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Difference between incidence and mortality (as it relates to cancer/tumors)
- Incidence: no. of patients that develop tumor
- Mortality: no. of patients that die from tumor
- Ex: prostate ca has high incidence but low mortality
Has the incidence of tumors increased or decreased over the last 100 years? Why?
- Incidence has risen over the past 100 years, due to:
- - increased exposure to environmental carcinogens
- - increased life expectancy (advances in medicine)
Is cancer the no. 1 cause of death in US? If not, what is? What percentage of deaths does it cause?
- Cancer is the 2nd leading cause of death in US, after cardiovascular disease.
- Cancer causes 23% of all deaths.
What are some epidemiologic trends in neoplasia?
- - Gender differences
- - age (cancer increases w age for most types, but different types represent highest mortality in different age groups)
- -geographic/environmental factors (ex- Australia has increased skin cancer incidence related to high sun exposure, while Asia has increased incidence of gastric cancer, related to dietary differences)
- - SES, occupation, etc.
Three most common cancer killers among men? Women?
- Men: 1) Lung & Bronchus, 2) prostate, 3) colon & rectum (next are pancreas & then leukemia)
- Women: 1) Lung & Bronchus, 2) Breast, 3) colon & rectum (next are pancreas & then ovarian)
List the age groups in order of greatest cancer incidence to least.
- 70-79 yrs (70,000 incidence), 60-69 (55,000), 50-59 ties w >80 (35,000), 40-49, 30-39, 10-19 ties w 20-29, <10 (1000).
- Additionally, the type of cancer that people get is to some extent age-dependent. For men: leukemia is greatest from before 20s to 39 yo & Lung/bronchus from 40+. For women: leukemia from less than 20 yo, Breast ca for 20-59, and Lung/Bronchus from 60+
What are the top 5 lowest 5-yr survival % and the lowest 5 for cancers?
- Most deadly (in order from most fatal): pancreas, liver cell, oesophagus, lung stomach
- Greatest 5-yr survival rate (from most likely to survive to least): non-melanoma skin, thyroid, Hodgkin's, testis, breast
Describe "chemical initiators", in reference to chemical carcinogenesis.
- Initiators are electrophilic agents that cause permanent, non-lethal DNA damage (ie: they're mutagens). Initiation must occur before promotion. Also, there must be a certain amount of exposure, especially to the promoting agent.
- * Mutations caused by initiators presumably involve tumor suppressor genes, apoptosis genes, and proto-oncogenes.
What's the difference between direct acting and indirect acting chemical carcinogens?
- - Direct Acting: do not have to be metabolized before they're mutagenic (ex: alkylating agents & acylating agents)
- - Indirect Acting: must be metabolized before they're mutagenic - basically, they must be made electrophilic (ex: procyclic and heterocyclic aromatic hydrocarbons, aromatic amines, amides, and azo dyes, natural plant & microbial products)
Describe "promotors", in reference to chemical carcinogens.
- Promoters do NOT cause DNA damage, and their effect is reversible.
- Promoters provide a growth stimulus so that clonal expansion occurs (the clone being expanded is composed of progeny of a cell mutated by the initiator) --> expansion provides the opportunity for more mutations to occur so that the fully malignant phenotype may be realized.
- - Some carcinogens do not require promotion, but most of the time, initiators and promoters are required for tumorigenesis.
- - Sequential restrictions: *The initiator MUST be applied before the promoter, and the promoter MUST be applied at certain times after the initiator for tumorigenesis to occur. (aka: tumor initiation must occur before pro-motion and a minimal degree of exposure to promoters must occur)
Aside from initiators and promoters, what are some other cancer causing agents?
- Ionizing and UV radiation (directly cause DNA damage/mutation)
- Viruses associated with carcinoma:
- - HPV (squamous cell carcinomas)
- - Epstein-Barr virus (Burkitt's lymphoma)
- - Hep B & C viruses (hepatocellular carcinoma)
- - Human T-cell leukemia virus (HTLV)
- Heredity and genetics
What are some clinical characteristics of hereditary tumors?
- - Higher incidence of tumor type in patients with the inherited predisposition than incidence in general population (many fold, in most instances)
- - Younger age at time of tumor development than in patients developing sporadic form
- - Phenotypic transmission via Mendelian inheritance patterns (Autosomal Dominant pattern of transmission - multiple family members in successive generations; associated w altered control of cellular proliferation, vs. Autosomal Recessive pattern of transmission - less common, frequently skip generations; associated w defective DNA repair)
A decrease in the size of a tissue/organ due either to a decrease in cell size or cell number. This process is often reversible. Ex: decrease in skeletal muscle mass due to disuse.
An increase in the size of a tissue/organ due to an increase in cell size. Ex: Increase in size of left ventricle of heart due to hyertension.
