Biomarkers in the detection
of Colon and Rectal Cancer
Gina Wallar, MPH
Colorectal CRC
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2009 Stats (US)
Risk Factors
Biomarkers
Current Screening Guidelines
Transferrin
Colorectal Cancer (CRC)
Picture in the U.S.
3rd most common cancer in men and
women
2nd major cancer killer
Detectable
Treatable
Screening- Compliance a major factor
2009 CRC Statistics
 106,100 cases of colon cancer expected
 40,870 cases of rectal cancer expected
• Accounts for 9% of all cancer deaths
• 5-year survival rate for Stage I is 90%
• 5-year survival rate for Stage IV is 11%
 Less than half of colon cancer cases are
detected when the cancer is localized
Colon Cancer-Risk Factors
 Family History/Genetics
 Age
 History of colon cancer, polyps, bowel disease
 Race/Ethnicity
 Alcohol
 Smoking
 Diet
 Sedentary Lifestyle
 Obesity
 Diabetes
Smoking (Incidence versus Mortality)
Alcohol and Colon Cancer
Alcohol and Rectal Cancer
Colon Cancer and Diet
 “Western Civilization”
 High in Animal Fat-Bile acid production
 Low Fiber
 Refined sugar-Hyperinsulinaemia
 Low Vegetable Intake
No longer considered a main contributor to
CRC
Red Meat Consumption
CRC and Fish Consumption
Geelen, A. et al. Am. J. Epidemiol. 2007 0:kwm197v1-197; doi:10.1093/aje/kwm197
Green Tea
Colon Cancer and Physical Activity
 Sedentary lifestyle is positively associated
with colon cancer (Giovannucci)
 Physical activity- obesity connection
 Sex steroid hormone levels change with
physical activity initiation
Estradiol decreases
SHBG increases
Testosterone increases
Obesity and Colon Cancer
Obesity and Rectal Cancer
Colon Cancer and Obesity
 Increase in adipose tissue
 Increase in insulin
 Association stronger in men and premenopausal
women
 Gender as an effect modifier on the obesity
colon cancer association suggest that sex
steroid hormones play a role though the
mechanism is not well understood
Biomarkers of Obesity
With Obesity
 Decreased SHBG
 Decreased total T (men)
 Increased free and total E
Does obesity drive these changes in
hormones or do hormones drive changes
in body shape, weight, and adiposity?
Mechanism
Hypothalamus/GnRH
Adipose tissue
Adrenal Secretion
Pituitary
LH/FSH
Ovary
Androstenedione
Testis
Cholesterol pathway
Liver
Testosterone
lo SHBG
Estrogens
Androgens
Hyperthyroidism Glucocorticoids
Hypothyroidism
Anorexia
Pregnancy
Obesity
Insulin/IGF-1
PCOS
Diabetes
Free T
+
Aromatase
Androgens
Bound T
SHBG
hi SHBG
Age, Obesity
Estradiol
Free E
+
Bound E
Estrogens
Adipose Tissue
Features
 Established relationship
with insulin resistance
 Play a role in the
regulation of insulin
signaling and action
 Source of inflammation
Adipocytokines
 Leptin
 Adiponectin
 IL-6
 TNFalpha
 FFA
 Resistin
Diabetes and Colon Cancer
 Similarity of lifestyle/environmental risk
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factors
Positively associated
Hyperinsulinaemia initiates carcinogenesis
Insulin is a growth factor for colonic
epithelial cells and can reduce apoptosis
Insulin is a mitogen of tumor cells in vitro
Diabetes and Colon Cancer
Mechanism
Adiposity
Varying levels of
Adipocytokines
Insulin
Resistance
IGF-1 Increases
Insulin Increases
Cell
Proliferation
Increases
Apoptosis
Decreases
Activates IR
Tumor Development
Activates
IGFR
Growth Hormones
 Insulin increases IGF-1
 IGF-1 activates the IGF receptor
 Decreases apoptosis
 Increases cell proliferation
 Physicians Health Study reported RR of
2.51 for those in the high IGF-1 quintile
Current CRC Screening
Goal: Reduce mortality via a reduction in
incidence of advanced disease
1-Stool-based tests (Occult Blood and DNA)
2-Structural exams (Colonscopy (CSPY),
Flexible Sigmoidoscopy (FSIG), DoubleContrast Barium Enema (DCBE), and
Computed Tomographic Colongraphy
(CTC))
Current Recommendations for
Average-Risk Individuals aged >50
Detection of adenomatous polyps and
cancer:
Every 5 years (1 of the following): FSIG,
DCBE, CTC
or Every 10 years: CSPY
Detection of cancer:
Annual Stool Blood Test
sDNA Test (Interval unknown)
Biomarkers
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APC (~70%)
p53 (~50%-70%)
K-ras (~50%)
IGF-1 and CEA
MSI
Stool DNA
Stool DNA, tissue
Stool and colonic DNA
Serum
Tissue, Stool and
Plasma DNA
Other various biomarkers in tissue: Src, SMAd4, SMAD2,
DCC, hMSH2, hMLH1, hPMS1, hPHMS2, hMSH6, Ploidy
Biomarkers
Srivastava et al Biomarkers for Early Detection of Colon Cancer
Meta-Analysis of GWAS
Transferrin
 77KD, β-globulin
 Main Function: Transport extracellular iron
into cells through membrane receptormediated endocytosis
 More stable than hemoglobin
 Required for cell growth and survival
 Increased Tf level in serum and body fluid
in several cancer types
Transferrin Dipstick
Disease
N
IFOBT Tf
Tf +
IFOBT
+ -
+ -
+ -
Colorectal Cancer
40
30
(75)
10
(25)
32
(80)
8
(20)
36
(90)
4
(10)
Premalignant
36
16
(44)
20
(56)
26
(72)
10
(28)
28
(78)
8
(22)
Low risk
34
4
(12)
30
(88)
8
(24)
26
(76)
10
(29)
24
(71)
Rao et al Transferrin Dipstick as a Potential Novel Test for Colon Cancer Screening
Summary
 Much research has been conducted on
risk factors and biomarkers for CRC
 Room for improvement in early detection
 New types of biomarkers
 New dipsticks/combinations with better
performance to potentially increase
compliance
Thank You