Transcript Fanconi Anemia - University of Kentucky

In Memory of
Brian Alan Frith
Utililzation of Genetics in
Screening for Fanconi
Anemia and Subsequent
Implications for Therapy
Cheryl Vanderford, PA-S
Bettye Hollins, PhD, Advisor
Why am I interested in this topic?
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At the age of seventeen
months, my brother was
diagnosed with
megakaryoblastic leukemia.
He fought a short four month
battle.
In 2003, doctors informed us
that Brian’s cell-line (CHRF288) was being used in
research for Fanconi Anemia.
http://www.affinityonline.net/local/1999-05/mcd-002.asp
Overview
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What is Fanconi Anemia?
Why are FA genes important?
What tests are used to screen for Fanconi
Anemia?
How do you diagnose Fanconi Anemia?
How can you treat Fanconi Anemia?
Implications
What is Fanconi Anemia?
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Fanconi Anemia is an autosomal recessive
disorder.
We all have FA genes.
Known mutations involved: FANCA,
FANCB, FANCC, FANCD1, FANCD2, FANCE,
FANCF, FANCG, FANCI, FANCJ, FANCL, and
FANCM (Kennedy and D’Andrea, 2006).
What is Fanconi Anemia?
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Fanconi Anemia predisposes an individual
to numerous types of cancer, including
acute myeloid leukemia, breast cancer,
squamous cell carcinoma of the head and
neck, and cancers of the gynecological
system, skin, esophagus, liver, and kidney
(Kennedy and D’Andrea, 2006).
Function of FA genes
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DNA repair
Cell cycle control
Oxygen sensitivity
Apoptosis and telomere maintenance
Haemopoiesis
Tischkowitz, M., Hodgson, S. Fanconi anaemia. J. Med. Genet. 2003; 40:1-10.
Fanconi Anemia Pathway: DNA Repair
Mirchandani, K., D’Andrea, A. The fanconi anemia/BRCA pathway: a coordinator of cross-link repair.
Experimental Cell Research. 2006; 312: 2647-2653.
FA Role in Cell Cycle Regulation
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G1
G0
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http://en.wikipedia.org/wiki/Mitosis
Checkpoint exists at G2/M
stage of mitosis to prevent
progression of damaged
DNA.
Mutated FA genes result in
a prolonged G2/M
checkpoint and reduced
efficacy of the DNA repair
mechanism.
Tischkowitz, M., Hodgson, S. Fanconi anaemia. J. Med. Genet. 2003; 40:1-10.
FA Role in Haemopoiesis
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Common presentations of patients with Fanconi
Anemia:
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Anemia
Pancytopenia
Bone marrow hypoplasia
Thrombocytopenia
Gene therapy to target this role of FA genes in
individuals with FA gene mutations.
S/Sx
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Low Birth Weight
http://www.successby6ottawa.ca/lbwfpn/images/pink.jpg
S/Sx
Short stature
http://www.emedicine.com/ped/
images/19911991PED302201A.JPG
This is a three year old boy with Fanconi Anemia.
S/Sx
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Absence of or malformity in hands and arms, for
example the absence of a thumb or the
presence of polydactyly
http://www.fanconi.org/aboutfa/Diagnosis.htm
Tischkowitz, M., Hodgson, S. Fanconi anaemia.
J. Med. Genet. 2003; 40:1-10.
S/Sx
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Presence of only one kidney or of a horseshoe kidney
Horseshoe Kidney
http://www.md.huji.ac.il/mirror/webpath/RENAL004.jpg
S/Sx
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Café-au-lait spots
http://www.dental.mu.edu/oralpath/lesions/cafe/cafe1.JPG
Screening
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DEB test
MMC test
Prenatal screening
Carriers of Fanconi Anemia
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Rapid means of screening population at large
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Blood test
Immunoblotting and immunofluorescence
Subtyping
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Retroviral vectors
Diagnosis
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DEB and MMC tests
Diagnosis typically occurs before the age of
twelve (Fanconi Anemia Research Fund, Inc., 2006).
MMC test is used to diagnose Fanconi Anemia at
the University of Kentucky.
