What is cancer, and what are 3 general types?
Malignant, clonal tumor of potentially unlimited growth that expands locally by invasion and systemically by metastasis.
- Sarcoma: mesenchymal tissue (bone, cartilage, muscle, fat)
- Carcinoma: epitheloid tissues
- Hematopoietic/lymphoid: leukemias (WBC from bone marrow) and lymphomas (WBC from spleen and lymph nodes)
A 1° cancer in a 2° location is known by the 1° classification (e.g., breast cancer tumor cells in the liver are still referred to as breast cancer).
What are the hallmarks of cancer?
- Mutation or loss of genes involved in cell control including growth/division, proliferation, metabolism
- Environmental elements may influence mutation
- Mutations may be inherited or acquired
- Chromosome instability (CIN): gain, loss, or rearrangement of chromosomes
What is the difference between constitutional findings and acquired anomalies?
Constitutional findings: the original DNA and chromosome complement that is the foundation for the genetic constitution in all cells of the body. Originated in zygote.
Acquired anomalies: change that has occurred in the constitutional DNA or karyotype. Usu. present in a single cell line (clone).
What is the genetic basis of cancer?
- Multistep process
- Involves many genes
“Driver” vs “Passenger” mutations:
- “Driver” mutations have been repeatedly identified in the same type of cancer, or in many diff. types of cancer, so they are presumed to be related to the changes leading to disease. Usu. proto-oncogenes, oncogenes, or tumor suppressors
- “Passenger” mutations are identified in cases of cancer without any apparent pattern. I.e., they are seen randomly, do not correlate to a particular disease type, and are not recurrent with a single type of cancer. Probably 2° changes resulting from genomic instability
What is an oncogene?
A dominantly acting gene involved in unregulated cell growth and proliferation.
- Carried by viruses
- Assoc. with disease in animals
- Examples: H-ras (Harvey rat sarcoma virus), sis (Simian sarcoma virus), abl (Abelson murine leukemia)
- There are few true oncogenes in humans (HPV [E6, E7], EBV, HHV-8, HTLV-1, HTLV-2); usu., we deal with proto-oncogenes
What is a proto-oncogene?
Structurally important “housekeeping” gene involved in cell proliferation and development. Mutation can result in “activation,” which can lead to tumorigenesis and a dominant (only 1 mutation required) gain of function mutation.
- Growth factors
- Cell surface receptors
- Intracellular signal transduction
- DNA binding proteins (transcription)
- Regulation of cell cycle
What is chronic myelogenous leukemia?
CML is a relatively common form of leukemia.
- Juxtaposition of 2 genes → chimeric protein product w/ a new, disease-associated function
- Loss of proper regulatory controls and overproduction of tyrosine kinase
- First to have been associated with a genetic marker: t(9;22)Ph’ (Philadelphia) chromosome
Why is CML treatment historically and scientifically important?
- Delineation of the CML genetic abnormality led to better understanding of proto-oncogenes
- Allowed development of a new class of drug: those targeted to the genetic lesion
- Targeting → fewer side effects
- First time a drug was developed from knowledge of the gene mutation and the resultant aberrant protein
What is acute promyelocytic leukemia?
APL is a proto-oncogene-related disease.
- Characterized by a 15;17 translocation that breaks the PML gene on chromosome 15 and the RARA gene on chromosome 17
- Chimeric gene and protein products
Translocation → fusion signal that can be detected using FISH technology:
- If the normal signal pattern returns after treatment, the patient has responded to therapy (gone into remission)
- If the fusion pattern subsequently returns, the patient has relapsed
What is a tumor suppressor?
Genetic element whose loss/inactivation allows the cell to display an alternate phenotype, leading to neoplastic growth. Unlike cancer, which is dominant, alternate tumor suppressor genotypes are recessive (require 2 mutations).
Normal functions include:
- Cell-cell interactions
- Regulation of growth
- Inhibitory substances
- Cell proliferation
- Cell differentiation
- Chromosome repair
What are the two kinds of tumor suppressors?
- Genes that function directly to suppress tumors by regulating cell cycle or inhibiting cell overgrowth. Formerly known as “gate keeper” genes. ex) Rb1
- Genes that maintain cellular integrity, often by repairing DNA damage. Formerly called “caretaker” genes. Indirect net effect because loss of this function may not appear to be linked directly to disease.
What is Rb1?
The classic tumor suppressor, which functions in regulation of the cell cycle.
- Controls progression from G1 → S
- Loss of function eliminates an important mitotic checkpoint → uncontrolled growth
- Retinoblastoma (prenatal-5yo) is directly related to mutations of the gene RB1, which is located on chromosome 13 at band 13q14.2
What is the “two hit” hypothesis?
Knudson’s “two hit” hypothesis states that retinoblastoma requires two mutations in the same cell (recessive).
- Sporadic (2 somatic mutations) → usu. unilateral retinoblastoma
- Inherited (1 inherited mutation, 1 somatic mutation) → usu. bilateral retinoblastoma
- Appearance of dominance in a pedigree
What is the relationship between familial vs. somatic mutations and early or late onset of disease?