An increase in the size of a tissue due to increase in cell number. Ex: increase in number of glands and stroma in the prostates of older men.
Abnormality of cellular differentiation in which one type of mature cell type is replaced by another type. Ex: replacement of respiratory epithelium by squamous epithelium in the lungs of cigarette smokers; replacement of intracervical epithelium by squamous cell epithelium as a result of HPV infection.
- Abnormalities of cellular differentiation that may be pre-neoplastic. These abnormalities are characterized by abnormal morphology including disordered maturation and cytologic atypia (increased nuclear cytoplasmic ratio, nuclear hyperchromatism). Generally, these cells have acquired some, but not all, of the mutations required for autonomous growth.
- Ex: dysplastic squamous cervical epithelium due to HPV infection and dysplastic squamous epithelium in the lungs of smokers.
- Abnormalities of cells that indicate malignancy. When you look at the cell, it's atypical.
- These abnormalities include more severe manifestations of changes seen in dysplastic cells such as increased nuclear to cytoplasmic ratio, and nuclear hyperchromatism (INCREASE in nuclear size and IRREGULAR nucleus)
- Anaplastic cells may also assume giant forms, possess bizarre mitotic figures, and suffer such a loss in organized ability that the benign counterpart of the cell cannot be ascertained (ie, the more anaplastic the cells of a particular malignancy are, the more poorly differentiated the malignancy is said to be).
This term is often used interchangeably with neoplasm, but technically it means swelling of any type, and was originally used to describe swelling associated with inflammation.
- An abnormal mass of cells that exhibits uncontrolled proliferation and persists after cessation of the stimulus producing it.
- Most neoplasms are irreversible, and some exhibit some degree of growth autonomy.
- may be benign or malignant.
Define "germline mutation"
- These mutations are transmitted to progeny by either the paternal or maternal genetic material at fertilization. Every cell in the progeny will carry the mutated gene.
- Ex: familial retinoblastoma.
Define "somatic mutation"
- Acquired mutation generally resulting from some type of environmental exposure. Mutation occurs in a single cell within an organism that can then become a precursor of cancer.
- Ex: oncogene mutation (ie: rats) producing clone of cells with increased proliferative capacity.
List the characteristics of a benign neoplasm.
- Slow growth
- well differentiated (closely resemble their cell of origin)
- not invasive in adjacent tissues
- does not metastasize (the absolute criterion for a benign neoplasm!)
- generally not lethal
What does the suffix "-oma" generally denote? Use it in some examples.
- "-oma" generally denotes benign mesenchymal neoplasm
- - First portion of name denotes the type of tissue from which neoplasm is derived:
- - Lipoma: benign neoplasm of fat
- - Leiomyoma: benign neoplasm of smooth muscle
- - Fibroma: benign neoplasm of fibrous tissue
- - Chondroma: benign neoplasm of cartilagenous tissue
Name some benign tumors of epithelium.
- Adenoma: benign neoplasm consisting of glandular structures (ex: colonic adenoma - benign tumor of colonic glands, or follicular adenoma of thyroid - a benign tumor of thyroid gland)
- Papilloma: benign growth consisting of squamous epithelium (papillary architecture)
- Cystadenoma: benign neoplasm composed of glandular epithelium with formation of large cystic structures (ex: ovarian serous cystadenoma)
For malignant epithelial neoplasms, use the word "x" after an appropriate descriptor, which indicates the cell type of origin.
What is a carcinoma? Give some examples.
- Malignancy derived from epithelium.
- Ex- renal cell carcinoma,
- follicular carcinoma of thyroid,
- adenocarcinoma (epithelial malignancy of glandular origin, ex- colonic adenocarcinoma),
- cystadenocarcinoma (epithelial malignancy of glandular origin that forms a cystic structure),
- squamous carcinoma (a carcinoma of squamous epithelium)
Give 5 examples where "oma" suffix is used, but it's not strictly mesenchymal and/or benign sense.
- Lymphoma: malignant tumor of lymphocytes
- Melanoma: malignant tumor of melanocytes
- Glioma: malignant tumor of glial cells
- Hepatoma: malignant tumor of liver cells; present preferred terminology is hepatocellular carcinoma
- Teratoma: benign tumor derived from germ cells which contains more than one germ layer, ie: ectoderm, mesoderm, endoderm
for malignancies of mesenchymal tissues, use "x" after an appropriate descriptor
Give examples of malignant mesenchymal neoplasms
- Liposarcoma: malignant neoplasm of adipose tissue
- Leiomyosarcoma: malignant neoplasm of smooth muscle
- Chondrosarcoma: malignant neoplasm of cartilage
- Osteogenic sarcoma: malignant neoplasm of bone
What is a blastoma?
