• can be determined by glucose-6-phosphate dehydrogenase (G6PD) enzyme isoforms

1. Multiple isoforms (G6PDa,b,c) exist; only one isoform is inherited from each parent
2. in females, one isoform is randomly inactivated in each cell by lyonization (G6PD is present on the X chromosome)
3. Normal ratio of active isoforms in cells of any tissue 1:! (ex 50% of cells have G6PDa, and 50% of cell have G6PDb)
4. 1:! ratio is maintained in hyperplasia, which is polyclonal cell (cells are derived from multiple cells)
5. Only one isoform is present in neoplasia which is monoclonal
6. Clonality can also be determine by androgen receptor isoforms, which are also present on the X chromosome

• The immunoglobulin (Ig) light chain phenotype
• Ig is comprised of heavy and light chains
• each B cell expresses light chain that is either kappa or lambda
• normal kappa to lambda light chain ratio is 3:!
• this ratio is maintained in hyperplasia, which is polyclonal
• Ratio increases to >6:1 or is inverted (ex kappa to lambda ratio=1:3) in lymphoma, which is monoclonal

benign or malignant

• bening=localized and do not metastasize
• malignant tumors (cancer) invade locally and have the potential to metastasize

benign=adenoma or papilloma

malignat=adenocarcinoma or papillary carcinoma

benign=lipoma 

malignant= liposarcoma

benign=nevus (mole)

malignant=melanoma

1. Cancer is the 2nd leading cause of death in both adults and children
2. The leading causes of death in adults are

1)Cardiovascular disease

2)Cancer

3)cerebrovascular disease

The leading causes of death in children are

1)accidents

2)cancer

3)congenital defects

The most common cancers by incidence in adults are 1)breast/prostate

2)lung

3)colorectal

The most common causes of cancer mortality in adults are

1)lung

2)breast/prostate

3)colorectal

• Cancer begins as a single mutated cell
• approximately 30 divisions occur before the earliest clinical symptoms arise
• each division (doubling time) results in increased mutations

1. Cancers that do not produce symptoms until late in disease will have undergone additional divisions and , hence, additional mutations
2. Cancers that are detected late tend to have a poor prognosis

• Goal of screening is to catch dysplasia (precancerous change) before it becomes carcinoma or carcinoma before clnical symptoms arise

1. Common Screening metods include

• Pap smear--detects cervical dysplasia (CIN) before it becomes carcinoma
• Mammography--detects in situ breast cancer (ex DCIS) before it invades or invasive carcinoma before it becomes clinically palable
• PSA and digital rectal exam-- detects prostate carcinoma before it spreads
• Hemoccult test (for occult blood in stool) and colonoscopy-- detect colonic adenoma before it becomes colonic carcinoma or carcinoma before it spreads

• Cancer formation is intitiated by damage to DNA of stem cells.  The damage overcomes DNA repair mechanisms, but is not lethal
• Carcinogens are agents that damage DNA, increasing the risk for cancer.  Important carcinogens include chemicals, oncogenic viruses and radiation
• DNA mutations eventually disrupt key regulatory systems, allowing for tumor promotion (growth) and progression (spread)
• Disrupted systems include proto-oncogenes, tumor suppressor genes and regulators of apoptosis

• Growth factors, growth factor receptors, signal transducers, nuclear regulators, and cell cycle regulators
• growth factors induce cellular growth (PDGFB in astrocytoma)
• Growth factor receptors mediate signals from growth factor (ex ERBB2, [HER2/neu] in breast cancer)
• Signal transducers relay receptor activation to the nucleus (ex ras)
• Ras is associated with growth factor receptors in an inactive GDP state
• Receptor binding causes GDP to be replaced with GTP, activating ras
• Activated ras sends growth signals to the nucleus
• Ras inactivates itself by cleaving GTP to GDP; this is augmented by GTPase activating protein
• Mutated ras inhibits the activity of GTPase activating protein.  This prolongs the activated state of ras, resulting in increased growth signlas
• Cell cycle regulators mediate progression through the cell cycle (ex cyclin and cyclin dependent kinase)
• cyclins and cyclin-dependent kinases (CDKs) form a complex which phosphorylates proteins that drive the cell through the cell cycle
• For example, the cyclinD/CDK4 complex phosphorylates the retinoblastoma protein, which promotes progression through the G1/S checkpoint

• Hepatocellular carcinoma
• derived from aspergillus, which can contaminate stored grains

• leukemia/lymphoma
• side effect of chemotherapy

• Squamous cell carcinoma of skin, lung cancer, and angiosarcoma of liver
• Arsenic is present in cigarette smoke

• Lung carcinoma and mesothelioma
• exposure to asbestos is more likely to lead to lung cancer than mesothelioma

• carcinoma of oropharynx, esophagus, lung, kidney, and bladder

• Most common carcinogen worldwide; polycyclic hydrocarbons are particularly carcinogenic

• Stomach carcinoma
• Found in smoked foods; responsible for high rate of stomach carcinoma in Japan

• Urothelial carcinoma of bladder
• derived from cigarette smoke

• Angiosarcoma of liver
• occupational exposure; used to make polyvinyl chloride (PVC) for use in pipes

• lung carcinoma
• occupational exposures

• nasopharyngeal carcinoma
• Burkitt lymphoma
• CNS lymphoma in AIDS

• Adult T-cell leukemia/lymphoma

• Squamous cell carcinoma of vulva, vagina, anus, and cervix; adenocarcinoma of cervix

• AML, CML, and papillary carcinoma of the thyroid
• generates hydroxyl free radicals

• Basal cell carcinoma, squamous cell carcinoma, and melanoma of skin
• results in formation of pyrimidine dimers in DNA, which are normall excised by restriction endonuclease