Early age of onset: If a person inherits one mutation, his/her disease will occur early in life (birth to 30s) since it generally will not take a long time for the second mutation to occur and initiate carcinogenesis
Late age of onset: If no mutation is inherited, 2 somatic mutations in one cell must occur sporadically to initiate the abnormal clone. This will require more time, and these cancers typically occur in the later decades of life
What are some common familial cancers?
- Breast and ovarian cancer
- Familial polyposis coli
- von Recklinghausen neurofibromatosis
- Wilm’s tumor
- von Hippel Lindau/renal cell cancer
What is Li Fraumeni cancer?
A type of familial cancer associated with the inheritance of a mutation of p53. p53 has no one target tissue and is not specific to one disease, so many different cancers (breast, lung, colon, prostate, brain, etc.) may occur in Li Fraumeni families.
What is breast cancer?
- Lifetime risk for American women: 1/8 to 1/10
- Also a risk for inheriting males
- Familial (5-10%, onset in 20s-40s) or sporadic (90-95%, onset post-50s)
- Mutations: errors in homologous recombination, DNA repair defects
- 2 known genes (BRCA1 on chromosome 17, BRCA2 on chromosome 13), but not well understood
What are the BRCA genes?
The BRCA1 (chr. 17) and BRCA2 (chr. 13) genes are responsible for 80-90% of familial breast cancer (5-9% of all BC).
- Multiple mutations
- Increased risk of male BC
- Increased risk in Ashkenazi Jewish population
- Counseling of patients critical
How are defects in DNA repair genes related to cancer?
The idea is NOT: gene mutation → aberrant protein → disease.
INSTEAD: malfunction in a normal cellular process → accum. of errors → system dysfunction
Can be inherited or acquired: Fanconi anemia, ataxia telangiectasia, breast cancer, HNPCC (hereditary non-polyposis colon cancer), bladder cancer
What are breakage syndromes?
Recessively inherited syndromes due to chromosome instability. Often involve defective DNA repair mechanisms and susceptibility to cancer.
- Fanconi anemia: 9q22.3, 11q23, 20q13
- Bloom syndrome: 15q26.1 (defective DNA ligase 1 or DNA helicase)
- Ataxia telangiectasia: 11q22-q23
- Xeroderma pigmentosum: 3p25, 13q33, chr. 9 (defective excision repair)
- Cockayne syndrome: 5q12, 10q11 (defective excision repair cross complementation)
What is HNPCC?
Hereditary Nonpolyposis Colon Cancer (HNPCC), or Lynch syndrome, which is linked to defects in DNA damage repair genes.
- 2-4% of hereditary CC
- 90% lifetime risk for males who inherit one mutation
- 70% lifetime risk for females who inherit one mutation
- Mutations in MSH2 and MLH1 account for 70-80% of HNPCC
Microsatellite analysis suggests the presence of a defect in mismatch repair (indirect test)
What is chromosome instability (CIN)?
A hallmark of cancer; de novo mutations that can be due to a wide variety of mechanisms:
- Breakage or recombination
- Chromosome rearrangement: duplications or deletions, translocations or inversions, tandem duplication of genes, generation of supernumerary chromosomes
- Gain or loss of whole chromosomes
How does cancer evolve?
Progression from normal → cancer cells requires a combination of environmental and genetic effects, which can be demonstrated by a classic pathway developed by studies on one type of colon cancer.
Mutations in many diff. genes arise, but the key principle is that these mutations must occur w/in a single cell. If all of the mutations do not arise, full disease expression may not occur. A person with an inherited mutation has a jump start on the process, passing the first checkpoint quickly.
What is clonality?
A key feature of cancer.
- A normal cell (1) may have a single mutation that proliferates and generates an abnormal clone (2) = an acquired Δ in a limited # of cells
- Further chromosomal changes may modify the karyotype and produce additional clones (2A, 2B)
- The path from 1 → 2 → 2A (assuming 2B does not exist) is linear evolution. As illustrated below, there is divergent evolution from 2 → 2A and 2B
- Karyotype analysis can be used to monitor the presence and evolution of clones
What is karyotype evolution?
The change over time in the karyotype due to acquisition of different mutations. Generally, increasing complexity and #s of chromosome abnormalities are assoc. w/ poorer prognosis. It is possible to use the chr. abnormalities to follow the patient from diagnosis to remission and relapse.
Depending on the abnormality, the diagnosis may be either specific or general.
What is a hematologic transplantation?
A bone marrow transplant, which provides the possibility of eradicating the disease clone and returning the individual to full health.
- Either autologous (from the patient) or allogeneic (from a matching donor)
- Use chemotherapy to destroy the bone marrow, incl. the disease clone, then infuse w/ healthy cells
- The stem cells will migrate to the bone marrow and re-establish hematopoiesis
- Problems with allogeneic stem cell use: immunosuppression, host vs. graft disease