Cancer I Flashcards

1
Q

Silent vs. Normal Gene

A
  • Silent gene – genes are present in the nucleus but they are not active (no mRNA produced)
  • Normal gene – genes are actively transcribed into mRNA  template for protein synthesis
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2
Q

Gene Overexpression vs. Amplification

A
  • Gene Overexpression – “overactive”; produce high levels of mRNA results in high level of proteins
  • Gene Amplification – multiple copies of the gene are present in the nucleus; each of them is active and produces mRNA  resulting in high levels of protein
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3
Q

Naming and Types Cancers

A

• Prefix – refer to location of cancer
• Suffix refers to benign (-oma) or malignant (-carcinoma, -sarcoma)
• Cancer – malignant neoplasia
o Carcinomas – cancer of epithelial origin; most common form of cancer
o Leukemias – cancer of bloodstream
o Lymphomas – cancer of lymph nodes
o Sarcomas – cancer of mesenchymal origin

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4
Q

Stages of Abnormal Growth (Hyperplasia, dysplasia, anaplasia, neoplasia)

A
o	Hyperplasia – increase in number of normal cells
o	Dysplasia – some cellular and nuclear changes leading to loss of cell uniformity and abnormal tissue architecture
o	Anaplasia – undifferentiated cells, variable in size and shape; numerous and atypical mitoses, lack of organized tissue architecture; will become invasive/cancerous
	Ex: rhabdomyosarcoma of skeletal muscle
o	Neoplasia (tumor) – abnormal tissue growth; result of loss of responsiveness to growth control signals; does not necessarily mean MALIGNANT/CANCER (ex: fibroids)
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5
Q

Benign Tumor

A

• Benign Tumor – well-differentiated cells with preserved specialized features of the parent cells
o Usually well demarcated, often encapsulated masses, no invasion of the surrounding tissue
o No distant metastases
o Ex: uterine fibroids (leiomyoma) – develop from smooth muscle

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6
Q

Malignant Tumor

A

• Malignant Tumor – lack of differentiation, anaplasia
o Locally invasive, infiltrating surrounding tissues
o Frequently present distant metastases

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7
Q

Normal Growth Regulation and Areas Proliferative Growth

A

• Normal Growth Regulation – most of the cells are quiescent; cell proliferation is limited to certain types of cells and processes, such as:
o Bone marrow myeloblasts; immune cells; epidermal cells; epithelial cells; regenerating tissues
o Cell proliferation tightly regulated process involving factors stimulating/inhibiting cell divisions
o Cell damage or perturbation in cell cycle leads to cell death (apoptosis)

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8
Q

Features of Malignant Cancer Cells

A
o	Self-sufficiency in growth signals
o	Insensitivity to growth-inhibitory signals
o	Evasion of apoptosis
o	Limitless replicative potential
o	Sustained angiogenesis
o	Ability to invade and metastasize
o	Evasion of host immune response
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9
Q

Normal Growth Mechanism

A

growth factors  cell surface receptors  signal transducing proteins that send signal from cell surface to nucleus via phosphorylation cascade  transcription factors inside nucleus  gene expression of previously unexpressed proteins  gene products required for cell division, cell cycle progression, & proliferation

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10
Q

Proto-oncogenes vs. Oncogenes

A

• Proto-oncogenes – encode proteins, which normally stimulate cell proliferation
o Mutations of proto-oncogenes usually arise somatically in the tumor cells and are DOMINANT
o Encode growth factor, growth factor receptor, signal transduction molecules, transcription factor
• Oncogenes (in cancers) – gain-of-function alterations/mutations of proto-oncogenes resulting from point mutations, chromosomal rearrangements/translocations, gene amplification, and over-expression due to changes in regulatory elements

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11
Q

Proto-oncogenes - Growth Factors

A

– overexpression of autocrine growth factors leading to overstimulation of proliferation
o Gain independence from host cells & stimulate the growth of nearby cells via paracrine signaling
o Platelet-derived growth factor (PDGF) – in glioblastomas
o Transforming growth factor alpha (TGFalpha) – in sarcomas

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12
Q

Proto-oncogenes - Growth Factor Receptors

A
  • extracellular part = control; intracellular part = activation
    o Mutated or truncated forms of the receptors - intracellular domain constitutively active
     Epidermal growth factor (EGF) receptor ERBB1 is truncated in glioblastoma
    o Overexpression of growth factor receptors
     ERBB1 in squamous cell carcinomas of the lung; ERBB2 (HER2) in breast cancer
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13
Q