P53

Regulates progression of the cell cycle from G1 to S phase

1. In response to DNA damage, P53 slows the cell cycle and upregulates DNA repair enzymes
2. If DNA repair is not possible, p53 induces apoptosis

• p53 upregulates BAX, which disrupts Bcl2

3.  Both copies of the p53 gene must be knocked out for tumor formation (knudson two-hit hypothesis)

• Loss is seen in >50% of cancers
• Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic), characterized by the propensity to develop multiple types of carcinomas and sarcomas

[image]

• regulates progression from G1 to S phase
• Rb  holds the E2F transcription factor, which is necessary for transition to the S phase
• E2F is released when RB is phosphorylated by the CyclinD/cyclin-dependent kinase 4 (CDK4) complex
• Rb mutation results in constituitively free E2F, allowing progresion through the cell cycle and uncontrolled growth of cells
• Both coies of Rb gene must be knocked out for tumor formation (knudson two-hit hypothesis)
• Sporadic mutation (both hits are somatic) is characterized by unilateral retinoblastoma
• germline mutation results in familial retinoblastoma (2nd hit is somatic), characterized by bilateral retinoblastoma and osteosarcoma

 [image]

Platelet-Derived Growth factor

overexpression autocrine loop

Associated with astrocytoma

• epidermal growth factor receptor
• mechanism=amplification
• associated with subset of breast carcinoma

neural growth factor receptor

mechanism:point mutation

associated: medullary carcinoma of thyroid

• Stem cell growth factor receptor
• mech. point putation
• associated tumor: GI stromal tumor

• GTP binding protein
• mech: poin mutation
• carcinomas, melanoma, and lymphoma

• Tyrosine Kinase
• t(9;22) with BCR
• CML and some tyes of ALL

• Transcription factor
• mechanism t (8:14) involving IgH
• associated with Burkitt lymphoma

• Transcription factor
• mech: amplification
• Lung carcinoma (small cell)

• Cyclin function
• mechanism t (11;14) involving IgH
• Associated with mantle cell lymphoma

• Cyclin-dependent kinase
• mechanism=amplification

• associated with melanoma

• Prevent apoptosis in normal cells, but promote apoptosis in mutated cells whose DNA cannot be repaired (ex Bcl2)

1. Bcl2 normally stabilizes the mitochondrial membrane, blocking release of cytochrome c
2. disruption of Bcl2 allows cytochrome c to leave the mitochondria and activate apoptosis

• Bcl2 is overexpressed in follicular lymphoma

1. t (14:18) moves Bcl2 (chromosome 18) to the Ig heavy chain locus (chromosome 14), resulting in increased Bcl2
2. Mitochondrial membrane is further stabilized, prohibiting apoptosis
3. B cells that would normally undergo apoptosis during somatic hypermutation in the lymph node germinal center accumulate, leading to lymphoma

• necessary for cell immortality
• normally, telomers shorten with serial cell divisions, eventually resulting in cellular senescence
• cancers often have upregulated telomerase, which preserves telomers

• production of new blood vessels is necessary for tumor survival and growth
• FGF and VEGF (angiogenic factors) are commonly produced by tumor cells

1. mutations often result in production of abnormal proteins, which are expressed on MHC class I
2. CD8+ t cells detect and destroy such mutated cells
3. Tumor cells can evade immune surveillance by downregulating expression of MHC class I
4. Immunodeficiency (both primary and secondary) increases risk for cancer

Tumor Invasion and Spread

• Accumulation of mutations eventually results in tumor invasion and spread

1. Epithelial tumor cell are normally attached to one another by cellular adhesion molecules (ex E-cadherin)
2. Downregulation of E-cadherin leads to dissociation of attached cells
3. Cells attach to laminin and destroy basement membrane (collagen type IV) via collagenase
4. Cells attach to fibronectin in the extracellular matrix and spread locally
5. Entrance into vascular or lymphatic spaces allows for metastasis (distant spread)

• Lymphatic spread is char. of carcinomas-initial spread is to regional draining lymph nodes
• Hematogenous spread-char. of sarcomas and some carcinomas-renal cell carcinoma-renal vein, hepatocellular carcinoma-hepatic vein, follicular carcinoma of the thyroid, choriocarcinoma
• Seeding of body cavities is characteristic of ovarian carcinoma, which often involves the peritoneum (omental caking)

Benign tumors

• Slow growing, well circumscribed, distinct, and mobile
• well differentiated
• organized growth
• uniform nuclei
• low nuclear to cytoplasmic ratio
• minimal mitotic activity
• lac of invasion (of basement membrane or local tissue)
• no metastatic potential

• Poorly differentiated
• disorganied growth (loss of polarity)
• nuclear pleomorphism and hyperchromasia
• high nuclear to cytoplasmic ratio
• high mitotic activity with atypical mitosis
• invasion (through basement membrane or into local tissue)
• Metastatic potential is the hallmark

• Proteins released by tumor into serum (ex PSA)
• useful for screening, monitoring response to treatment, and monitoring recurrence
• Elevated levels require tissue biopsy for diagnosis of carcinoma (ex biopsy of prostat with elevated PSA)

• Microscopic assessment of differentiation (ie how much a cancer resembles the tissue in which it grows); takes into account architectural and nuclear features
• Well differentiated (low grade)-resembles normal parent tissue
• Poorly differentiated (high grade) does not resemble parent tissue
• Important for determining prognosis; well-differentitated cancers have better prognosis than poorly-differentiated cancers

• Assessment of size and spread of cancer
• Key prognostic factor; more important than grade
• Determined after final surgical resection of the tumor
• Utilizes the TNM staging system
• T-tumor (size and/or depth of invasion)
• N-spread to regional lymph nodes; second most important prognostic factor

M- Metastasis; single most important prognostic factor