Subtyping via use of retroviruses needs to be
incorporated into standard protocol when
diagnosing a patient with Fanconi Anemia.
Treatment
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Retrovirus mediated
gene transfer
Lentivirus mediated
gene transfer
http://www.kfdunn.com/vector/gene-therapy.gif
Risks of Gene Therapy
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Retrovirus potential to stimulate
oncogenes.
Lentivirus association with arthritis and
encephalitis in goats, leukemia in cattle,
anemia in horses, and immunodeficiency
in cats, cattle, primates, and humans.
Anson, D. The use of retroviral vectors for gene therapy-what are the risks? A review of retroviral
pathogenesis and its relevance to retroviral vector-mediated gene delivery. Genetic Vaccines and
Therapy. 2004; 2(1): 9. (Published online).
Somatic Mosaicism
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Reversal of mutated FA genes has been
successfully accomplished by nature alone.
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How?
Better understanding of nature’s own gene
therapy for Fanconi Anemia may allow us
to someday mimic the same mechanism to
eliminate Fanconi Anemia.
Sensitivity to Treatment
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CHRF-288 is Brian’s cell line.
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Hypermethylation of FANCF
is hypothesized to “be an
early step in sporadic
carcinogenesis”
Recent studies have shown
that the degree of
methylation to FANCF can
indicate the responsiveness
of the individual to a
specific treatment.
Tischkowitz, M., Ameziane, N., Waisfisz, Q., De Winter, J., Harris, R., Taniguchi, T.,
D’Andrea, A., Hodgson, S., Matthew, C., Joenje, H. Bi-allelic silencing of the fanconi anaemia
gene FANCF in acute myeloid leukaemia. Br J Haematol. 2003; 123: 469-471.
Genetic Counseling
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Provide knowledge about:
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http://www.childbirthsolutions.
com/articles/preconception/gen
eticcounseling/Gen-1.jpg
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What Fanconi Anemia is
What symptoms are
associated
Who can be affected
What the disorder means for
the future of the individual
What treatments are available
and their risks and benefits
Importance of screening
other family members at
risk
Is this ethical?
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A genetic disorder that predisposes an individual
to cancer—why not screen the population at
large?
Cost/benefit
Wait until Fanconi Anemia shows symptoms
before finding out you carry mutated FA genes?
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Early intervention
Carriers
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Guilt if not aware of the risk of possibly passing
mutated FA genes to your child.
Summary
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Fanconi Anemia is an autosomal recessive
disorder that predisposes individuals to a variety
of cancers.
Screening techniques exist, such as the DEB and
MMC tests, that should be used to screen the
population at large.
Subtyping of which FA gene(s) is (are) mutated
should become standard protocol with diagnosis.
Gene therapy may someday eliminate Fanconi
Anemia.
References
 Anson, D. The use of retroviral vectors for gene therapy-what are the risks?
A review of retroviral pathogenesis and its relevance to retroviral vectormediated gene delivery. Genetic Vaccines and Therapy. 2004; 2(1): 9.
(Published online).
 Fanconi Anemia Research Fund, Inc., Diagnosis. 2006, Available at:
http://www.fanconi.org/aboutfa/Diagnosis.htm, Accessed on 2006 Nov 26.
 Kennedy, R., D’Andrea, A. DNA repair pathways in clinical practice: lessons
from pediatric cancer susceptibility syndromes. Journal of Clinical Oncology.
2006; 24: 3799-3808.
 Mirchandani, K., D’Andrea, A. The fanconi anemia/BRCA pathway: a
coordinator of cross-link repair. Experimental Cell Research. 2006; 312:
2647-2653.
 Pettigrew, A. Personal Interview. January 2007.
 Tischkowitz, M., Ameziane, N., Waisfisz, Q., De Winter, J., Harris, R.,
Taniguchi, T., D’Andrea, A., Hodgson, S., Matthew, C., Joenje, H. Bi-allelic
silencing of the fanconi anaemia gene FANCF in acute myeloid leukaemia.
Br J Haematol. 2003; 123: 469-471.
 Tischkowitz, M., Hodgson, S. Fanconi anaemia. J. Med. Genet. 2003;
40:1-10.