chromosomal abnormalities and tumors seminar no 524, course: cells and tissues development
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Chromosomal abnormalities Chromosomal abnormalities and tumorsand tumors
SeminarSeminar
No 524, course: Cells and tissues developmentNo 524, course: Cells and tissues development
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Key words: chromosomal aberrations, translocation, amplification,double minutes,
HSR (homogenously staining regions), genotoxicity, DSB (double strand breaks), fused gene, LOH („loss of heterozygosity“), LOI („loss of imprinting“), chronic myelogenous leukemia (CML), Burkitt lymphoma (BL), retinoblastoma (RB), Wilms tumour (WT), syndromes with increase chromosome breakage = chromosomal instability syndromes: Bloom syndrome (BS), Fanconi anemia (FA), Ataxia teleangiectasia (AT), Xeroderma pigmentosum (XP), Nijmegen breakage syndrome (NBS), syndromes of prematury ageing: Werner syndrome, Cockayne syndrome
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Structural chromosomal aberrations (CHA) =
result of unrepaired or misrepaired DNA damage =
early biological effect of genotoxicity
Late biological effect of genotoxicity = tumors
Primary event leading to CHA origin are double-strand breaks (DSB)
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Primary changes connected with initiation of malignant process:
Rearrangement changing position of protooncogenes:
- abnormal activity of product
- abnormal gene expression
rearrangement only in tumor cells (chronic myelogenous
leukemia, Burkitt lymphoma)
Deletion of tumor suppressor genes
in tumor cells or constitutional aberrations (heterozygosity)
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Primary changes connected with initiation of malignant process:
Translocations – 2 types of translocations
1. Translocations leading to fused genes (genes with function in cell
division regulation or differentiation)
Ph1 chromosome in chronic myelogenous leukemia (CML)
= reciprocal translocation 46,XX or XY,t(9;22)(q34;q11)
protooncogen abl is transfered from 9q to 22q near the gene bcr fused
gene bcr/abl abnormal product=chimeric protein with
increased tyrosinkinase activity
Ph1 in CML good prognosis
during blastic crisis - other chromosome changes
In B-ALL (acute lymphoblastic leukemia) other site of break in bcr
Ph1 in ALL = bad prognosis
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Wysis katalog 1996/97
Fused gene brc/abldetected by FISH method in interphase cell
t 9/22
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2. Translocation of protooncogenes to the position, where they
are abnormally stimulated to transcription
Burkitt lymphoma (BL) –B lymphocytes
t(8;14)(q24;q32) also in other lymphomas
protooncogen myc transfered from 8q to 14q – near genes for heavy
chains of immunoglobulins abnormal stimulation of gene activity
abnormal amount of normal product
Other translocations: t(8;22) or t (2;8) – to neighbourhood of light
chains of immunoglobulins
T-lympho malignancies - breaks near genes for T-cells receptors
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Translocation produces premalignant clone – probably other genetic
changes (mutations, epigenetic changes..) are necessary for full
malignancy
This changes (translocations, inversions
involving protooncogenes) are present only in
malignant or premalignant cells, it is not
constitutional change (present in all cells) !!!
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Primary events:
Deletions of tumor suppressor genes
Retinoblastoma (Rb) – eye cancer of children
heritable type (familiar or „de novo“ origin) - AD (with reduced penetrance)
sporadic type – nonheritable
• familiar Rb – 1st step - germinal mutation or deletion in all cells of body =
heterozygote (constitutional abnormality)
2nd step : mutation in one cell of retina = loss of heterozygosity (LOH)
del(13)(q141-142)
• sporadic Rb – both mutations in one cell of retina
heterozygosity for mutation or deletion = predisposition to tumor
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Retinoblastoma
heritable
sporadic
heterozygote
Mutation of second allele in one somatic cell = loss of heterozygosity
Mutation of both alleles consecutively in one somatic cell
→
→ →
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Interstitial deletion 11p
Wilms tumor = nephroblastoma
WT1 locus on 11p13 mutation or deletion
isolated or a part of syndrome WAGR
association (Wilms, aniridia, urogenital
anomaly, mental retardation)
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Deletion of one allele of tumor suppressor gene
can be constitutional aberration, present in alll
cells of body - heterozygote
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Gain of material
Amplification of oncogenes:
„double minutes“ = amplified circular oncogenes (in solidtumors)
HSR (homogenously stainin regions) = amplification and recombination of oncogenes into
chromosome tandemly or into different sites
Amplification especially in solid tumors
Targeted therapy: Herceptin =monoclonal antibody against ERBB2 oncogene (=Her2/Neu= tyrosin-kinase receptor) in women with breast cancer and amplification of oncogene
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Oncogene Her-2/neu amplification in breast cancer – FISH method
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Tetraploid nucleus with amplification of Her2/neu
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Trisomy and tetrasomy in cells of breast tumor
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Chromosome loss in cells of breast tumor
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Secondary changes – consequences of malignancy (genome instability in tumor cell):
Losses or gains of whole chromosomes, structural chromosomal rearrangements
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UroVysionBladder Cancer FISH Probe Panel CEP 3 (spektrum red) CEP 7 (spektrum green) CEP 17 (spektrum aqua) LSI p16 (spektrum gold) = 9p21- tumor suppressor gene (p16)
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Chromosomal changes in bladder cancer cells – FISH method
(a) normal cell
(c) Homozygous 9p21 loss
(b) Trisomy 7
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Karyotype of breast cancer cells from tissue culture – G-bands
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Karyotype of breast cancer cells from tissue culture – G-bands
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Chromosomal changes after radiotherapy, chemotherapy:
Breaks and rearrangements – detected in peripheral lymphocytes
Aberrations after irradiation - chromosome: dicentrics, tricentrics, chromosome breaks (on both chromatids), ring chromosomes
Aberrations after chemicals: – chromatid: chromatid breaks, chromatid exchanges
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Dicentric chromosome + difragment
Aberrations after irradiation
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Dicentric chromosome
Aberrations after irradiation
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Ring chromosomes and difragments
Aberrations after irradiation
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Aberrations after bleomycine (BLM) in vitro
BLM was added for the last 5 hours of cultivation
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Chromatid breaks
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Chromatid break
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Multiple breaks
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Chromatid exchange
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Chromatid exchangeand breaks
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Chromatid exchangeand breaks
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Irradiated mouse cells in tissue culture
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Questions:• Explain why translocations in somatic cells sometimes lead to cancer? • What is Ph 1 chromosome? • Can you describe cytogenetic manifestation of oncogene amplification?• Which chromosomal aberrations are primary events in malignancy?• Explain mechanisms of activation of protooncogene to oncogene. • Explain mechanisms of inactivation of alleles of tumor supressor gene. • Describe origin of heritable and sporadic retinoblastoma.• State expamples of malignancy connected with deletion of tumor suppressor gene.• Describe chromosomal abnormalities secondary to malignant process. • Describe translocation leading to origin of fused gene.• Describe translocation leading to abnormally increased synthesis of product.
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• What is the cause of Li Fraumeni syndrome?
• Describe chromosomal aberrations followed in peripheral lymphocytes of patients after chemotherapy, radiotherapy.
• What is the role of viruses in tumor origin?
• Describe difference between oncogene of DNA tumor viruses and RNA tumor viruses.