Biomarkers in the detection Biomarkers in the detection of Colon and Rectal Cancerof Colon and Rectal Cancer

Gina Wallar, MPHGina Wallar, MPH

Colorectal CRCColorectal CRC

2009 Stats (US)2009 Stats (US) Risk FactorsRisk Factors BiomarkersBiomarkers Current Screening GuidelinesCurrent Screening Guidelines Transferrin Transferrin

Colorectal Cancer (CRC)Colorectal Cancer (CRC)

Picture in the U.S.Picture in the U.S.33rdrd most common cancer in men and most common cancer in men and

womenwomen22ndnd major cancer killer major cancer killerDetectableDetectableTreatableTreatableScreening- Compliance a major factorScreening- Compliance a major factor

2009 CRC Statistics2009 CRC Statistics

106,100 cases of colon cancer expected106,100 cases of colon cancer expected 40,870 cases of rectal cancer expected40,870 cases of rectal cancer expected

• Accounts for 9% of all cancer deathsAccounts for 9% of all cancer deaths

• 5-year survival rate for Stage I is 90%5-year survival rate for Stage I is 90%

• 5-year survival rate for Stage IV is 11%5-year survival rate for Stage IV is 11% Less than half of colon cancer cases are Less than half of colon cancer cases are

detected when the cancer is localizeddetected when the cancer is localized

Colon Cancer-Risk FactorsColon Cancer-Risk Factors

Family History/GeneticsFamily History/GeneticsAgeAgeHistory of colon cancer, polyps, bowel diseaseHistory of colon cancer, polyps, bowel diseaseRace/EthnicityRace/EthnicityAlcoholAlcoholSmoking Smoking DietDietSedentary LifestyleSedentary LifestyleObesityObesityDiabetesDiabetes

Smoking (Incidence versus Mortality)Smoking (Incidence versus Mortality)

Alcohol and Colon CancerAlcohol and Colon Cancer

Alcohol and Rectal CancerAlcohol and Rectal Cancer

Colon Cancer and DietColon Cancer and Diet

““Western Civilization”Western Civilization” High in Animal Fat-Bile acid productionHigh in Animal Fat-Bile acid production Low FiberLow Fiber Refined sugar-HyperinsulinaemiaRefined sugar-Hyperinsulinaemia Low Vegetable IntakeLow Vegetable IntakeNo longer considered a main contributor to No longer considered a main contributor to

CRCCRC

Red Meat ConsumptionRed Meat Consumption

Geelen, A. et al. Am. J. Epidemiol. 2007 0:kwm197v1-197; doi:10.1093/aje/kwm197

CRC and Fish Consumption

Green TeaGreen Tea

Colon Cancer and Physical ActivityColon Cancer and Physical Activity

Sedentary lifestyle is positively associated Sedentary lifestyle is positively associated with colon cancer (Giovannucci)with colon cancer (Giovannucci)

Physical activity- obesity connectionPhysical activity- obesity connection Sex steroid hormone levels change with Sex steroid hormone levels change with

physical activity initiationphysical activity initiation

Estradiol decreasesEstradiol decreases

SHBG increasesSHBG increases

Testosterone increasesTestosterone increases

Obesity and Colon CancerObesity and Colon Cancer

Obesity and Rectal CancerObesity and Rectal Cancer

Colon Cancer and ObesityColon Cancer and Obesity

Increase in adipose tissueIncrease in adipose tissue Increase in insulinIncrease in insulin Association stronger in men and premenopausal Association stronger in men and premenopausal

womenwomen

Gender as an effect modifier on the obesity Gender as an effect modifier on the obesity colon cancer association suggest that sex colon cancer association suggest that sex steroid hormones play a role though the steroid hormones play a role though the mechanism is not well understoodmechanism is not well understood

Biomarkers of ObesityBiomarkers of Obesity

With ObesityWith Obesity Decreased SHBGDecreased SHBG Decreased total T (men)Decreased total T (men) Increased free and total E Increased free and total E

Does obesity drive these changes in Does obesity drive these changes in hormones or do hormones drive hormones or do hormones drive changes in body shape, weight, and changes in body shape, weight, and adiposity?adiposity?

MechanismMechanism

Adipose tissue

TestosteroneOvary

Adrenal Secretion

Androstenedione

Age, Obesity Aromatase

Cholesterol pathway

Estradiol

Testis

Pituitary LH/FSH

Hypothalamus/GnRH

Liver SHBG

hi SHBG

Estrogens

Hyperthyroidism

Anorexia

Pregnancy

lo SHBG

Androgens

Glucocorticoids

Hypothyroidism

Obesity

Insulin/IGF-1

PCOS

Diabetes

Free T

+

Bound T

Free E

+

Bound E

Androgens

Estrogens

Adipose TissueAdipose Tissue

FeaturesFeatures Established relationship Established relationship

with insulin resistance with insulin resistance Play a role in the Play a role in the

regulation of insulin regulation of insulin signaling and actionsignaling and action

Source of inflammationSource of inflammation

AdipocytokinesAdipocytokines LeptinLeptin AdiponectinAdiponectin IL-6IL-6 TNFalphaTNFalpha FFAFFA ResistinResistin

