How common is colorectal cancer, and what is the mortality?
Excluding skin cancers, colorectal cancer is the fourth most common cancer in the US overall
third leading cause of cancer-related deaths in the US overall
List key molecular pathways as causes for colorectal cancer.
Chromosomal instability pathway
Microsatellite instability pathway
Hypermethylation phenotype pathway
Describe the molecular pathways leading to colorectal cancer.
Chromosomal instability pathway in colon cancer: The adenoma-carcinoma sequence is the progressive accumulation of mutations in oncogenes (e.g., KRAS) and tumor suppressor genes (e.g., APC, TP53) that results in the slow transformation of adenomas into carcinomas.
APC gene mutation (loss of cellular adhesion and increased cellular proliferation) → KRAS gene mutation (unregulated cellular signaling and cellular proliferation) → TP53 and DCC gene mutation
Most cases of sporadic CRC develop via this pathway.
Microsatellite instability pathway in colon cancer: due to methylation or mutations in mismatch repair genes (MMR genes, e.g., MLH1 or MSH2)
Hypermethylation phenotype pathway in colon cancer
CpG island methylator phenotype (CIMP): global hypermethylation of CpG islands → silencing of MMR gene expression
Associated with BRAF mutations
Up to 20% of sporadic CRCs develop from serrated polyps that underwent malignant transformation via this pathway.
Associated with colorectal cancer
Possible protective effect of long-term use of aspirin and other NSAIDs
List risk factors of colorectal cancer.
Age: older age (> 40 years)
Family history: Approx. 25% of individuals with colorectal cancer (CRC) have a positive family history.
Familial adenomatous polyposis: 100% of individuals will have developed CRC by the age of 40 years, Gardner syndrome, Turcot syndrome, Peutz-Jeghers syndrome, Juvenile polyposis syndrome)
Hereditary nonpolyposis colorectal cancer (HNPCC): progression to CRC in 80% of cases
Colorectal adenomas and serrated polyps
Inflammatory bowel disease: chronic inflammation → hyperplasia → non-polypoid dysplasia → neoplasia
Endocarditis and bacteremia due to S. gallolyticus
Diabetes mellitus type 2
High-fat and low-fiber
Other: History of abdominal radiation during childhood