A malignancy resembling embryonic cells (eg: retinoblastoma)
Describe the growth kinetics of malignant tumors
- Rapid growth:
- - unregulated growth factor signaling
- - varies from tumor to tumor (even for same type)
- Autonomous growth (also seen in benign tumors):
- - neoplasms not dependent on some outside stimulus (ex- growth factors, hormones) for growth --> growth is dysregulated
Name some cytologic features of malignant tumors.
- Anaplasia: generally refers to nuclear atypia with enlarged nuclei, increased nuclear to cytoplasmic ratio, irregular nuclei, and prominent nucleoli.
- Hyperchromasia: dark chromatin; increased staining, particularly of nucleus. Correlated in some tumors w hyperdiploidy (large amts of DNA)
- High mitotic rate indicative of rapid proliferative rate
- Increased cellularity indicative of dysregulation
- Necrosis indicative of rapid growth - rapidly growing malignancy may outgrow its blood supply; often secondary to lack of adequate blood supply
What does it mean in anaplasia when we say the cell is "well differentiated" vs "poorly differentiated"?
- Malignant neoplasms composed of cells that resemble their normal counterparts have little anaplasia and are said to be well differentiated.
- Malignant neoplasms composed of very anaplastic cells are said to be poorly differentiated.
What are some behavioral features of malignant tumors?
- Stromal invasion/absence of capsule
What is "stromal invasion"?
- Benign neoplasms frequently are encapsulated and do not grow into surrounding tissue. Malignant neoplasms generally lack a capsule and spread freely (invade) into adjacent benign stroma and tissue.
- Carcinomas grow through basement membrane
- Malignancies elicit stromal desmoplasia
What does "metastases" mean?
- Defining feature of malignant tumors
- spread via blood or lymphatic vessels to distant, non-adjacent sites
What is "seeding" in the context of malignant tumors?
- If malignant tumor spreads by invasion or metastasis to a conducive surface (ex: peritoneum, pleura) it may take up residence and grow on the surface
- Ex: ovarian malignancies may seed the peritoneum resulting in an abdomen full of malignant tumor
What is "tumor grading"?
- Histological classification used to predict how aggressively a tumor will behave. It's based on:
- 1) tumor differentiation: more poorly differentiated tumor will behave more aggressively
- 2) tumor proliferation rate: immunostains for proliferation markers or assessment of mitotic rate can also help predict aggressiveness. Generally if a tumor is growing rapidly and numerous mitotic figures can be seen microscopically, the tumor will behave more aggressively.
What is "tumor staging"?
- Determination of size of tumor, the extent of local spread, and whether or not and to where metastases occur provides the most significant prognostic information for help in determining appropriate therapeutic options and patient counseling.
- Treatment options are determined by tumor stage - probability of effective response to type of treatment is dependent on stage of tumor
- The TNM system
- Is tumor confined to mucosa - carcinoma in situ - or has it invaded beyond the basement membrane to become a truly invasive tumor?
Describe the TNM system.
- T = how big is the primary tumor and/or how deeply has it invaded the organ involved?
- N = are there metastases to lymph nodes?; which lymph node regions are involved?
- M = are there metastases to other organs? (eg: bone, liver, lungs, brain)
- Stage is determined by how behavior is for specific tumor type with given TNM classification. Prospective studies have documented which clinical TNM features are associated with a statistically significant survival, etc.
What are some systemic features of neoplasia?
- - These often lead to ultimate lethal effects of neoplams.
- Mass (local) effects - compression/obstruction, hemorrhage, infection, etc.
- Cachexia - decreased appetite, increased metabolism (TNF-alpha, IL-1); tumors elaborate substances that lead to loss of appetite
- Paraneoplastic syndromes - secretion of hormones and other factors from tumors that create clinical symptoms; distant effects not associated w metastases. There are characteristic associations between tumor type and syndrome (ex- lung cancer and finger clubbing, neuropathy and small cell cancer)
What is "malignant transformation" in the context of the genetic basis of neoplastic disease?
- Malignant transformation is initiated by non-lethal damage to the genome. The damage is not repaired, it's passed on from one progenitor to subsequent generations of neoplastic daughter cells (ie- cancer is monoclonal).
- The genetic damage can come about through the action of several different agents including radiation, chemicals, or viruses
- Genetic abnormalities that predispose to malignancy may be inherited.
Name some cellular processes that mutations, either inherited (germline) or acquired (somatic), generally affect.
- Control of proliferation
- Cellular senescence/death
- Maintenance of integrity of the DNA code
What is considered "the hallmark of neoplastic disease" and is also the initial step in the development of malignancy?
- Transformation: refers to altered control of cellular proliferation in which a cell has gained the ability to reproduce independent of normal inhibitory mechanisms.
- *Transformation is necessary but not sufficient alone to produce a malignant lesion.
