Cancer occurrence

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NS 521 3/5/08 Lipids and cancer

• Cancer occurrence
• 2. Mechanisms
• Evidence

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US Mortality, 2003
of all deaths
No. of deaths

• 1. Heart Diseases 685,089 28.0
• 2. Cancer 556,902 22.7
• 3. Cerebrovascular diseases 157,689 6.4
• 4. Chronic lower respiratory diseases 126,382
  5.2
• 5. Accidents (Unintentional injuries) 109,277
  4.5
• 6. Diabetes mellitus 74,219 3.0
• 7. Influenza and pneumonia 65,163 2.7
• 8. Alzheimer disease 63,457 2.6
• Nephritis 42,453 1.7

Rank
Cause of Death
Source US Mortality Public Use Data Tape 2003,
National Center for Health Statistics, Centers
for Disease Control and Prevention, 2006.
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American Caner Society Global Cancer Facts and
Figures 2007
4
2006 Estimated US Cancer Cases
Men720,280
Women679,510

• 31 Breast
• 12 Lung bronchus
• 11 Colon rectum
• 6 Uterine corpus
• 4 Non-Hodgkin lymphoma
• 4 Melanoma of skin
• 3 Thyroid
• 3 Ovary
• 2 Urinary bladder
• 2 Pancreas
• 22 All Other Sites

Prostate 33 Lung bronchus 13 Colon
rectum 10 Urinary bladder 6 Melanoma of
skin 5 Non-Hodgkin 4
lymphoma Kidney 3 Oral cavity 3 Leukemia 3 Pa
ncreas 2 All Other Sites 18
Excludes basal and squamous cell skin cancers
and in situ carcinomas except urinary
bladder. Source American Cancer Society, 2006.
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2006 Estimated US Cancer Deaths
Men291,270
Women273,560

• 26 Lung bronchus
• 15 Breast
• 10 Colon rectum
• 6 Pancreas
• 6 Ovary
• 4 Leukemia
• 3 Non-Hodgkin lymphoma
• 3 Uterine corpus
• 2 Multiple myeloma
• 2 Brain/ONS
• 23 All other sites

Lung bronchus 31 Colon rectum 10 Prostate 9
Pancreas 6 Leukemia 4 Liver
intrahepatic 4bile duct Esophagus 4 Non-Hodgki
n 3 lymphoma
Urinary bladder 3 Kidney 3 All other sites
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ONSOther nervous system. Source American Cancer
Society, 2006.
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Possible Causes of Cancer
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Proportion of Cancer Causes
American Caner Society Global Cancer Facts and
Figures 2007
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A multi-step process
Initiation
Promotion
Progression
Kumar, Cotran, Robbins Basic Pathology, 6th ed.
1997
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Acquired capabilities of cancers
Hanahan Weinberg Cell 10057, 2000
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Cancer Pathogenesis
Kumar, Cotran, Robbins Basic Pathology, 6th ed.
1997
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Targets of genetic damage

• Growth promoting oncogenes
• Promote cellular proliferation
• Growth inhibiting tumor suppressor genes
• Inhibit cellular proliferation
• Genes that regulate apoptosis
• Genes that regulate DNA repair

