CANCER Flashcards
What is Cancer?
Diseases characterized by:
- uncontolled cell growth caused by genetic mutations and epigenetic alterations in gene transcription
- spread of abnormal cell throughout the body (metastasis)
Carcinogenesis
Initiation
normal cell (melanocyte)
**Cell DNA altered **
- chemicals, radiation, and viruses can alter cell DNA (in this case, radiation from the sun is the likely cause)
- altered cell-this can grow into a cancer
Promotion
inc. cell division-this is needed to promote the cancer process
**cancer cells **
Further Progression
- cancerous tumor (malignant melanoma)
“Cancer” can refer to either a benign or a maglignant tumor.
A) True
B) False
B) False
Maglignant cells
- invade neighboring tissues, enter blood vessels, and metastasize to different sites
- spread throughout the body
Begnign tumor
not cancer
- cells grow only locally and canot spread by invasion or metatasis
- resticited grwoth doens’t spread
The breat cancer risk genes BRCA1 and BRCA2 are:
A) oncogenes/proto-oncogenes
B) Tumor supressor genes
C) Genes invovled in estrogen metabolism
B) Tumor suppressor genes
Tumor Supressoe Genes
DNA methylation patterns cause loss-of-function effects that contribute to the maligant phenotype
- gene silenced
Oncogenes
DNA methylation patterns alternations cause gain-of-function
- gene active
What are molecular changes in cancer?
- inhibition of tumor suppressor genes
- activation of oncogenes
- changes in signal transduction pathways
- chromosomal rearrangements
- genome instability
Three-stage Carcinogenesis
Initiation: ranges from minutes to days (short)
- Cancer causing agent
- No DNA repair, impaired regulation of apoptosis
Promotion: may last months or even years
- Altered DNA leads to changes in gene expression, protein
function, etc.
- Cell proliferates in uncontrolled way
- Alcohol, estrogen in breast tissue, Helicobacter pylori in the stomach,
HPV in cervix may act as promoters
Progression
- Malignant cells invade surrounding tissue and metastasize to other sites
How does genetic alteration causes these changes in cancer?
Point mutations
Polymorphisms
Copy number variants
- Genetic predisposition may only account for ~5-10% of risk for cancer
E.g., BRCA1 and BRCA2 are hereditary breast and ovarian cancer
- 55-65% of women with a harmful BRCA1 mutation and 45% of women with a harmful BRCA2 mutation will develop breast cancer by age 70 years (12% risk in general population)
- 39% of women with a harmful BRCA1 mutation and 11-17% of women with a harmful BRCA2 mutation will develop ovarian cancer by age 70 years (1.4% risk in general population)
- mutation in these genes inc. the risk of breast cancer, but doesn’t nessarily mean everyone w/ mutation get cancer
BRCA1 and BRCA2 Mutations
- missing protein
- non-functional protein
Defective: - DNA repair
- Trancription
- G2/M cell cycle checkpoint regulation
- spindle checkpoint
How do we know factors other than genetics contribute to cancer risk?
Environmental factors
Colon cancer higher in U.S compared in Japan, but similars cases in Japanese families in U.S
Stomach cancer higher in japan compared to U.S and Japanese families in U.S
How does epigenetic alternations causes these changes in cancer?
DNA methylation
Histone covalent modifications
microRNAs
- which genes are expressed and non-expressed
- epigenome responds to the environment - abrasions can cause functional changes
What is epigenetics?
The study of heritable changes in the phenotype or gene
expression caused by mechanisms other than changes in DNA
sequences
E.g., Genetics vs Epigenetic
- writing and reading
- musical notes and melody
- computer and software
Examples: A twin approach to unravelling epigentics
Identical twins who were given up for adoption to different
families at birth and only discovered this in their mid-30s.