What is the Multistep Theory of Carcinogenesis?
accumulation of additional mutations allow for the development of malignant characteristics
Describe the process of tumor progression.
Mutations associated with transformation frequently create conditions in which additional abnormalities are acquired thus leading to the establishment of a malignant clone of cells from precursor dysplastic lesions.
Describe the cell cycle.
- G1 phase: period between mitosis and DNA synthesis (G0 phase: pause feature in cell cycle)
- S phase: DNA replication
- G2 phase: period between DNA synthesis and mitosis
- M phase: Mitosis
Which protein is considered the central gatekeeper/nexus in the cell cycle progression? At which stage transition is it found?
- Retinoblastoma protein (Rb)
- - Hypophosphorylated Rb blocks expression of pro-proliferation genes (hangs on to E2F)
- - Hyperphosphorylated Rb allows expression of pro-proliferation genes (releases E2F)
- G0/G1 to S phase is the key to cellular proliferation and is controlled by a variety of mechanisms (esp Rb)
What classes of factors can cause cellular transformation?
- Growth factors (EGF, PDGF) and their downstream mediators for the family of proto-oncogenes --> promote Rb hyperphosphorylation, so promotes transition from G to S-phase
- Growth inhibitors (TGF-Beta, TP53, others) may act as tumor suppressors --> promote Rb hypophosphorylation, so prevents transition from G1 to S-phase
What's the role of apoptosis in the cell cycle?
- Apoptosis (programmed cell death) removes cells from viable pool in appropriate situations and may also lead of transformation if factors that promote or inhibit this pathway are mutated producing altered activity
- Pushes cells from G0/G1 to programmed cell death
Describe generally the process of cellular proliferation.
- 1) a growth factor (ligand) interacts with its receptor at the cell surface
- 2) the Receptor-Ligand interaction leads to activation of the receptor by a tyrosine kinase. Tyrosine kinase activity may be endogenous to the receptor itself, or it may involve a separate tyrosine kinase protein that interacts with the receptor after receptor ligand binding has occurred.
- 3) phosphorylation of cytoplasmic protein induces enzymatic cascade that activates a number of intracellular proteins "secondary messengers" that transmit the growth signal.
- 4) Secondary messenger action includes phospholipase, threonine kinase, serine kinase, and GTPase activities
- 5) result of secondary messenger activity: activation of nuclear transcription factors; transmit growth signal to nucleus. Nuclear transcription factors are proteins that interact directly with DNA to stimulate the transcription of genes that regulate the cell cycle and lead to cellular proliferation.
- Note: Normally each of these steps in the induction of cellular proliferation is tightly regulated with precisely scheduled inactivation of growth factors, receptors, secondary messengers and transcription factors.
Describe some abnormalities of growth factor action.
- May be a major factor in malignant transformation.
- Alterations in any steps of growth factor signal transduction can lead to transformation of cells
- - Redundancy: multiple GFs and GFRs activate the same secondary messengers/trans factors. Classically, one pathway stimulates growth (for lung ca, EGFR is activated). In redundancy, lots of other factors activate these same pathways.
- - Bypass: alteration of downstream factors relieves dependence on upstream factors (If cell is mediated by EGFR usually, it doesn't matter if you have active blockage or not; classical pathway with Ras --> can get abnormal proliferation even if blocking the original system
What is an "oncogene"? What is a "proto-oncogene"?
- Oncogenes - encode genes whose protein products stimulate cell growth and proliferation - GFs, GFRs, TKs, secondary messengers, nuclear transcription (regulatory) factors.
- Normal form of gene is called a "proto-oncogene".
- * alteration of proto-oncogene activity leads to uncontrolled growth
List some ways that proto-oncogenes are converted to oncogenes.
- - point mutation in the proto-oncogene leads to production of a protein that functions in an uncontrollable manner, resulting in unregulated cell proliferation (changes in aa sequence; hyperactive protein made in normal amounts)
- - reduplication of and amplification of DNA encoding proto-oncogenes may lead to over-expression of the proto-oncogene protein product (normal protein greatly overproduced)
- - chromosomal translocations may result in over-expression of a proto-oncogene (nearby regulatory DNA sequence causes normal protein to be overproduced), or structural changes in the proto-oncogene so that it becomes an oncogene (fusion to actively transcribed gene greatly overproduces fusion protein)
Do oncogenes act in a dominant or recessive fashion?
Oncogenes act in dominant fashion - only one allele needs to be altered to produce stimulatory effect on cellular proliferation.
Describe the normal mitotic signal transduction.
- Binding of mitogenic ligands (ex PDGF and EGF) to receptors at cell surface.