Proto-oncogenes - Signal-Transducing Proteins - RAS

A

– encodes p21 G-protein
 Point mutations changing amino acids in the pocket binding GTP and region essential for GTP hydrolysis lead to constitutive activation of RAF-MAPK mitogenic cascade
 Mutant RAS proteins cannot release or hydrolyze GTP, causing constitutive activation of RAF-MAPK cascade
 RAS mutations are most common abnormalities in human cancer
• Particularly high incidence in colon and pancreatic cancers

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14
Q

Proto-oncogenes - Signal-Transducing Proteins - ABL

A

– non-receptor tyrosine kinase that normally promotes apoptosis
 Chronic myeloid leukemia – ABL gene is translocated from chromosome 9  chromosome 22 where it fuses with part of breakpoint cluster region (BCR) gene; aberrant chromosome 22 is designated the Philadelphia chromosome
 Normal ABL is localized to the nucleus; abnormal BCR-ABL is in cytoplasm
 Stimulates kinase activity that phosphorylates proteins involved in proliferation pathways

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15
Q

Proto-oncogenes - Nuclear Transcription Facters

A

o Stimulate expression of several growth-related genes, such as cyclin-dependent kinases (CDKs)
o MYC – most commonly involved in human cancer
 C-MYC = normal version of gene
 Burkitt lymphoma – overexpressed due to translocation from chromosome 8  chromosome 14, in close proximity to an Ig gene
 Breast, lung and other cancers – overexpressed due to gene amplification
• Common in neuroblastoma (N-MYC) and small cell cancer of lung (L-MYC)
• Neuroblastoma has 2 forms; mainly affects children and infants
o Aggressive phenotype that requires immediate treatment/chemotherapy
 MYC amplification is diagnostic marker
o Less aggressive phenotype that spontaneously regresses at one year of age and does NOT require treatment

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16
Q

Cell Cycle Regulation

A

o Upon proliferation stimulation, a cell enters the cell cycle
o Cyclins and cylin-dependent kinases (CDKs) are important to the cycle
o Transition from G1 to S phase is particularly important checkpoint
o Most common cancerous mutations affect proteins involved in G1-S transition
 Overexpression of cylcin D (breast, esophagus, liver cancers, lymphomas)
 Amplification of CDK4 (melanomas, sarcomas, glioblastomas)

17
Q

Tumor Suppressor Genes - Proliferative Breaks

A

o Encode proteins, which normally inhibit cell proliferation or stimulate apoptosis upon cell damage; often inactivated in cancer cells by mutations, truncation, deletions or methylation (epigenetics), leading to uncontrolled growth and accumulation /propagation of defective cells
o Mutations of tumor suppressor genes are usually RECESSIVE  2 alleles must be altered to lose their function
o Inherited mutations of the tumor suppressor genes contribute to familial cancers
 Hereditary cancers develop earlier in age than sporadic malignancies and often arise in multiple locations
 Oncogenes are not typically associated with heritable cancers because a fetus is less likely to develop properly

18
Q

Tumor Suppressor Genes - Retinoblastoma

A

– encodes DNA-binding protein; controls G1-S checkpoint – RECESSIVE
o First tumor suppressor identified and served as foundation for the “Two Hit Hypothesis”
o Retinoblastoma - pediatric tumor developing in retina due to deletion of RB tumor suppressor gene; Treatment: removing the eye (enuclation)
o In quiescent cells, active unphosphortylated RB prevents progression into S-phase genes
o Upon growth factor stimulation, RB protein is inactivated by phosphorylation, which allows progression of cell cycle
o Deregulation of G1-S checkpoint by mutations has been found in majority of cancers

19
Q

Familial vs. Sporadic Form of Retinoblastoma

A

o Sporadic form – both mutations in RB gene are acquired AFTER birth; frequency of the tumor is relatively low; usually develops later in life
o Familial form – one mutation in RB protein is inherited; therefore, only one additional mutation has to occur in one of the retinal cells  MORE common
 Frequency of retinoblastoma is very high and the tumors often arise bilaterally
 Cells in the retina do not undergo apoptosis as well as other cells

20
Q

Tumor Suppressor Genes - Adenomatous Polyposis Coli (APC)

A

o Controls proliferation and adhesion of cells through interactions with beta-catenin – signaling molecule in WNT pathway
o In absence of WNT, APC binds beta-catenin and stimulates its degradation
o Upon WNT stimulation, APC releases beta-catenin; beta-catenin translocates to the nucleus and activates genes promoting cell cycle
o Germline mutations of APC gene  development of multiple benign tumors (polyps) in colon;
 Transform to malignant cancer nearly 100% of time; associated w/ loss of 2nd APC allele
o APC mutations also occur in majority of sporadic colorectal cancers