- Identical twins start with the same genetic make-up but over time in phenotype they drift apart
- Epigenetic variation as a dynamic quantitative trait
- High monozygotic twin discordance rates for common diseases
Epigenetics alterations and disease state
Autoimmune and inflammatory diseases
Rheumatoid arthritis
Inflammatory bowel disease
Multiple sclerosis
Diabetes
Lupus
Aging
Parkinson’s disease
Alzheimer’s disease
Cardiovascular disease
Behavioral and psychiatric disorders
(Schizophrenia, Autism, Anxiety, ADHD)
Chronic pain
Components of epigenome
DNA methylation
Non-coding RNA (microRNA)
Histone modifications
DNA methylation and gene activity
addition of methyl group to DNA by DNA methyltransferase to stabilize the chromatin and dynamic
**Unmethylated CpG island **
- gene expressed
**Methylated CpG island **
- trancription factors can not bind and completed silenced
Hypermethylation
silencing
Hypomethylation
activation
Nutrition and the epigenome
diet provides folic acid, betaine, choline, B vitamins, and methionone to synthesize in the SAM in the body
- regulate methylation; methyl groups
Bioactive componds in fruits, vegetables, and spices
Genistein
- soy, tofu
Pterostilbene
- blueberry
Resveratrol
- grapes
Sulforaphane
- broccoli
Functional benefits of nutritional epigenetic effects
- Decrease in cell proliferation
- Decrease in cell migratory and invasive properties
- Inhibition of oncogenic signaling pathways
Functional Benefits: nutrients and bioactive compounds
- Anti-oxidant role to prevent oxidative DNA damage
- Activation of pathways for detoxifying potential carcinogens - target multiple molecules and metabolic pathways
- Decrease in inflammatory response
Nutrients and Bioactive food components modulate cellular processes linked to cancer
Food nutrients, and bioactive food components
- DNA repair
- Proliferation
- Hormonal regulation
- Differentiation
- Apoptosis
- Cell cycle
- inflammation and immunity
- carcinogen metabolism
Carcinogens in Food
substance capable of causing cancer
- E.g., Nitrosamines, heterocyclic amines & polycyclic aromatic hydrocarbons
What are aspects of diet that may be related to cancer?
Energy balance, growth rates & body size
- directly related to individual nutritional
Fat intake
Processed or red meat
Dairy
Fiber
Alcohol
Fruits and Vegetables
Vitamins and Minerals
Based on current evidence, it is very likely that a diet low in fruits and vegetables may increase risk for lung cancer.
A) True
B) False
B) False
- confounding factors smoking
- fruits and vegs are bioactive
Body fatness is associated with increased risk of breast cancer in postmenopausal women, but may be associated with decreased risk of breast cancer in premenopausal women.
In this case, menopausal status is a(n):
A) Secondary outcome
B) Dependent variable
C) Confounder
D) Effect modifier
E) Intervening variable
D) Effect modifier
Secondary Outcome
used to evaluate additional effects of the intervention, additional events of interest, but which the study is not specifically powered to assess (e.g., primary outcome – liver cancer, secondary outcome – HBV-related liver cancer)
Dependent variable
the values of dependent variables (outcome variable) depend on the values of independent variable (exposure variable).
E.g., Independent variable is the dose of a drug; dependent variable is the
frequency/intensity of symptoms upon different doses.
Confounder
influences both the dependent variable (outcome) and independent variable (exposure) causing an association-like appearance.
Effect modifier
it modifies the relationship between exposure and outcome
Intervening variable
a hypothetical variable used to explain causal links between exposure and outcome.
E.g., being poor and having a shorter life span: lack of access to healthcare or poor nutrition could be the intervening variables.
Body fatness is associated with increased risk of breast cancer in postmenopausal women, but may be associated with decreased risk of breast cancer in premenopausal women.
In this case, breast cancer is a(n):
A) Secondary outcome
B) Dependent variable
C) Confounder
D) Independent variable
E) Intervening variable
B) Dependent variable
Would you expect to find a relationship between energy intake and cancer? In other words, do you think higher energy intakes would be associated with higher incidence of cancer?