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Oncogenes
Genes with ability to cause rapid induction of
tumors Encode oncoproteins resemble normal
proteins but lack regulatory elements Thus, can
alter cell proliferation through changes in
growth factors, growth factor receptors, signal
transduction molecules, nuclear transcription
factors e.g. ras 50 of colon cancers
associated with ras oncogene
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Tumor Suppressor Genes
Genes whose normal function is to monitor and
inhibit cell proliferation when appropriate.
Cancer develops when cells become homozygous for
mutant gene. eg. p53 homozygous loss of p53
found in every human cancer. Normally inhibits
cell cycle allows time for DNA repair if not
repairable, induces apoptosis. Loss of p53
results in unrepaired DNA damage, fixed mutations.
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Kumar, Cotran, Robbins Basic Pathology, 6th ed.
1997
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Apoptotic Genes
Genes whose normal function is to regulate
apoptosis. eg. bax and bcl-2 bcl-2 protects
cells from apoptosis, bax opposes bcl-2 action
and accelerates cell death. Relative levels of
bax and bcl-2 seem to regulate cell death and
survival.
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Apoptosis related genes
Kumar, Cotran, Robbins Basic Pathology, 6th ed.
1997
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DNA repair Genes
DNA repair genes code for proteins whose normal
function is to correct errors that arise when
cells duplicate their DNA prior to cell
division Mutations in DNA repair genes can lead
to a failure in repair, which in turn allows
subsequent mutations to accumulate Genes whose
normal function is to regulate apoptosis.
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DNA Repair Genes
Normal DNA repair
T
C
A
G
C
Base pair mismatch
No cancer
T
C
A
T
C
A
G
T
C
G
T
C
A
T
C
T
C
A
T
C
A
G
T
C
G
Cancer
A
G
T
G
A
G
T
A
G
No DNA repair
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Cancer Pathogenesis
Kumar, Cotran, Robbins Basic Pathology, 6th ed.
1997
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How might dietary fat influence carcinogenesis?
Antioxidants Apoptosis
DNA Damage
Tumor Progression
Kolonel LN. JNCI 91414, 1999
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How might dietary fat influence carcinogenesis?
Antioxidants Apoptosis
DNA Damage
Tumor Progression
Lipid oxidation Free radicals Inflammation
Proliferation Differentiation
Kolonel LN. JNCI 91414, 1999
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How might dietary fat influence carcinogenesis?
Antioxidants Apoptosis
DNA Damage
Tumor Progression
Lipid oxidation Free radicals Inflammation
Proliferation Differentiation
Gap junctions Hormone levels Receptor
function Signal transduction Eicosanoid synthesis
Kolonel LN. JNCI 91414, 1999
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How might dietary fat influence carcinogenesis?
Antioxidants Apoptosis
DNA Damage
Tumor Progression
Lipid oxidation Free radicals Inflammation
Proliferation Differentiation
Gap junctions Hormone levels Receptor
function Signal transduction Eicosanoid synthesis
Immune function Angiogenesis
Kolonel LN. JNCI 91414, 1999
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Possible Effects of Fat Intake

• Low fat diet may be beneficial with respect to
  several putative mechanisms of carcinogenesis,
  but it could also be detrimental
• Combination of prevention of lipid oxidation by
  vit E repair of oxidized phopholipids by
  selenium-containing peroxidases

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Animal Tissue Culture Evidence

• N-6 FAs promote tumor growth metastasis
• N-3 FAs inhibit tumor growth metastasis
• Inhibition of tumor growth in animals fed very
  low fat diets is believed to result from a lack
  of EFA, leading to a general growth inhibition

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A meta-analysis of effect of fat on the mammary
tumors in rodents

• Meta-analysis from 97 reports of animal
  experiments
• 12,803 mice or rats
• the effect on mammary tumor incidence of
  different types of dietary fatty acids ( of
  total calories from each fatty acid)
• Findings
• n-6 PUFAs have a strong tumor-enhancing effect
• saturated fats have a weaker tumor-enhancing
  effect
• n-3 PUFAs have a small protective effect
  (non-significant)
• no significant effect of monounsaturated fats.
• Fay et al. Cancer Res 1997 Sep
  1557(18)3979-88

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Evidence for role of dietary fat in human cancer
development

• Cancers of breast, colorectum and prostate
• 1. Ecological studies
• Case control studies
• Cohort studies
• Studies with biomarkers of dietary fat intake

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Breast Cancer
American Caner Society Global Cancer Facts and
Figures 2007
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Carroll KK. Cancer Res. 353374, 1975
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Trends in Fat IntakeTable. Mean of calories
from total fat and saturated fat among adults
aged 20-74 years, by sex and age group NHANES,
1971-2000.
MMWR Feb 6, 2004/53(04)80-82
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Nurses Health Study - Cohort Study
Holmes, et.al. JAMA. 281914, 1999
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Holmes, et.al. JAMA. 281914, 1999
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Summary of Nurses Health Study

• We found no evidence that lower intake of total
  fat or specific major types of fat was associated
  with a decreased risk of breast cancer.

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1.12
Boyd, Br J Cancer 2003891672-1685
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Womens Health Initiative study

• Table 5. Risk of Invasive Breast Cancer and Other
  Major Clinical Outcomes
• No. of Cases
  HR (95 CI) P Value
• Intervention
  Comparison
• Breast cancer
• Incidence 655
  1072 0.91 (0.83-1.01) .07
• Mortality 27
  53 0.77 (0.48-1.22) .26
• Total cancer
• Incidence 1946 3040
  0.96 (0.91-1.02) .15
• Mortality 436
  690 0.95 (0.84-1.07) .41
• Total mortality 950 1454
  0.98 (0.91-1.07) .70
• Global index 2051 3207
  0.96 (0.91-1.02) .16
• Defined for a participant as the time to the
  earliest invasive breast cancer, colorectal
  cancer, coronary heart disease, or mortality from
  any other cause.

