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Fusion Genes in Cancer

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Fusion Genes in Cancer Wednesday, June 27th Outline: Transcription Fusion genes Examples of fusion genes in cancer Summary and conclusions Chromosomes and Genes In ... – PowerPoint PPT presentation

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Title: Fusion Genes in Cancer


1
Fusion Genes in Cancer Wednesday,
June 27th
2
Outline Transcription Fusion genes Examples
of fusion genes in cancer Summary and conclusions
3
Chromosomes and Genes
  • In humans, every somatic cell has 23 pairs of
  • chromosomes for a total of 46 chromosomes
  • in its nucleus (except mature RBC)
  • Each chromosome is made up of genes,
  • and gene expression is a highly regulated
  • process
  • Chromatin regulation (epigenetics)
  • Transcriptional regulation
  • Different cell types have different gene
  • expression patterns, and this results in
  • cellular phenotype
  • (skin cell vs. intestinal cell)

Lodish et al. (2000) Molecular Cell Biology
4
Gene Expression
Beads Histone proteins String DNA
Histone proteins are positively charged DNA is
negatively charged Acetyl groups neutralize the
positively charged histone proteins
Histone Acetyltransferase (HAT) adds acetyl
group to histone protein Histone Deacetylase
(HDAC) - Removes acetyl group from histone protein
5
Gene Transcription
Coactivators
Corepressors
DNA RNA PROTEIN
6
Fusions genes in cancer
The Cancer Genome Project website lists at least
326 genes that have been shown to form gene
translocations in cancer
http//www.sanger.ac.uk/genetics/CGP/Census/
7
Fusion genes
A fusion gene is a hybrid gene formed from two
previously separate genes. (Wikipedia)
ftp//ftp.sanger.ac.uk/pub4/theses/kong/chapter4.p
df
8
Fusion genes result in aberrant gene expression
  • Gene 2 expression and transcriptional
  • regulation is now dictated by the Gene 1
  • promoter and all its regulatory units
  • If Gene 1 has a highly active promoter
  • region, Gene 2 will be overexpressed

9
Fusion genes
Genes X and Y
DNA Is lost
WT
DNA Is gained
TEL
Promoter
TEL
Y
WT
21
X
Y
AML
X
Y
TEL
AML
AML
TEL
Promoter
TEL-AML1 (ALL) t(12  21)
DNA is neither gained nor lost
10
Fusion gene detection cancer diagnostics
  • Fusion genes are commonly found in all 4 types
    of leukemia CML, AML,
  • CLL, and ALL

CML chronic myelogenous leukemia CLL chronic
lymphocytic leukemia ALL acute lymphoblastic
leukemia AML acute myelogenous leukemia
  • Leukemia cells can be collected by taking a
    blood sample from the patient
  • Fusion genes are less commonly found in solid
    tumors, and these tumor
  • cells can be collected by invasive surgery and
    biopsy of the tumor
  • New and more sensitive detection
    methods are making fusion gene
  • detection in solid tumors more feasible
  • Fusion genes are detected in patient samples
    using Fluorescent In Situ
  • Hybridization (FISH) or Polymerase Chain
    Reaction (PCR)
  • New methods for future? high throughput
    sequencing

11
Fusion genes are detected in patient samples
using Fluorescent In Situ Hybridization (FISH)
Hofer et al. (2009) Cancer Research
Deletion
Insertion
Wild Type
12
Fusion genes are detected in patient samples
using Polymerase Chain Reaction (RT-PCR)
  • Extract mRNA from patient tumor sample, use
    reverse transcriptase to convert
  • mRNA into cDNA
  • Use fusion gene specific primers to amplify
    cDNA detect and quantify fusion
  • gene presence in the patient tumor sample

13
Fusion gene detection cancer diagnostics
  • Fusion genes can serve as prognosis indicators,
    meaning if the patient
  • harbors that certain gene fusion in a specific
    type of cancer the presence
  • of the fusion can be used as a predictor of
    cancer aggressiveness
  • However, certain fusion genes may indicate poor
    prognosis, but in some
  • cases the presence of the fusion gene is
    actually a good thing for the patient
  • because certain drugs have been developed that
    specifically inhibit the fusion
  • gene

t(821) AML1/ETO Favorable prognosis t(1517)
PML/RAR Favorable prognosis t(922) BCR/ABL
Unfavorable prognosis
Hrusak et al. (2002) Leukemia
14
Examples of fusion genes in cancer
Bcr-Abl (CML and ALL)
liquid cancer (leukemia)
PML-RARa (AML)
TMPRSS2-ERG (prostate cancer)
Solid tumors
EML-ALK (lung cancer)
15
Fusion genes in cancer Bcr-Abl (CML and ALL)
t(922)
  • Poster child for fusion genes in cancer due to
    the development of the
  • drug Imatinib

