COLON CANCER

Molecular biology

• Chromosomal instability is a feature of up to 80% of CRCs and is commonly associated with activating KRAS point mutations and loss of regions that encompass P53 and other tumor suppressors on 18q and 17p.

Genetic pathways to colorectal carcinoma.• All colorectal cancers (CRCs) arise within benign

adenomatous precursors, fueled by mutations that serially enhance malignant behavior.

• Mutations that activate the Wnt signaling pathway seem to be necessary initiating events, after which two possible courses contribute to the accumulation of additional mutations.

Wnt signaling

• The key driver pathway in colorectal cancer. • Members of the Wnt family of glycoprotein

morphogens bind the cell surface coreceptors Frizzled and LRP5/6.

• In the absence of Wnt binding, normal cells use a complex containing APC, Axin, and other cytoplasmic proteins to promote GSK-3β–mediated phosphorylation.

• About 20% of CRCs are euploid but defective in DNA mismatch repair (MMR), resulting in high microsatellite instability (MSI-hi).

• MMR defects may develop sporadically, associated with CpG island methylation (CIMP), or as a result of familial predisposition in hereditary nonpolyposis colorectal cancer (HNPCC).

• Mutations accumulate in the KRAS or BRAF oncogenes, p53 tumor suppressor, and in microsatellite-containing genes vulnerable to MMR defects, such as TGFβIIR.

Epigenetics

• Epigenetic inactivation of the MMR gene MLH1 and activating BRAF point mutations are especially common in serrated adenomas, which progress, in part, through the silencing of tumor suppressor genes by promoter hypermethylation.

• Progression from adenoma to CRC takes years to decades, a process that accelerates in the presence of MMR defects.

Epidemiology

• 90% of cases occurs after age 50. • Third leading cause of cancer in the US

• Average lifetime risk for developing this cancer is 6%• Men and women are affected equally• Women are more likely to have right sided colonic

adenomas• Distributed evenly among various racial groups• African Americans and Hispanics have lower survival rate

• In India, the annual incidence rates (AARs) for colon cancer and rectal cancer in men are 4.4 and 4.1 per 100000, respectively.

• The AAR for colon cancer in women is 3.9 per 100000.

• In the 2013 report, the highest AAR in men for CRCs was recorded in Thiruvananthapuram (4.1) followed by Bangalore (3.9) and Mumbai (3.7) .

• The highest AAR in women for CRCs was recorded in Nagaland (5.2) followed by Aizwal (4.5) .

Risk Factors

Inherited Predisposition • Family history confers an increased lifetime risk

of CRC.• Familial factors contribute importantly to the risk

of sporadic CRC, depending upon the involvement of first- or second-degree relatives and the age of onset of CRC.

Involvement of at least one first-degree relative with CRC serves to double the risk of CRC.

FAP

• Familial adenomatous polyposis (FAP) constitutes 1% of all CRC incidence

• Hallmark features include hundreds to thousands of colonic polyps that develop in patients in their teens to 30s, and if the colon is not surgically removed, 100% of patients progress to CRC.

HNPCC

• Hereditary nonpolyposis CRC (HNPCC) accounts for about 3% of all CRCs.

• Salient features include up to 100 colonic polyps (hence the term nonpolyposis)

• The lifetime risk of CRC in HNPCC is 80%, up to 50% to 60% for endometrial cancer, and 1% to 13% for all other cancers.

• Environmental Factors

• Eleven risk factors were independently associated with colon cancer, some which have little or no previous support in the literature (age, waist girth, use of hormone therapy at baseline [protective], years smoked, arthritis [protective presumably due to medications used], relatives with CRC, lower hematocrit levels, fatigue, diabetes, less use of sleep medication, and cholecystectomy.

Diet

• Total Calories ,Meat, Fat, and Protein.• Probst-Hensch et al. found fried, barbecued,

and processed meats to be associated with CRC risk, especially for rectal cancer.

• Coffee- Decreased risk.• Fiber- Decreased risk.• Vegetables and Fruit-Decreased risk.• Other dietary factors under recent investigation

include calcium,magnesium, and vitamin D. Calcium has been historically implicated as having a protective effect, perhaps due to its ability to bind injurious bile acids with reduction of colonic epithelial proliferation.

Lifestyle

• Physical inactivity has been associated with CRC risk, for colon more than rectal cancer.

• A sedentary lifestyle may account for an increased CRC risk.

Diabetes

• Type 2 diabetes has previously been

implicated in the development of CRC, but it has been difficult to separate this association

From other confounding lifestyle factors such as smoking and obesity.

• Yuhara et al.65 identified 14 studies, most of which controlled for smoking, obesity, and physical exercise, and demonstrated that diabetes was associated with increased risk of both colon and rectal cancer .

Drugs

• Nonsteroidal anti-Inflammatory Drugs Population-based studies strongly support inverse associations between use of aspirin and other nonsteroidal anti- Inflammatory drugs (NSAID) and the incidences of both CRC and adenomas.

• As a result, NSAIDs and selective cyclo oxygenase 2 (COX-2) inhibitors have been investigated intensively in hereditary and sporadic CRC.

NSAIDs & PIK3CA

• Liao et al. have reported evidence that suggests that aspirin therapy after CRC diagnosis may be beneficial to those patients whose tumors have a PIK3CA mutation, but not in those with wild-type PIK3CA.

Bisphosphonates

• Bisphosphonates- have been shown to have various antiproliferative, antiangiogenic, proapoptotic, and antiadhesive effects.

• Singh et al. performed a recent meta-analysis demonstrating a statistically significant 17% reduction in CRC incidence with bisphosphonate use.

HPV

• In the first meta-analysis Damin, Ziegelmann, and Damin reported a high prevalence of human papillomavirus (31.9%) in affected patients, but also found a strong correlation between human papilloma virus positivity and increased CRC risk .

• These results may indicate an alternative pathway of colorectal carcinogenesis that could have vast implications for treatment and prevention

Biomarkers

• (1)C-reactive protein • (2) serum amyloid A• (3) Leptins• (4)IGF-I&II

• Toriola et al. evaluated the role of C-reactive protein and serum amyloid A, two common inflammatory mediators.

• Elevated concentrations of both C-reactive protein and serum amyloid a conferred significantly increased risk of colon cancer.

Leptins • A peptide hormone produced by adipocytes, is

also thought to contribute to CRC pathogenesis.

• A recent prospective analysis found that soluble leptin receptor levels, which may regulate leptin function, was strongly inversely associated with colon cancer risk.

IGF-I&II• Chi et al. performed a investigation of insulin-

like growth factor peptides, also implicated in CRC carcinogenesis, and found that high levels of insulin-like growth factor I and insulin-like growth factor II significantly increased cancer risk.