- Binding results in dimerization and autophosphorylation of receptors on tyrosine residues --> enables them to associate with and activate specific SH2 domain-containing downstream components of signaling pathway
- PLC association with SH2 leads to tyrosine phosphorylation by receptor kinase and enhanced ability to hydrolyze PIP to IP3 and DAG. DAG activates PKC and IP3 mobilizes Ca from intracellular stores
- If Grb2-Sos, association with phosphorylated receptors stimulates ability to facilitate Ras GTP-GDP exchange. GTP-ras activates MAPK cascade, which eventually induces serine/threonine phosphorylation of nuclear proteins that modulate gene transcription. (slide 7-lecture 2)
What are some examples of oncogenes?
- Growth factors: c-sis proto-oncogene encodes the B-chain of platelet derived growth factor (PDGF); overexpressed in tumors such as astrocytomas and osteosarcomas. Tumors also have receptors for PDGF. End result: constant stimulation of tumor cell by a GF that the tumor itself produces.
- Growth factor receptors: overexpression of EGFR (erb-B1) secondary to amplification of the gene is seen in a number of malignancies including lung cancer; tumors often distinct in respect to organ and cell type when compared to those with amplification
- Secondary messengers (signal transduction proteins): oncogenic forms of ras proto-oncogenes are ubiquitous (30% of all human tumors contain and express ras oncogenes). Ras proteins are G-proteins, which are signal transduction proteins that transduce signals (for growth, growth factor production, etc.) when they bind GTP. After the signal's transduced, the G-protein rapidly hydrolyzes GTP to GDP. Mutant ras proteins have limited ability to hydrolyze GTP to GDP, and thus have problems in terminating signal transduction. End result is inappropriate stimulatory signals to the cell.
- Nuclear transcription (regulatory) factors: "myc: proto-oncogenes are expressed in most cell types and appear to activate the transcription of a number of genes necessary for cellular proliferation. Ex - Burkitt's lymphoma places myc adjacent to enhancer element of immunoglobulin heavy chain or disrupts regulatory elements of the myc proto-oncogene. End result in either instance is too much myc protein and too much cellular proliferation. Ex2 - in Neuroblastoma, the myc gene is re-duplicated (amplified) many times; end result is too much myc protein and too much proliferation.
What is the normal function of "tumor suppressor genes"? What does loss of these genes mean?
- - regulation of cellular proliferation
- - loss or perturbation of these genes leads to unregulated cellular growth, and a potential for malignant transformation
Are tumor suppressor genes dominant or recessive mode of action?
- Recessive mode of action:
- - protein product from one allele is generally sufficient to provide normal control of cellular proliferation
- - both genes must be altered to produce transformation of a cell, but alteration of second allele relatively common
What are some possible ways of eliminating a normal Rb gene, if there's a healthy cell with only 1 normal Rb gene copy and the other with a mutation at the Rb locus?
- Nondisjunction (chromosome loss)
- Nondisjunction and duplication
- Mitotic recombination
- Gene conversion (copying of abnormal gene into normal chromosome)
- Point mutation
What is the APC gene product important in?
- -it's a tumor suppressor gene
- - important in the pathogenesis of colon cancer (as well as stomach and pancreas)
What is the rate limiting step in tumor suppressor gene activity?
- RLS: in the production of the first functionally abnormal allele. The remaining allele need only be silenced (in contrast to proto-oncogenes, which must gain activity).
- Silencing can occur by a variety of very non-specific mechanisms and thus occurs at a relatively high frequency
What is p53's normal function? What is the result of point mutations here? And homozygous loss?
- Tumor suppressor category
- Normal function is to allow time for cells to repair DNA damage before entering S-phase; arrest cells in G1 when DNA damage has occurred --> arrest gives cell time to repair DNA damage & do away with mutations that may ultimately lead to malignant transformation.
- Point mutations alter function, allowing unchecked progress through the cell cycle
- Homozygous loss of p53 is seen in nearly half of all malignancies (70% colon ca, 30-50% of breast ca, and 50% of lung ca)
What is the normal function of Rb? What happens when it's mutated? When it interacts with inhibitory proteins?
- Normal function characterized by binding of transcription factors responsible for inducing cell cycle gene expression thus preventing entry into S phase; Rb produces a protein that prevents cells from leaving G1 or G0 and entering the cell cycle --> effective block of cell division and proliferation occurs when phosphorylated forms of Rb bind and inactivate TFs that are responsible for initiating transcription of cell cycle genes.
- Mutated forms of Rb are unable to bind and inactivate transcription factors. When both genes are altered, the tumor develops.
- Interactions with inhibitory proteins (E7 protein of HPV) prevents interactions with cell cycle gene products
What is the primary control of apoptosis? What happens when it's overexpressed? How could it be inappropriately activated?