A) Yes
B) No
C) I don’t know
B) No
Energy intake varies with energy expenditure: Individuals with higher energy intake may also be more physically active
There is convincing evidence that someone who was classified as obese by BMI would be at increased risk for certain types of cancers.
A) Yes
B) No
B) No
Dependent on the body composition
Red & Processed Meat WHO/IARC Classification of Carcinogens
WHO/IARC Classification of Carcinogens:
- Processed meat Group 1 (Carcinogenic)
- Red meat Group 2A (Probably carcinogenic)
What are the probable evidence about dairy and fish?
Dec. risk of cancer
- may be due to calcium, possibly vitamin D or other components of milk (e.g., polysaturated fatty acids)
Which of the following could be a CONFOUNDER in the relationship between milk (dairy) and cancer?
A) Vitamin D
B) Genetics
C) Better nutrition knowledge
D) Type of cancer
Answer: C) Better nutrition knowlegde
A) Vitamin D - Mediating variable
B) Genetics - Effect modifiers
D) Type of Cancer - Outcome variable
Milk -> Colon Cancer -> Lower Vitamin D
Dietary Fiber
Probale evidence that foods containing dietary fiber dec. risk of colorectal cancer
Possible mechanisms:
- provides bulk to speed transit time
- may bind carcinogens in gut
- alters colonic flora
- substrate for generation of short chain fatty acids, which may be protective
Alcohol
Convincing and Probable evidence to inc. risk of cancers
Mechanism:
- Toxic effects of alcohol?
- Anti-folate effects of alcohol?
disrupts folate absorption and SAM synthesis
Vegs and Fruits
Probable evidence that non-starchy vegetables and fruits decrease risk of aerodigestive cancers
- Although the evidence for the link with individual cancers is limited, the pattern of association is consistent and in the same direction
- Overall, the evidence is more persuasive of protective effects
Protective interest of vegs and fruits
- Dark green and orange vegetables
- Cruciferous vegetables (sulforaphane)
- Soy products (genistein)
- Allium vegetables (organosulfides)
- Red vegetables and fruits (lycopene, anthocyanins)
Beta-carotene and lung cancer
Convincing evidence that high dose beta-carotene supplements
increases risk of lung cancer in people who smoke and used to
smoke tobacco
- pre-disposed to cancer
- oxidative stress -> apoptosis; too much cancer cells can proliferate
Vitamins & Minerals
Limited evidence that:
- Foods containing beta-carotene and retinol decrease risk of lung cancer
- Multivitamin supplements decrease risk of colorectal cancer
- Vitamin D decreases risk of colorectal cancer
- Selenium or vitamin E may decrease risk of prostate cancer
- Foods containing vitamin C decrease risk of colorectal and lung (people who smoke) cancers
- Diets high in calcium increase risk of prostate cancer
Probable evidence that calcium supplements decrease
risk of colorectal cancer
Dietary fat
Evidence is limited and not conclusive
- Difficult to separate effects of fat intake from intake of total energy
- Possible confounding effects (eg. animal protein intake or other lifestyle factors)
- Types of fat may be important (limited suggestive evidence for saturated fat and pancreatic cancer)
Sugars and sugary beverages
Limited-suggestive evidence that foods and drinks containing fructose increase risk of pancreatic cancer
Limited evidence that foods and drinks containing fructose increase risk of colorectal, oesophageal, lung, gallbladder, breast, prostate, kidney and bladder cancer
Which of the following statements best represents the certainty & benefit:risk ratio for fruit and vegetables and cancer prevention?
A. High certainty, low
benefit:risk
B. Low certainty, low
benefit:risk
C. Low certainty, high
benefit:risk
C. Low certainty, high benefit: risk
Recommendation for cancer prevention
Be a healthy weight
Be physically active
Eat a diet rich in wholegrains, vegs, fruits and beans
Limit consumption of ‘fast foods’ and other processed foods high in fat, startches or sugars
Limit consumption of red and processed meat
Limit consumption of sugar sweetened drinks