Diabetes and Colon CancerDiabetes and Colon Cancer

Similarity of lifestyle/environmental risk Similarity of lifestyle/environmental risk factorsfactors

Positively associatedPositively associated Hyperinsulinaemia initiates carcinogenesisHyperinsulinaemia initiates carcinogenesis Insulin is a growth factor for colonic Insulin is a growth factor for colonic

epithelial cells and can reduce apoptosisepithelial cells and can reduce apoptosis Insulin is a mitogen of tumor cells in vitroInsulin is a mitogen of tumor cells in vitro

Diabetes and Colon CancerDiabetes and Colon Cancer

MechanismMechanismAdiposity

Varying levels of Adipocytokines

Insulin Resistance

Insulin Increases

IGF-1 Increases

Activates IGFR

Activates IR

Cell Proliferation Increases

Apoptosis Decreases T

umor

Dev

elop

men

t

Growth HormonesGrowth Hormones

Insulin increases IGF-1Insulin increases IGF-1 IGF-1 activates the IGF receptorIGF-1 activates the IGF receptor Decreases apoptosisDecreases apoptosis Increases cell proliferationIncreases cell proliferation Physicians Health Study reported RR of Physicians Health Study reported RR of

2.51 for those in the high IGF-1 quintile2.51 for those in the high IGF-1 quintile

Current CRC ScreeningCurrent CRC Screening

Goal: Reduce mortality via a reduction in Goal: Reduce mortality via a reduction in incidence of advanced diseaseincidence of advanced disease

1-Stool-based tests (Occult Blood and DNA)1-Stool-based tests (Occult Blood and DNA)2-Structural exams (Colonscopy (CSPY), 2-Structural exams (Colonscopy (CSPY),

Flexible Sigmoidoscopy (FSIG), Double-Flexible Sigmoidoscopy (FSIG), Double-Contrast Barium Enema (DCBE), and Contrast Barium Enema (DCBE), and Computed Tomographic Colongraphy Computed Tomographic Colongraphy (CTC))(CTC))

Current Recommendations for Current Recommendations for Average-Risk Individuals aged >50Average-Risk Individuals aged >50

Detection of adenomatous polyps and Detection of adenomatous polyps and cancer:cancer:

Every 5 years (1 of the following): FSIG, Every 5 years (1 of the following): FSIG, DCBE, CTC DCBE, CTC

or Every 10 years: CSPYor Every 10 years: CSPY

Detection of cancer: Detection of cancer:

Annual Stool Blood Test Annual Stool Blood Test

sDNA Test (Interval unknown)sDNA Test (Interval unknown)

BiomarkersBiomarkers

APC (~70%)APC (~70%) p53 (~50%-70%)p53 (~50%-70%) K-ras (~50%)K-ras (~50%) IGF-1 and CEAIGF-1 and CEA MSIMSI

Stool DNAStool DNAStool DNA, tissueStool DNA, tissueStool and colonic DNAStool and colonic DNASerumSerumTissue, Stool and Tissue, Stool and

Plasma DNAPlasma DNA

Other various biomarkers in tissue: Src, SMAd4, SMAD2, DCC, hMSH2, hMLH1, hPMS1, hPHMS2, hMSH6, Ploidy

BiomarkersBiomarkers

Srivastava et al Biomarkers for Early Detection of Colon Cancer

Meta-Analysis of GWASMeta-Analysis of GWAS

TransferrinTransferrin

77KD, 77KD, ββ-globulin-globulin Main Function: Transport extracellular iron Main Function: Transport extracellular iron

into cells through membrane receptor-into cells through membrane receptor-mediated endocytosismediated endocytosis

More stable than hemoglobinMore stable than hemoglobin Required for cell growth and survivalRequired for cell growth and survival Increased Tf level in serum and body fluid Increased Tf level in serum and body fluid

in several cancer typesin several cancer types

Transferrin DipstickTransferrin Dipstick

DiseaseDisease NN IFOBTIFOBT TfTf Tf + Tf + IFOBTIFOBT

++ -- ++ -- ++ --

Colorectal CancerColorectal Cancer 4040 30 30

(75)(75)

1010

(25)(25)

3232

(80)(80)

88

(20)(20)

3636

(90)(90)

44

(10)(10)

PremalignantPremalignant 3636 1616

(44)(44)

2020

(56)(56)

2626

(72)(72)

1010

(28)(28)

2828

(78)(78)

88

(22)(22)

Low riskLow risk 3434 44

(12)(12)

3030

(88)(88)

88

(24)(24)

2626

(76)(76)

1010

(29)(29)

2424

(71)(71)

Rao et al Transferrin Dipstick as a Potential Novel Test for Colon Cancer Screening

SummarySummary

Much research has been conducted on Much research has been conducted on risk factors and biomarkers for CRCrisk factors and biomarkers for CRC

Room for improvement in early detectionRoom for improvement in early detection New types of biomarkersNew types of biomarkers New dipsticks/combinations with better New dipsticks/combinations with better

performance to potentially increase performance to potentially increase compliancecompliance

Thank YouThank You