- Bcl-2 normally functions by preventing cells from undergoing apoptosis (ie, allows clonal expansion of lymphocytes specific for elimination of pathogen)
- Overexpression leads to abnormal survival and proliferation of cells
- Activation occurs when chromosomal translocation places it near the immunoglobulin heavy gene promoter, as in Burkitt's lymphoma; end result is overproduction of bcl-2 protein and "immortalization" of cells that normally undergo apoptosis.
How are telomerase and cellular senescence related?
- Genetic material lost from the end of chromosomes with each division eventually signals senescence (time to die!).
- Abnormal expression of telomerase in cancers prevents this loss (telomerase repairs the chromosome) resulting in extended lifespan of the cell.
What's the inheritance pattern of autosomal dominant phenotype? What type of mutation is the most common underlying alteration?
- Phenotypic expression of increased cancer incidence due to inheritance of single mutated gene allele.
- Pattern of dominant inheritance shows classic Mendelian features, with 50% of offspring affected and consistent occurrence in every generation.
- Tumor suppressor gene mutations most common underlying alteration (one normal allele allows maintenance of normal growth suppression function initially. Germline mutation of oncogene usually lethal in utero)
How does a germline mutation of tumor suppressor gene affect subsequent neoplastic transformation?
Germline mutation of tumor suppressor gene increases subsequent neoplastic transformation to nearly 100% in individual's lifetime.
Explain the phenomenon of tumor suppressor gene mutations yielding dominant phenotype but recessive mode of action.
- Recessive mode of action at the cellular level - both alleles must be knocked out to lose function; both alleles must be altered to develop cancer, one by germline and other by somatic mutation
- Dominant at organismic level (pattern of inheritance) - inheritance of single altered allele associated with phenotypic expression of hereditary cancer syndrome because of association with greatly enhanced (nearly 100%) progression to neoplastic transformation; 50% of offspring affected and cases seen in every generation of affected families
What is hereditary retinoblastoma? How does it differ from sporadic retinoblastoma?
- Hereditary retinoblastoma: inherit germline mutation of one Rb gene
- - only single allele needs somatic mutation
- - 80-90% with germline mutation develop tumor
- - 90% develop bilateral retinoblastoma
- - average age at development of tumor = 2 yrs
- - increased incidence of other tumors (osteosarcoma)
- Sporadic Retinoblastoma - both alleles of Rb genes normal initially
- - single cell needs two somatic mutations of Rb
- - overall incidence < 1/20,000
- - never bilateral
What is Familial Adenomatous Polyposis (FAP)? How does it differ from Sporadic Colon Carcinoma?
- Familial Adenomatous Polyposis:
- - Hereditary neoplasia
- - germline mutation in APC gene
- - somatic mutations in unaffected allele causes growth of hundreds of adenomas in young adults
- - 100% develop colon cancer by 50 yo (untreated)
- - average age at diagnosis: 40 yrs
- Sporadic Colon Carcinoma:
- - somatic mutations of both APC genes must occur in a single cell
- - additional mutations must occur in only one of a few adenomas for cancer to develop
- - average age at diagnosis of cancer = 65 yrs
How many mutated gene alleles are present in autosomal recessive phenotypes? What is the pattern of inheritance?
- Phenotypic expression of increased cancer incidence due to inheritance of two mutated gene alleles (one from each parent).
- Pattern of recessive inheritance shows classic Mendelian features of rare incidence, only 25% of offspring of crossed heterozygotes affected and generations frequently skipped.
What are some activities of genes altered in autosomal recessive hereditary cancer syndromes?
- usually associated w DNA repair enzymes
- Genes altered are involved in activities such as genomic instability, anti-tumor immune surveillance, enzymatic conversion of chemicals to carcinogens, etc.
Describe the variety of tumors associated with autosomal recessive hereditary cancer syndromes.
- - all associated with hematologic malignancies (ie: lymphoma/leukemia) are more frequent than solid tumors
- - associated w general cellular mechanisms so many associated abnormalities (anemia, opportunistic infections, etc)
- - variable variety of solid tumors associated with most, although at lesser frequency than hematologic malignancies
List 4 examples of autosomal recessive hereditary cancer syndromes:
- 1) Xeroderma pigmentosa (genomic instability, carcinogen hypersensitivity)
- 2) Fanconi's Anemia (genomic instability)
- 3) Ataxia-telangiectasia (genomic instability, defective immunosurveillance, carcinogen hypersensitivity)
- 4) Severe Combined ImmunoDeficiency (defective immunosurveillance)
Which of the following are sufficient to cause malignant transformation of the cell?:
A) activation of an oncogene
B) Inactivation of a tumor suppressor gene
C) Perturbation of an apoptosis regulatory gene
D) None of the above
- D) None of the above. A-C alone are not sufficient to cause malignant transformation of the cell. Rather, one of these events causes the cell to proliferate abnormally and/or "live" abnormally. In either event, the cell and its progeny are around for a longer time and in greater numbers (clonal expansion), increasing the chance that other mutations will occur.
