Colon cancer arises from mutations in genes that regulate the Wnt signaling pathway and accumulate additional mutations over time. Key genetic changes activate oncogenes like KRAS and inactivate tumor suppressors like p53. Approximately 20% of cases involve defective DNA mismatch repair leading to microsatellite instability. Risk factors include family history, conditions like FAP and HNPCC, western diet high in red meat and low in fiber, lack of exercise, obesity, diabetes, and potentially HPV infection. NSAIDs and bisphosphonates may reduce risk while certain biomarkers like elevated CRP, leptin, and IGF levels are associated with increased risk.
2. • 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.
3. 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.
4. 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.
5.
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8.
9. • 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.
10. 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.
11. 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
12. • 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.
13. • 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) .
14. 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.
15. 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.
16. 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.
23. • 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.
24. 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.
25. • 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.
26. 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.
27. 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.
28. • 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 .
29. 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.
30. 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.
31. 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.
32. 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
34. • 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.
35. 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.
36. 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.