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Cumulative Hazard (risk) for Invasive Breast
Cancer in WHI study
Prentice et al, JAMA 2006295629-642
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Meta-analysis of Biomarkers of Fatty Acids
Saadatian-Elahi Intl J Cancer 2004
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Discussion points

• Why results are inconsistent?
• Do we need more research?
• What future studies do you propose?

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Colon cancer

• Nurses Health Study
• Health Professional Study
• Meta-analysis

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Nurses Health Study
Willett WC NEJM. 3231664, 1990
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Summary of Nurses Health Study on Colon Cancer

• Positive association with total fat intake RR
  (highest vs. lowest quintile) 2.00 (95 CI
  1.10 3.63)
• Positive association with animal fat intake RR
  (highest vs. lowest) 1.89 (95 CI 1.13 -
  3.15), but didnt hold after adjusting for red
  meat
• Positive association with red meat intake RR
  (highest vs. lowest) 1.77 (1.09 2.88)

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Health Professionals Study (male)
Giovannucci E. Cancer Res 1994542390-97
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Summary of Health Professionals Study on Colon
Caner

• No significant findings relating total,
  saturated, or animal fat to colon CA risk
• Positive association with red meat intake RR
  (highest vs. lowest quintile)
• 1.71 (95 CI 1.15- 2.55)

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Red Meat Consumption
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Summary of dietary fat and colon cancer

• Most data consistent with positive association
  between red meat and colon CA risk
• The increased risk of colon cancer due to fat
  disappears in many studies when adjustments are
  made for energy and/or red meat intake
• Other important dietary factors (e.g., fiber)

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Prostate Cancer

• Ecological study
• Case-control study
• Cohort study

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Saturated fat and prostate cancer

• Ecological studies
• 8 of 9 found ? assoc. w/ animal and SFA
• Case-control studies
• 8/23 ? assoc. w/ total, animal, or SFA
• 6/23 NO assoc. w/ total, animal, or SFA
• 8/23 ? assoc. w/ meat, dairy, or egg
• 1/23 NO assoc. w/ meat dairy, or egg

Kolonel LN. JNCI 199991414-28
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Unsaturated fat and prostate cancer

• Case-control studies
• MUFA
• 1/5 pos. assoc. (not adjusted for energy)
• 4/5 no association
• PUFA
• 1/5 pos. assoc. (not adjusted for energy, PUFA as
  group)
• 4/5 no association

Kolonel LN. JNCI 199991414-28
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Cohort studies, prostate cancer
Kolonel LN. JNCI 91414, 1999
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Unsaturated fat and prostate cancer
Kolonel LN. JNCI 91414, 1999
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Summary of dietary fat and prostate cancer

• Considering the epidemiologic evidence as a
  whole, an association between dietary fat and
  human prostate cancer must, at present, be viewed
  as tentative.
• Consistent findings of association between
  increased risk and intake of animal foods,
  particularly meat.

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WCRF/AICR report 2007

• Limited evidence suggesting an association
• Total fat lung and postmenopausal breast
• Foods containing animal fats colorectum
• Butter Lung (c.f., principal cause for lung
  cancer is tobacco smoking)

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Will eating less fat lower cancer risk?

• Diets high in fat are also high in calories and
  contribute to obesity, which in turn is
  associated with an increased risk of cancer at
  several sites.
• Although all types of fats have similar numbers
  of calories, there are certain types, such as
  saturated fats, that may have a greater effect on
  increasing cancer risk.
• Fats containing omega-3 fatty acids (e.g., fish
  oils) may reduce cancer risk.

http//www.cancer.org/docroot/PED/content/PED_3_2X
_Common_Questions_About_Diet_and_Cancer.asp
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Body Weight and Cancer Risk
Bray, et al. J Nutr 20021323451S-5S
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WCRF/ACIR recommendation

• Limit intake of red meat and avoid processed meat
• Eat mostly foods of plant origin
• Limit consumption of energy-dense foods
• Be as lean as possible within the normal range of
  body weight

http//www.aicr.org/site/PageServer?pagenameres_r
eport_second
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Eat Fruits and Vegetables
NCI www.cancer.gov