- The accumulation of several genetic perturbations affecting numerous cellular processes must be accumulated to establish malignant phenotype.
Tumor cell growth kinetics: random mutations create cells that lose proliferative advantages as well as those that gain a proliferative advantage. Subsequently tumor progression depends on whether (2 things):
- 1) significant portion of transformed cells retain increased proliferation
- 2) additional mutations occur in cells with proliferative phenotype
A transformed population of tumor cells is genetically unstable. This instability facilitates the generation of subclones of tumor cells with new phenotypic characteristics. Some of these characteristics will enhance the malignant potential of the tumor and thus the survival of particular subclones (and the tumor in general). What are some of these "beneficial" characteristics?
- - Enhanced rate of growth (production of autocrine growth factors)
- - decreased susceptibility to anti-neoplastic drugs
- - decreased susceptibility to host defenses against cancer (evasion of host anti-neoplastic defenses)
- - decreased dependence on exogenous growth factors/hormones for growth
- - increased ability to recruit blood supply (angiogenesis)
- - enhanced ability to invade and metastasize (the "sin qua non" of malignancy)
Describe the "invasion" step in tumor progression.
- - facilitated by a loss of surface proteins that "glue" cells together (integrins)
- - acquisition of increased no. of receptor components that facilitate adherence to extra-cellular matrix components (BM & interstitial CT)/stromal proteins in tissue that tumor will invade
- - production of enzymes (metalloproteinases, type IV collagenase, plasminogen activator, etc) that chew through ECM & eventually into blood or lymphatic vessel
- - acquisition of ability to migrate through digested ECM
Describe the "metastasis" stage of tumor progression.
- -Occurs after "invasion" stage
- - - once in circulation, acquisition of membrane proteins by tumor cells allows them to associate with each other and with platelets to form tumor emboli.
- --> further membrane protein acquisition (adhesins) enables tumor cells in tumor emboli to adhere to vascular endothelial cells of specific organs via endothelial receptors
- - once adherent to vas. endothelium, enzymes enable tumor cells to chew through vessel wall into surrounding tissue and establish metastatic focus --> metastatic tumor develops via proliferation of malignant cells in new site
Tumors have high metabolic needs and thus, need to recruit additional blood supply via new vasculature to facilitate their growth. What is this process called?
- *note: tumors do not exceed approximately 1 mm in diameter without recruiting additional blood supply via new vasculature*
What determines the net angiogenic activity in tumor progression?
- the balance between pro-angiogenic (ie: vascular endothelial growth factor) and anti-angiogenic factors (ie: angiostatin)
- - angiogenic factors are elaborated by tumor or tumor associated cells (ie: macrophages) --> angiogenic factors provide potential targets for the diagnosis or treatment of tumors
List four normal host defenses/responses against tumors.
- 1) tumor cells produce mutant forms of normal protein - tumor specific antigens (TSAs), which bind to MHC I and form a complex that's recognized as foreign by cytotoxic T-cells
- 2) NK cells can lyse tumor cells after IL-2 activation (even without prior sensitization!). Abs can also induce an Ab-dependent cell-mediated cytotoxicity (ADCC) by NK cells
- 3) Macrophages activated by IFN-gamma kill tumor cells by elaborating TNF-alpha.
- 4) Abs on tumor cell surface can activate complement, which facilitates tumor cell destruction
List some tumor mechanisms of evasion of host defenses:
- - since immunogenic clones will be rapidly eliminated, antigen negative clones emerge that don't activate the immune system
- - tumor cells produce less MHC I, which means fewer immunogenic peptides will be presented to cytotoxic T-cells
- - tumors may produce and secrete substances that suppress the immune system (ex: TGF-beta)
How is CML (Chronic Myelogenous Leukemia) characterized? What type of molecular diagnostics are handy in diagnosing this?
- CML is characterized by the Bcr-Abl translocation between chromosomes 9 & 22 (Bcr/Abl fusion). This translocation is present in >95% of CML cases.
- FISH cytogenic testing is used to establish a diagnosis
- PCR for sensitive detection can be used to rule out minimal residual disease
The myeloproliferative disorders polycythaemia vera (PV), essential thombocythaemia (ET), and primary myelofibrosis (PMF) are clonal disorders of multipotent haematopoietic progenitors. The genetic cause of these diseases was not known until 2005, when several independent groups demonstrated that most patients with PV, ET and PMF acquire a single point mutation in the cytoplasmic tyrosine kinase JAK2 (JAK2V617F). Describe this mutation. In what types of cancer is this mutation NOT present?
- JAK2 is a proto-oncogene membrane receptor in myeloid blood cells that promotes proliferation. Constitutive activity without growth factor interaction occurs when the V617F (amino acid position 617) mutation is present.
