VARIABILITY AND CHANGES OF GENETIC INFORMATION II Flashcards
WHAT CAUSES A TUMOR?
mutations and other genetic changes and alterations of epigenetic mechanisms
-all cancers are genetic
WHAT ARE THE 2 FORMS OF ORIGINS OF TUMORS?
SPORADIC = consequences of mutations of specific genes (growth controlling genes) in somatic cells
-random
HERITABLE = predisposition is inherited = increased predisposition = increased susceptibility;
-from about 5 %, are AD with reduced penetrance
-inheritance of tumours is multifactorial or bilateral or there is a family history of a similar tumour
WHERE DO TUMORS ORIGINATE FROM?
-one cell
-multi-step formed due to genetic change in one cell and division of cell
-genes and environment play a role
(clonal nature)
WHAT ARE TUMORS?
abnormal pass of tissues
BENIGN = non-cancerous
MALIGNANT = cancerous
EG: carcinomas (epithelial tissue) / sarcomas (mesenchymal tissue) / hematopoetic or lymphoid malignancies (leukemias or lymphomas)
WHAT ARE SPECIAL ABOUT MALIGNANT TUMORS?
-suppress surrounding cells
-able to metastasize
-form their own blood system (angiogenesis)
-uncontrolled growth
-invasivity
WHAT DOES THE MUTATION OF A PROTO-ONCOGENE TO AN ONCOGENE CAUSE?
abnormal cell division
-autosomal dominant
WHAT DOES THE MUTATION IN TUMOR SUPPRESSOR GENES CAUSE?
abnormal cell division
-autosomal recessive
-products suppress cell division and abnormal proliferation (promote apoptosis)
-mutations due to: point mutation / deletion / chromosome loss / abnormal methylation / mitotic recombination
-gene function is compromised only if loss of both alleles leads to the loss of gene function -> drastic cellular division
WHAT DOES THE MUTATION IN MUTATOR GENES (REPARATION GENES)?
increased frequency of mutations and chromosomal changes which leads to genome instability and high risks of tumors due to indirect effect
-cell does not produce reparatory enzymes -> DNA is not repaired
-autosomal recessive
WHAT ARE ENVIRONMENTAL (GENOTOXIC) FACTORS OF CANCER ORIGIN?
CHEMICAL = carcinogens
BIOLOGICAL = viruses (do not have to be genotoxic viruses)
PHYSICAL = UV and ionizing radiation
WHAT ARE PROTO-ONCOGENES?
genes which:
-stimulate cell division
-common in our organism
-proliferation
-differentiation
- via mutation transform into oncogene, their mutation has a dominant character
- either the production of an abnormal protein or overproduction of a normal protein
- products of oncogenes are various, but generally stimulate proliferation and/or block apoptosis
CONSEQUENCES OF PROTO -> ONCO
Qualitative change = synthesis of an abnormal product due to change in gene structure via mutation or fused gene
Quantitative change = increased synthesis of normal product due to change in regulation of transcription or amplification
-only change of one allele needed for abnormal cell division
code for:
-growth factors and receptors
-transcription factors
-anti-apoptotic proteins
-cell cycle regulation proteins
-cytoplasmatic proteins
-tyrosinkinases
-GTPases
WHAT ARE ONCOGENES?
abnormal form of a gene involved in normal cell growth
WHAT FACTORS CAUSE A PROTONCOGENE TO CHANGE INTO AN ONCOGENE?
-gene mutation
-chromosomal rearrangement / translocation / inversion = proto-oncogene fuses with a different gene→ abnormal protein
or associates with other regulatory sequences → overexpression of regular protein
-retroviral insertion = insertion of viral promoter near cell proto-oncogene using viral RNA reverse transcriptase
-amplification = gene copy is usually in cytoplasm as double minutes and linked at the end of chromosome as homogenously staining regions
-epigenetic changes = no change in primary structure; methylation; histone modification
autosomal dominant
-deletion within genes = 2 proto oncogenes close together and fuse
WHAT ARE DOUBLE MINUTES?
small fragments of extrachromosomal DNA, which have been observed in a large number of human tumors including breast, lung, ovary, colon, and most notably, neuroblastoma
-free circular molecules of amplified protooncogene
HOW DO VIRUSES CHANGE DNA?
caused by integration of viral DNA into the host genome (nucleus of the cell)
WHAT DO DNA VIRUSES CARRY?