Philadelphia chromosome
Prevalence of Bcr-Abl in leukemia patients
CML (Adults) 90 (Children) CML rare
in children
ALL (Adults) 25-30 (Children) 2-10
http//www.cancer.gov/cancertopics/pdq/treatment/a
dultALL/Patient/page1
16
Fusion genes in cancer Bcr-Abl (CML and ALL)
BCR Breakpoint Cluster Region- contains
important N-terminal region of Bcr-Abl fusion
protein that is essential for dimerization and
Bcr-Abl activation
Abl nonreceptor tyrosine kinase- The Bcr-Abl
fusion protein is a constitutively Active
nonreceptor tryrosine kinase that is overactive
in leukemia cell cytoplasm
http//www.medscape.org/viewarticle/416483_2
17
Fusion genes in cancer Bcr-Abl (CML and ALL)
Oncogenic properties of Bcr-Abl lending to the
development of leukemia
http//www.medscape.org/viewarticle/416483_2
18
Fusion genes in cancer Bcr-Abl (CML and ALL)
Treatment of CML- first line therapy is Bcr-Abl
tyrosine kinase inhibitors
First generation Imatinib (Gleevec) Small
molecule TK inhibitor, binds to and inhibits ATP
binding pocket of Bcr-Abl kinase (can be used in
combination with standard chemotherapy)
Problem drug resistance, mutations in Bcr-Abl
that render the kinase no longer Inhibited by
Imatinib. Solution develop new inhibitors
similar to Imatinib, but better
Second generation Dasatinib, Nilotinib
Small molecule TK inhibitor, inhibits Bcr-Abl
with higher affinity than Imatinib
19
Fusion genes in cancer PML-RARa (AML)
t(1517)
AML (Adults) 12.5 (Children) 15
Prevalence of PML-RAR a
http//flipper.diff.org/app/items/info/482
Bhatia et al. (2012) Mediterr J Hematol Infect
Dis
20
Fusion genes in cancer PML-RARa (AML)
  • The RARa gene encodes for a transcription factor
    known as the Retinoic
  • Acid Receptor. This receptor is important in
    activating RBC development
  • and maturation via binding to target genes and
    inducing their expression.
  • Thus, RAR is essential for the induction of RBC
    differentiation and proper
  • RBC development
  • Upon DNA binding, the PML-RARa fusion protein
    causes RAR to recruit
  • corepressors to its target genes, inhibiting
    their transcription activation.
  • This results in the rapid accumulation of
    numerous immature RBCs and the
  • depletion of normal mature RBCs

Corepressors
PML-RAR recruits corepressors
Transcription of differentiation genes
Ncor
RA response element
21
Fusion genes in cancer PML-RARa (AML)
22
Fusion genes in cancer TMPRSS2-ERG (prostate
cancer)
  • The TMPRSS2-ERG fusion gene is present in
    approximately 50 of prostate
  • cancer patients

Chromosome 21
Tomlins et al. (2009) European Urology
23
Fusion genes in cancer TMPRSS2-ERG (prostate
cancer)
  • The TMPRSS2-ERG gene fusion results in AR
    induced overexpression of the
  • transcription factor ERG in prostate tumor cells
  • The prognostic value of TMPRSS2-ERG fusion genes
    in prostate cancer remains
  • controversial. There are currently no drugs
    targeting this fusion gene used in the
  • clinic to treat prostate cancer. It was
    discovered at U of M in 2005

St. John et al. (2012) - J Cancer Sci Ther - In
Press
24
Summary and Conclusions
ALL
Some encouraging proof to not give up on the
cure for cancer
Better detection, new drugs, and better use of
classical drugs
25
Summary and Conclusions
  • Selective therapies that target gene fusions in
    cancer have been successful in
  • some cases and have increased overall survival
    rates for many patients
  • who harbor these fusion genes, especially in
    leukemia
  • The search for new selective therapies will most
    likely continue to prove
  • beneficial in many cases, especially when
    treatment is combined with
  • classical chemotherapy drugs (e.g. Methotrexate)
  • New and more sensitive diagnostic techniques
    will be invaluable to future
  • detection methods. This will hopefully yield
    more information in the detection
  • of fusion genes in patients samples, especially
    in solid tumors

26
Knowledge is power and knowing is half the
battle! (Mr. Joe, G.I.)
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