- Mutation in non-CML myeloproliferative neoplasms.
- This mutation is NOT present in solid tumors, reactive myeloproliferative states, or lymphoid malignancies.
T/F: Lung cancers with EGFR mutations are associated w longer survival than those without.
What does HER2 expression mean for prognosis of breast cancer?
HER2 positive breast cancers are more aggressive. This feature has implications for treatment also with HER2 positive tumors being responsive to Herceptin.
What value do biochemical assays offer to prognostic lab testing?
- Biochemical testing is for screening or recurrence tests only.
- Tissue specific factors may be released from tumors of a specific organ. Ex- Prostate Specific Antigen (PSA) is released from prostate duct and Carcinoembryonic antigen (CEA) is released from cells of the GI tract.
- These factors have been employed as screening tools for tumors but b/c non-neoplastic processes such as inflammation may also lead to increases in their levels, they do not display adequate specificity (false + are too common) for diagnosis of tumors.
- They do, however, have strong sensitivity (false - are uncommon) and can be used as screening tests or to detect recurrence of disease. Ex- Elevated PSA in treated prostate carcinoma suggests bone metastases & Elevated CEA suggests recurrence of colon, pancreatic, and other tumors.
What does Minimal Residual Disease Detection in prognostic lab testing entail? What's a significant concern with this type of prognostic method? What are some examples of when this is employed?
- Powerful technologies like PCR have allowed for detection of very small amounts of malignant cells in patients who are evaluated for effectiveness of treatments; can be important in determining when additional therapy is needed.
- Significant concern: they amplify targets, thus minute contamination can lead to false + results. (Labs must use very thorough sterile technique and employ special preventative strategies.)
- Ex: Bcr/Abl in CML: PCR based test for increased sensitivity. Ex2: clonal immunoglobulin rearrangement as patient/tumor specific marker for detection --> can be used to track lymphoma prognosis
What are three significant points to traditional chemotherapeutic agents?
- - employ agents that exploit high mitotic activity of malignant cells
- 1) DNA base modifying agents: damage inducing agents create a multitude of mistakes within genes that ultimately cause such a high level of dysfunction that the cell dies
- 2) Genetic polymorphisms (if a variation in normal sequence of gene is present in >1% of pop, it's a polymorphism rather than a mutation); typically germline level genetic characteristic & associated w significant differences in protein activity
- 3) Excision repair system reverses damage: ERCC1 polymorphism characterization can predict the chance that a patient will be sensitive to DNA damage inducing chemotherapeutic agents
Targeted agents/therapies in molecular diagnostics: some pathways are specific to the development and progression of certain types of tumors. Why is this beneficial?
This has given promise that therapeutic agents aimed at a sufficiently specific target should provide effective anti-tumor therapy & be associated with minimum systemic toxicity (decreased side effects).
Describe why EGFR is a target for therapy in lung cancer.
- - Dramatic responses to EGFR inhibitors are seen in only 15-20% of patients. The PRESENCE of activating mutations in EGFR is predictive of a response.
- - activating mutations are associated w alterations in receptor conformation causing constitutive activity in the internal tyrosine kinase domain. EGFR mutation + patients: >75% response rate
- - rare mutations (such as the T790M) are associated w resistance to EGFR inhibitor therapy
- - EGFR amplification is more frequent and also predicative of response. Many mutation - patients may also respond to EGFR inhibitor therapy; EGFR gene amplification may be found in many of these tumors (ex: squamous cell carcinoma SCC, which is 25-35% amplification + but never mutation +)
- - EGFR mutations are seen in adenocarcinoma but almost never in SCC
Describe the role of EGFR as a target for therapy in colon cancer.
- In colon cancer, bypass of the EGFR pathway may lead to lack of sensitivity to EGFR inhibitors.
- - mutations in Kras are present in 40% of colon cancers and indicate resistance to EGFR inhibitors
- - tumors with wild-type (non-mutated) Kras are responsive to EGFR inhibitors
What is the benefit of patient specific tumor profiling? How is this type of profiling made possible?
- High throughput methodologies are now making it possible to characterize the expression pattern of the entire genome in a given tumor. Although these expression profiles may not be identical for every gene in each tumor cell, such a profile will allow for:
- 1) identification of primary characteristics of tumors
- 2) predict tumor behavior
- 3) choose very effective therapies in a patient specific manner.
- Possible by negotiating though:
- - complex data management
- - gene expression microarrays (level of RNA expression from every gene in genome is measured and overactive/underactive pathways are identified; exact identity of gene is established by the sequence of the probe present at the spot on the microchip from which the signal is generated)
- - proteomic profiling (high res mass spec provides specific protein patterns that indicate amount by height of peak and a degree of identity by the molecular weight at which peak is detected. Identity of characteristic proteins not given but the patterns prove to be specific).