Sollars Flashcards by Brent Smith II

Core UNIVERSAL properties of cancer (4)

Uncontrolled proliferation, Immortalization, Protection from anti-proliferative signals, Protection from apoptosis

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Uncontrolled proliferation

autocrine growth and stimulation present

- no contact inhibition (anchorage dependence)

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Immortalization

Normal cells, except stem cells, have a finite number of cell divisions they are cable of

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Protection from anti-proliferative signals

differentiation is prevented

- cancer cells do not exhibit density-dependent inhibition

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Protection from apoptosis

-normal cells respond to programed cell death signals when necessary, cancer cells do not

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Core Properties of Solid Tumors (2)

Angiogenesis

- Invasion and metastasis

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normalization hypothesis

hit w/ high dose of chemo during cancers normalization phase (stage after receiving a low dose of chemo)

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Emerging Properties of Cancer (2)

deregulation of cellular energetics

- evasion mechanisms for the immune system

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Enabling Properties of Cancer (2)

genome instability and mutation

- tumor-promoting inflammation

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dedifferentiation

cancer cells in a given tissue revert to characteristics and morphology of precursor cells

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Guardians of genome/ Gatekeepers

Tumor suppressors and DNA repair mechanisms

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first mutation cancer usually aquires

uncontrolled cellular proliferation

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Is cancer monoclonal or polyclonal?

Monoclonal (same X chormosome inactivated/ G6PD test/ Kappa:lamda light chain ratio test)

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multi-hit hypothesis

accounts for increasing incidence of cancer with increasing age.

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Oncogenes require how many hits to fuck shit up?

Only one hit

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Tumor suppressors require how many hits to fuck shit up?

TWO hits. Both copies of the tumor must be non-functional in order to contribute to cancer progression.

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Oncogenes have stimulatory effect on cells usually through gain of function mutations with result of: Name a few

conferring sustained cellular proliferation
advancement of cell cycle progression
decreased requirement for growth factors
promotion of metastasis
protection from apoptosis

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Proto-oncogenes

normal (functional alleles)

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Genes whose products normally negatively regulate cell proliferation, promote apoptosis, or maintain homeostatic growth and differentiation potential.

Tumor suppressor genes

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Proto-oncogene conversion: deletion or point mutation in DNA results in what? Example?

Hyperactivity

- Example: Ras

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Proto-oncogene conversion: gene amplification in DNA results in what? Examples?

over-expression

- Examples: Myc and ErbB

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Proto-oncogene conversion: chromosomal rearrangement in DNA (due to genomic instability) associated with a novel promotor results in what? Examples?

Over-expression

Examples: Bcl2 and Myc

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Proto-oncogene conversion: chromosomal rearrangement in DNA (due to genomic instability) associated with a new coding region results in what? Examples?

Novel product

Examples: BRC/ABL, PBX, PBL/RAR-alpha

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Loss of heterozygosity

Tissue surrounding the tumor is heterozygous for Tumor Suppressors while the actual tumor tissue is homozygous

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Tumor Suppressor: RB1

cell cycle control

Tumor Suppressor: TP53

p53, cell cycle

Tumor Suppressor: BRCA1

double stranded break repair

Tumor Suppressor: NF1

GTPase activator

RB1 familial tumor suppressor disorder

Retinoblastoma

TP53 familial tumor suppressor disorder

Li-Fraumeni Syndrome

BRCA1 familial tumor suppressor disorder

Familial breast cancer

NF1 familial tumor suppressor disorder

Neurofibromatosis

Sporadic / somatic disorders

patients must acquire both hits during a life time. Do not inherit a nonfunctional Tumor Suppressor gene like seen in familial.

RBI sporadic (somatic) tumor suppressor disorder

small cell lung carcinoma

TP53 sporadic (somatic) tumor suppressor disorder

Lung and breast cancer

BRCA1 sporadic (somatic) tumor suppressor disorder

Breast and OVARIAN cancer

How to pick up babes at the gym: "Excuse me shawtayy, are you in to fitness?"

Because soon I'll be fitness dick in yo mouth

Most common ocular malignancy (usually a pediatric disorder)

Retinoblastoma

Treatment of early stage Retinoblastoma

Radioiodine or cryotherapy to remove tumor

Treatment of late stage Retinoblastoma

remove that SOB / take out the eye

Inheritance pattern for Retinoblastoma?

Autosomal DOMINANT with incomplete penetrance (80%)

Sporadic retinoblastoma tumors are usually ...

unilateral

Familial retinoblastoma tumors are usually ...

bilateral

Early onset, 40% of all cases, often bilateral, and MULTIPLE tumors

Familial retinoblastoma

60% of all cases, not transmitted to progeny, single tumor, unilateral, and later onset

Sporadic retinoblastoma

Mendelian transmission through germline

Familial retinoblastoma

Loss of Heterozygosity (LOH)

Refers to loss of information of one allele, discovered by RFLP analysis of Rb gene; RFLP was heterozygous in all tissues except tumor

Knudson's Hypothesis

Familial retinoblastoma: only one hit needed so tumors occur more frequently Sporadic retinoblastoma: two mutations/ hits (in each allele) and in same same cell are needed to knock out Rb. Because this rarely happens, tumors are rarer and more often unilateral

germline mutation + somatic mutation in Rbs =

Familial retinoblastoma

somatic mutation + somatic mutation in Rbs=

Sporadic Retinoblastoma

How is second allele inactivated in Rb (4 ways)

local events, somatic recombination, loss of chromosome (can be with or without duplication of other nonfunctional chromosome) ex: nondisjunction

The environment influences cancer risk through exposure to ______ in environment.

carcinogens

The _______ ________ of a person can affect cancer risk by influencing ones ability to deal with carcinogen or production of carcinogens upon exposure to a precursor.

genetic make-up

What kind of mutation in in CYP1A1 increases lung cancer risk for patient who uses tobacco?