21
Q

Tumor Suppressor Genes - p53

A

– believe this mutation occurs first and is responsible for the error leading to malignancy; LATER an oncogene mutation results in cancer
o p53 controls cell proliferation and apoptosis at the G1 S phase transition
 “detects” cellular stress and prevents propagation of damaged cells
o p53 is one of most commonly mutated genes in human cancer (over 70%)
o Normally p53 is bound to MDM2 gene, which causes its degradation and short half-life
o Upon cellular stress, p53 is released from the complex with MDM2, which increases its half-life
 Active p53 is a tetrameric transcription factor that stimulates transcription of CDK inhibitor p21 which leads to G1 cell cycle arrest and apoptosis
• Simultaneously DNA repair systems are activated (GADD45)  if repair is successful then cell resumes normal function
 Mutations/loss of p53  accumulation and propagation of mutated and damaged cells  allows survival of the cells with overexpressed or deregulated mitogenic factors
 p53tumor-associated mutations very often affect DNA-binding domain (DBD)

22
Q

Types and Consequences of p53 Mutations

A

o Loss of function – mutant p53 not functional but doesn’t interfere with actions of wild type allele
 Least dangerous - Requires additional mutation to lead to symptoms/disease
o Dominant negative mutant – mutant p53 forms a complex with the wild type allele and prevents its binding to the target gene promoters
o Gain of function (most dangerous) – mutant p53 binds to different DNA sequences and activates different target genes, which can lead to stimulation of cell proliferation instead of cell cycle arrest and apoptosis

23
Q

Li Fraumeni Syndrome

A

– germline mutations in p53 gene – LFS-DOMINANT
o Very high penetrance in people with the mutation
o Elevated risk of development of number of tumors often at younger age and multiple locations (soft-tissue sarcomas, osteosarcomas, brain tumors, breast cancer)

24
Q

Tumor Suppressor Genes - Breast Cancer Predisposition Genes

A

o Function: Encode nuclear proteins involved in response to DNA damage and DNA repair
o BRCA1 – germline mutation cause increased risk of breast & ovarian cancers (85% & 50%)
 Mutations have been found in 40-50% of families with multiple breast cancer cases
 No BRCA1 mutations have been described in sporadic breast cancers; while incidence in sporadic ovarian cancers is only 5%
o BRCA2 – germline mutation cause increased risk of breast cancer (80%) in MEN & women

25
Q

Tumor Suppressor Genes - DNA Repair Genes

A

o DNA repair genes are NOT directly involved in cell cycle regulation
o Lack of DNA repair activity leads to genetic instability and facilitates mutations in other genes such as tumor suppressors and oncogenes that will directly affect the cell cycle
o Hereditary nonpolyposis colorectal cancer (HNPCC) – associated with defects of DNA mismatch repair genes; NO benign polyps present, making it extremely dangerous
o Xeroderma pigmentosum – increased risk of UV-induced skin cancers due to the defects in the nucleotide excision repair; increased number of UV-cross-linked residues

26
Q

Familial Tumors Caused by Mutations in Oncogenes

A

Anaplastic Lymphoma Kinase (ALK ) – receptor tyrosine kinase ONLY expressed in CNS/PNS neuronal tissue
o Germline activating mutations of ALK have been associated with familial neuroblastoma, which segregates as autosomal-dominant disease with limited penetrance
o Exception to the rule that oncogenes are not associated with familial cancer

27
Q

MicroRNAs

A

– important regulatory molecules – heavily associated in the differentiation process
o Bind to mRNA and either cause degradation or block translation
o Oncogenic miRNAs target tumor suppressors AND tumor suppressor miRNAs target oncogenes
 Alteration of their balance can trigger/facilitate malignant transformation

28
Q

Deregulation of Apoptotic Mechanisms

A

– leads to propagation of damaged, mutated cells
 Genes promoting apoptosis can be downregulated/inhibited (ex: caspases)
 Genes inhibiting apoptosis can be upregulation/stimulated (ex: BCL2)
o Extrinsic mechanism – receptors on cell membrane get activated and induce apoptosis
o Intrinsic mechanism – triggered by things like hypoxia, overexpression of oncogenes, and DNA damage (all of which activate the p53 pathway)

29
Q

Telomeres and Telomerase

A

o Due to shortening of telomeres, most normal cells have a capacity of 60-70 replications
 After this the cells enter a nonreplicative senescence (stop proliferating) or apoptosis
o Telomerase - enzyme that maintains normal telomere length preventing their senescence/death
 Stem cells AND most cancers - telomerase is upregulated  allows unlimited cell divisions