alleles are necessary to initiate polyp formation. Mutation of K-ras results in an inability to hydrolyze guanosine triphosphate ( GTP), thus leaving the G-protein permanently in the active form. It is thought that this then leads to uncontrolled cell division. MYH is a base excision repair gene, and biallelic deletion results in changes in other downstream molecules. Since its discovery, MYH mutations have been associated with an AFAP phenotype in addition to sporadic cancers. The tumor suppressor gene p53 has been well characterized in a number of malignancies. The p53 protein appears to be crucial for initiating apoptosis in cells with irreparable genetic damage. Mutations in p53 are present in 75% of colorectal cancers.
A 64-year-old man presents to the clinic with a 1 -month history of 10-lb weight loss and rectal bleeding. His hematocrit is found to be 27. On colonoscopy he is found to have a large cecal mass. What risk factors should he have modified to prevent development of colon cancer?
A diet high in saturated or polyunsaturated fats increases risk of colo rectal cancer, while a diet high in oleic acid (olive oil, coconut oil, fish oil) does not increase risk. Animal studies suggest that fats may be directly toxic to the colonic mucosa and thus may induce early malignant changes. In contrast, a diet high in vegetable fiber appears to be protective. A correlation between alcohol intake and incidence of colorectal carcinoma has also been suggested. Ingestion of calcium, selenium, vitamins A, C, and E, carotenoids, and plant phenols may decrease the risk of developing colo rectal cancer. Obesity and sedentary lifestyle dramatically increase cancer-related mortality in a number of malignancies, including colorectal carcinoma. This knowledge is the basis for primary prevention strategies to eliminate colorectal cancer by altering diet and lifestyle.
A 63-year-old man undergoes a screening colonoscopy and is found to have a polyp in his sigmoid colon. Which type of polyp is most associated with malignancy?
Adenomatous polyps are common, occurring in up to 25% of the population older than 50 years of age in the United States. By definition, these lesions are dysplastic. The risk of malignant degeneration is related to both the size and type of polyp. Tubular adenomas are associated with malignancy in only 5% of cases, whereas villous adenomas may harbor cancer in up to 40%. Tubulovillous adenomas are at intermediate risk (22%). Invasive carcinomas are rare in polyps smaller than 1 cm; the incidence increases with size. The risk of carcinoma in a polyp larger than 2 cm is 35 to 50%. Although most neoplastic polyps do not evolve to cancer, most colorectal cancers originate as a polyp.
A 50-year-old woman presents to the ED after having her first colonoscopy on her birthday. She endorses left lower quadrant abdominal pain and is febrile to 38.5°C. What complications after a colonoscopy require emergent laparotomy?
Complications of polypectomy include perforation and bleeding. A small perforation (microperforation) in a fully prepared, stable patient may be managed with bowel rest, broad-spectrum antibiotics, and close observation. Signs of sepsis, peritonitis, or deterioration in clinical condition are indications for laparotomy. Bleeding may occur immediately after polypectomy or may be delayed. The bleeding will usually stop spontaneously, but colonoscopy may be required to resnare a bleeding stalk or cauterize the lesion. Occasionally angiography and infusion of vasopressin may be necessary. Rarely, colectomy is required.
A 36-year-old woman with a complicated family history including her grandmother, mother, and sister who were diagnosed with colon cancer and a younger sister who was recently diagnosed with pancreatic cancer presents to the clinic for genetic counseling. What is a correct statement about this syndrome?
Hereditary nonpolyposis colorectal cancer (HNPCC; Lynch syndrome) is extremely rare (1-3% of all colon cancers). The genetic defects associated with HNPCC arise from errors in mismatch repair, the phenotypic result being MSI. HNPCC is inherited in an autosomal dominant pattern and is characterized by the development of colorectal carcinoma at an early age (average age, 40-45 years). Approximately 70% of affected individuals will develop colorectal cancer. Cancers appear in the proximal colon more often than in sporadic colorectal cancer and have a better prognosis regardless of stage. The risk of synchronous or metachronous colorectal carcinoma is 40%. HNPCC may also be associated with extracolonic malignancies, including endometrial carcinoma, which is most common, and ovarian, pancreas, stomach, small bowel, biliary, and urinary tract carcinomas. The diagnosis of HNPCC is made based on family history. The Amsterdam criteria for clinical diagnosis of HNPCC are three affected relatives with histologically verified adenocarcinoma of the large bowel (one must be a first-degree relative of one of the others) in two successive generations of a family with one patient diagnosed before age 50 years. HNPCC results from mutations in mismatch repair genes, and like PAP, specific mutations are associated with different phenotypes. For example, mutations in PMS2 or MSH6 result in a more attenuated form of HNPCC when compared to mutations in other genes. MSH6 inactivation also appears to be associated with a higher risk for endometrial cancer. Further significance of these specific mutations remains to be determined.
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