Missense mutation

Carcinogen

a physical or chemical agent that induces cancer. Most carcinogens are mutagens

Mutagen

a physical or chemical agent that raises the frequency of mutation above the spontaneous rate

Aryl hydrocarbon hydroxylase

a P450 gene whose activity is associated with lung cancer risk upon exposure to cigarette smoke

Cytochrome P450 genes (CYP) are responsible for

detoxification of foreign chemicals. A number of CYP genes are polymorphic and underlie variation in drug metabolism

CYP1A1

a phase I, predominantly extrahepatic, microsomal enzyme involved in the bioactivation of carcinogenic polycyclic aromatic hydrocarbons including benzo(a)pyrene.

Cytosolic glutathione-S-transferases are a large family of isozymes involved in detoxification of many electrophilic substrates by their conjugation with reduced glutathione. GSTM1 and GSTT1

``` GSTM1= has been shown to play a role in the metabolism of organic epoxides and peroxides and in particular to conjugate known carcinogens as epoxides of polycyclic aromatic hydrocarbons, suggesting that people lacking the functional gene are at greater risk of developing cancers associated with exposure to polycyclic aromatic hydrocarbons. GSTT1= smokers lacking GSTT1 cannot conjugate monohalomethanes found in tobacco smoke. ```

“extra risk score” (ERS)

product of the lifetime risk and the total number of stem cell divisions

If the ERS for a tissue type is high—that is, if there is a high cancer risk of that tissue type relative to its number of stem cell divisions—then one would expect that ...

environmental or inherited factors would play a relatively more important role in that cancer’s risk.

______ _______ in the adenomatous polyposis coli gene (APC) cause the most common form of hereditary polyposis syndromes termed familial adenomatous polyposis

Germline mutations

FAP (familial adenomatous polyposis) inheritance pattern?

- AD | - 80-100% penetrance

Fulminant FAP

- 100s-1000s of polyps | - early onset and increased risk (100%)

Juvenile Polyposis is also a autosomal dominant disorder caused by mutations in what genes?

SMAD4/DPC4 gene or BMPR1A/Alk3 gene.

True or False: Juvenile Polyposis is usually asymptomatic until puberty

True

Juvenile Polyposis has less numerous polyps than FAP and has what phenotype of the polyps in comparison to FAP polyps?

large and lobulated

Hereditary Breast and Ovarian Cancer Syndrome genes

BRCA1 and BRCA2 (Tumor suppressor in DNA repair)

Cowden Syndrome gene

PTEN (tumor suppressor in cell cycle regulation)

FAP gene

APC (tumor suppressor in WNT pathway)

HNCC (hereditary nonpolyposis colorectal cancer) genes

MLH1, MSH2, MSH6, or PMS2 (tumor suppressors in DNA mismatch repair)

Li-Faumeni Syndrome gene

TP53 (tumor suppressor in cell cycle regulation)

Von-Hippel-Lindau Disease gene

VHL (tumor suppressor in ubiquination)

Multiple Endocrine Neoplasias genes

MEN1 and RET (tumor suppressor in signal transduction)

______ tumors tend to be more aggressive than sporadic and BRCA2 tumors.

BRCA1

True or False: Tumor biology of some sporadic tumors and tumors with an inherited predisposition are different, which may influence their prognosis.

True Note that determination of BRCA1 vs. BRCA2 familial tumors gives some important information regarding prognosis.

Sporadic Breast Cancer

One boob gets cancer

Familial BRCA1/2 Breast Cancer

Higher chance that both tits get cancer. Remember Rb familial vs. sporadic.

I1307K APC mutation is seen in what population?

Ashkenazi Jews

As compared with noncarriers, carriers of I1307K APC polymorphism/mutation have approximately twice the risk of colorectal cancer. The T-to-A change results in a stretch of eight adenosines (AAAAAAAA) that is believed to increase the risk of somatic mutations as a result of slippage during replication.

For instance, an addition of one A (+A) has been seen in the affected allele of many carriers. The addition or loss of a nucleotide causes a FRAME SHIFT and loss of function of APC, constituting an important somatic event in tumor initiation.

Example of a mutation that does not impune the function of the protein produced by the gene or the gene itself, but instead the stability of the gene.

I1307K APC mutation/polymorphism (neutral variant)

In the I1307K APC polymorphism doubles the rate of colon cancer in those expressing it (in contrast to other APC mutations which are 100% penetrance). In this odd polymorphism: A single nucleotide base pair-substitution replaces Ile (isoleucine) with ....

Lys (lysine)

True or False: People respond to medications differently based upon environment and genetics

True

Monogenic disorders

- variation in a single gene - disease phenotype driven by a single genetic mutation - most people who possess the mutant gene will exhibit the disease

Complex disorders

- arise form interactions of several different genes - each mutant contributes to the risk of acquiring the disease phenotype (some maybe more than others) - % of risk due to any gene varies