carry oncogene that they introduce into the cell oncogene
-product of viral oncogene interfere with normal cell processes after integration
EG: HPV – human papilloma virus (vaginal carcinoma)
NAME AND EXPLAIN EXAMPLES OF CHROMOSOMAL TRANSLOCATIONS INVOLVING PROTO-ONCOGENES
CHRONIC MYELOGENOUS LEUKEMIA:
-philadelphia chromosome Ph1 is a derivative of chromosome 22, the product of balanced reciprocal translocation t(9q,22q)
-translocation moves the proto-oncogene c-ABL from its normal position on long arm of chromosome 9 to the BCR gene on the long arms of chromosome 22
-juxtaposition of the 2 genes produces a fused gene BCR/ABL
-product of fused gene is an abnormal chimeric BCR/ABL protein which has stable tyrosine-kinase activity causing abnormal stimulation of cell division
BURKITT LYMPHOMA (B-cell tumor of the jaw)
-during balanced reciprocal translocation t(8q,14q), the proto-oncogene c-MYC is transferred from 8q to 14q alongside the promoters of immunoglobulin genes (IgH)
-causes abnormal transcriptional activity of proto-oncogene in new position and an increased synthesis of normal product
EXPLAIN RETRO RNA TUMOUR VIRUSES
-oncogenic retroviruses causing cell transformation
-ACUTE retroviruses: transforming viruses that carry oncogenes and induce tumors rapidly, transduction (introduce oncogene which is homologous to a cell proto-oncogene to the host genome), overproduction of stimulation products in the cell stimulate cell proliferation and rapid tumor development
EG: RSV -> SRC = oncogene integrated into cell oncogene
If SCR is taken→ means that the virus reproduces but the cell is not transformed to become malignant
-NON ACUTE / LATENT retroviruses: do not carry oncogenes (integrate into neighboring region of protooncogene) and induce tumors more slowly, insertion mutagenesis (promotor sequences and viral enhancers integrated to specific sites near cell proto-oncogene), LTR sequences increase the expression of the cell proto-oncogene
EG: AVIAN LEUKOSIS VIRUSES
TRANSACTIVE VIRUSES: contain a gene whose product activates transcription of cellular protooncogene
EG: HTLV – T-cell leukemia in human
-protein TAX – activates transcription of cellular protooncogene
EXPLAIN RESTINOBLASTOMA
-mutation RB1 gene = tumor suppressor gene on Chromosome 13
-sporadic forms occur at an older age because the mutation of both alleles must occur in the same cell or their offspring (mutation of both alleles are somatic - in one cell of retina), unilateral
-hereditary forms have an early manifestation, autosomal dominant, bilateral (tumor can occur in both eyes)
-begins with a germline mutation of one allele of Rb1 gene (de novo origin in one germ cell of parent mutation in all cells of body = heterozygote)
-Second step is usually a somatic mutation of the 2nd allele in one cell of retina (loss of heterozygosity)
-→ once one healthy allele gets mutated -> tumor (retinoblastoma has 90 % penetrance)
then mutation is found in majority of cells – carrier is heterozygote, after loss of healthy allele left tumor begins to form
-if at time of diagnosis the tumor lays only inside the eye – good prognosis, treatment is 90 to 100% successful; if it occurs also outside the eye – success of treatment is only 10%)
EXPLAIN LI-FRAUMENI SYNDROME.
-mutation of one allele TP53, which is the gene that codes for p53 protein
-main tumor suppressor gene activates gene for protein p21, which stops the cell cycle and activates gene for protein repairing DNA
(If DNA is repaired → cell cycle continues (G1 or G2 cell cycle check points )
(if DNA is not repaired –> apoptosis)
-Heterozygotes of TP53 have a high incidence of tumors at a young age ( sarcoma, breast, and other cancers)
EXPLAIN WILMS TUMOR.
-tumor suppressor gene on 11p (p = short arm)
(Chromosome 11) is affected
-causes embryonal tumor of kidney → nephroblastoma
GIVE AN EXAMPLE OF A TUMOR REPRESSOR GENE
BRCA1
GIVE EXAMPLES OF MUTATOR GENES IN RECESSIVE HOMOZYGOTES
A: heritable nonpolyposis colon cancer
B: chromosome instability syndromes = chromosomal breakage syndromes
-cause multistage tumor formations
NAME THE CHARACTERISTICS OF NORMAL IN VITRO CELLS
-euploidy
-specific shape
-contact inhibition
-hayflick limit
-normal antigens
NAME THE CHARACTERISTICS OF MALIGNANT IN VITRO CELLS
-accumulation
-immorality
-abnormal antigens
-genome instability
-various genome aberrations
-loss of differentiation
WHAT ARE THE THREE TYPES OF GENES WITH POLYMORPHISMS WHICH EFFECT CARCINOGENS?
a) genes responsible for chemical transformations/metabolisms (= detoxification)
EG: enzyme aryl hydrocarbon hydroxylase processes polycyclic hydrocarbons (such as cigarette smoke) to epoxides which are carcinogenic -> defected enzyme leads to lung cancer resistance
b) DNA reparation genes
c) Genes of immune response – immune failure (AIDS, genetic disease) -> tumors
WHAT CAUSES A GENOTOXIC EFFECT?
combination of factors such as mutagenic, carcinogenic, teratogenic, allergenic, immunosuppressive
CAN EVERY CARCINOGEN BE A MUTAGEN?
no
-any mutagen can be a carcinogen but not vice versa – not all carcinogens can be mutagens
WHAT ARE NONGENOTOXIC MUTAGENS?
cause cancer even without the change of DNA’s primary structure = are not mutagenic
