VARIABILITY AND CHANGES OF GENETIC INFORMATION II

Question 1

WHAT CAUSES A TUMOR?

Answer 1

mutations and other genetic changes and alterations of epigenetic mechanisms
-all cancers are genetic

Question 2

WHAT ARE THE 2 FORMS OF ORIGINS OF TUMORS?

Answer 2

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

Question 3

WHERE DO TUMORS ORIGINATE FROM?

Answer 3

-one cell
-multi-step formed due to genetic change in one cell and division of cell
-genes and environment play a role
(clonal nature)

Question 4

WHAT ARE TUMORS?

Answer 4

abnormal pass of tissues
BENIGN = non-cancerous
MALIGNANT = cancerous

EG: carcinomas (epithelial tissue) / sarcomas (mesenchymal tissue) / hematopoetic or lymphoid malignancies (leukemias or lymphomas)

Question 5

WHAT ARE SPECIAL ABOUT MALIGNANT TUMORS?

Answer 5

-suppress surrounding cells
-able to metastasize
-form their own blood system (angiogenesis)
-uncontrolled growth
-invasivity

Question 6

WHAT DOES THE MUTATION OF A PROTO-ONCOGENE TO AN ONCOGENE CAUSE?

Answer 6

abnormal cell division
-autosomal dominant

Question 7

WHAT DOES THE MUTATION IN TUMOR SUPPRESSOR GENES CAUSE?

Answer 7

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

Question 8

WHAT DOES THE MUTATION IN MUTATOR GENES (REPARATION GENES)?

Answer 8

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

Question 9

WHAT ARE ENVIRONMENTAL (GENOTOXIC) FACTORS OF CANCER ORIGIN?

Answer 9

CHEMICAL = carcinogens
BIOLOGICAL = viruses (do not have to be genotoxic viruses)
PHYSICAL = UV and ionizing radiation

Question 10

WHAT ARE PROTO-ONCOGENES?

Answer 10

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

Question 11

WHAT ARE ONCOGENES?

Answer 11

abnormal form of a gene involved in normal cell growth

Question 12

WHAT FACTORS CAUSE A PROTONCOGENE TO CHANGE INTO AN ONCOGENE?

Answer 12

-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

Question 13

WHAT ARE DOUBLE MINUTES?

Answer 13

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

Question 14

HOW DO VIRUSES CHANGE DNA?

Answer 14

caused by integration of viral DNA into the host genome (nucleus of the cell)

Question 15

WHAT DO DNA VIRUSES CARRY?

Answer 15

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)

Question 16

NAME AND EXPLAIN EXAMPLES OF CHROMOSOMAL TRANSLOCATIONS INVOLVING PROTO-ONCOGENES

Answer 16

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

Question 17

EXPLAIN RETRO RNA TUMOUR VIRUSES

Answer 17

-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

Question 17

EXPLAIN RESTINOBLASTOMA

Answer 17

-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%)

Question 17

EXPLAIN LI-FRAUMENI SYNDROME.

Answer 17

-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)

Question 18

EXPLAIN WILMS TUMOR.

Answer 18

-tumor suppressor gene on 11p (p = short arm)
(Chromosome 11) is affected
-causes embryonal tumor of kidney → nephroblastoma

Question 19

GIVE AN EXAMPLE OF A TUMOR REPRESSOR GENE

Answer 19

BRCA1

Question 20

GIVE EXAMPLES OF MUTATOR GENES IN RECESSIVE HOMOZYGOTES

Answer 20

A: heritable nonpolyposis colon cancer
B: chromosome instability syndromes = chromosomal breakage syndromes

-cause multistage tumor formations

Question 21

NAME THE CHARACTERISTICS OF NORMAL IN VITRO CELLS

Answer 21

-euploidy
-specific shape
-contact inhibition
-hayflick limit
-normal antigens

Question 22

NAME THE CHARACTERISTICS OF MALIGNANT IN VITRO CELLS

Answer 22

-accumulation
-immorality
-abnormal antigens
-genome instability
-various genome aberrations
-loss of differentiation

Question 23

WHAT ARE THE THREE TYPES OF GENES WITH POLYMORPHISMS WHICH EFFECT CARCINOGENS?

Answer 23

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

Question 24

WHAT CAUSES A GENOTOXIC EFFECT?

Answer 24

combination of factors such as mutagenic, carcinogenic, teratogenic, allergenic, immunosuppressive

Question 25

CAN EVERY CARCINOGEN BE A MUTAGEN?

Answer 25

no
-any mutagen can be a carcinogen but not vice versa – not all carcinogens can be mutagens

Question 26

WHAT ARE NONGENOTOXIC MUTAGENS?

Answer 26

cause cancer even without the change of DNA’s primary structure = are not mutagenic