Colorectal cancer

Chapter 17 COLORECTAL CANCER





RISK FACTORS


Environmental and genetic factors can increase the likelihood of developing colorectal cancer (CRC) (Table 17.1). Although inherited susceptibility most strikingly increases the risk, the majority of CRCs are sporadic. Age is a very important risk factor. It rarely occurs before the age of 40, and the incidence begins to increase significantly in the sixth decade, with the highest rate between 65 and 75 years. The incidence rate is higher in industrialised regions, higher in African American than in whites, and it is nearly equal for males and females (M:F ratio1.3:1.0 for rectal tumours).


TABLE 17.1 Risk factors for colorectal cancer (CRC)














































































Risk factor Examples Risk
Genetic disorders Familial adenomatous polyposis I
Hereditary non-polyposis colorectal cancer I
Peutz-Jeghers syndrome I
Hyperplastic polyposis I
Cowden’s syndrome I
Juvenile polyposis syndrome I
Personal history of CRC or adenoma   I
Family history of CRC or adenoma   I
Inflammatory bowel disease Ulcerative colitis, Crohn’s disease I
Medications NSAIDs, aspirin, calcium, vitamin D, statins, hormone replacement therapy (in postmenopausal women) D
Endocrine disorders Diabetes mellitus I
Insulin resistance I
Acromegaly I
Obesity I
Gastrin I
Surgical interventions Cholecystectomy I
Ureterocolic anastomoses I
Environmental factors Smoking I
Moderate physical activity D
Healthy diet (low calorie, rich in fruits and vegetables with low animal products) D
Alcohol (moderate and high amount) I

D = decrease risk for CRC; I = increase risk for CRC; NSAIDs = non-steroidal antiinflammatory drugs.




GENETICS


Cancers are all caused by abnormalities in genes, although most cancers are not caused by inherited genetic disorders. Cancer is the result of complex interactions between the fingerprints of the genome and interaction with the environment. For most cancers, the wide variations seen among different national groups appear to be explained almost entirely by environmental factors with familial factors playing a minor role. The exception to this is malignancy in the colon where genetics is much more important. CRC follows three major patterns:







MULTI-STEP MODEL OF CRC



Specific genetic mutations


The APC (adenomatous polyposis coli) gene on chromosome 5 is the most critical gene in the early development of CRC. Somatic mutations in both alleles are present in 80% of sporadic CRCs. Most sporadic CRCs with wild-type APC have mutations in other genes of the Wnt signalling pathway, mostly in β-catenin.


The K-ras oncogene is found in up to 50% of sporadic adenomas and CRC. It encodes a family of G-proteins that regulate cellular signal transduction by acting as a one-way switch for the transmission of extra-cellular growth signals to the nucleus. Once mutations occur, they leave the ras in a constitutively active state that leads to a continuous growth stimulus.


The p53 gene located on chromosome 17p is the most commonly mutated gene in human cancer. It serves as the guardian of the genome. It is particularly critical when cells are under stress. Normally, cells arrest their growth in response to DNA damaging agents by induction or activation of p53. Once activated, p53 induces a variety of growth-limiting responses, including cell cycle arrest (to facilitate DNA repair), apoptosis, senescence and differentiation. In about 50%–70% of CRCs, p53 inactivation occurs by a mutation of one allele followed by loss of heterozygosity (LOH), as a late event in the transition from large adenoma into CRC. Patients who harbour p53 mutations have worse outcomes and shorter survival.


There are three candidate tumour suppressor genes on chromosome 18q. DCC (deleted in colon cancer), SMAD4 and SMAD2 genes were identified through studies of allelic loss. One copy of 18q was lost in 73% of sporadic CRC, and in 47% of advanced adenomas. For patients in stage II with DCC gene the prognosis is similar to that of patients with advanced stage III disease. The practical importance of this knowledge may be the identification of a subgroup of patients with stage II disease who may benefit from adjuvant chemotherapy.


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Mar 29, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on Colorectal cancer

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