Download Abigail Rousseau

A Study of Genetic Susceptibility
to Hodgkin’s Lymphoma in a
Cohort of Families
Abi Rousseau
Cheshire and Merseyside Regional
Molecular Genetics Laboratory
Lymphoma
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Cancer of the
lymphatic system
Broadly subdivided
into non-Hodgkin’s
and Hodgkin’s
Hodgkin’s defined by:
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Reed-Sternberg cells
Hodgkin cells
Lymphoma
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Cancer of the
lymphatic system
Broadly subdivided
into non-Hodgkin’s
and Hodgkin’s
Hodgkin’s defined by:
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Reed-Sternberg cells
Hodgkin cells
Lymphoma
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
Cancer of the
lymphatic system
Broadly subdivided
into non-Hodgkin’s
and Hodgkin’s
Hodgkin’s defined by:
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Reed-Sternberg cells
Hodgkin cells
Clinical Features
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Lymphodenopathy
Other symptoms:
Significant weight loss
 Itchy skin
 Recurrent fevers
 Drenching night sweats
 Fatigue
 Increased sensitivity to alcohol
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Incidence
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Rare – accounts for 5% of all cancers diagnosed in UK
Cancer Research UK figures for 2006:
1611 new cases – incidence 2.7/100,000
 Bimodal age distribution
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Causes
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Environmental
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Developed countries show higher incidence than developing
countries
Study of incidence trends among Chinese immigrants to British
Columbia supports an environmental influence (Au et al, 2004)
Impact of environmental risk factors such as smoking and diet
– weak and inconsistent evidence
Clustering
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31 cases connected by common contacts in Albany, New York
(Vianna et al, 1971 & 1972)
Lacked control group and results not replicated in similar
studies
Causes continued
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Viral
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Epstein-Barr Virus (EBV) infection in ~50% of cases
Localised to HRS cells
HRS cells arise from B cells that have acquired disadvantageous
mutations – rescued from apoptosis by EBV infection
3 viral proteins expressed: EBNA1, LMP1 and LMP2A
Causes continued
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Genetic
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Reports of familial HL (Robertson et al, 1987)
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Risk of HL higher in individuals with a family history of the
condition (Razis et al, 1959)
Risk of developing HL higher in gender concordant siblings
(Grufferman et al, 1977)
Increased risk in monozygotic twins (Mack et al, 1995)
HL co-occurring with congenital genetic disorders, e.g. LWD
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3 families with multiple cases
Family 1
Family 2
MP
HD116
CP
HD141.2
SP
HD141
EW
HD141.1
JP
HD105
Family 3
IC
KK746.1
JC
KK746.2
HL
JC
KK746
PL
HD115
Aims of this study

Analyse affected members of each family for
copy number variation using oligo arrayCGH
BlueGnome Cytochip Oligo 4x44K and 2x105K
 4x44K – 350Kb genome wide backbone
 2x105K – 150Kb genome wide backbone

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Investigate any shared regions of copy number
variation for potential candidate genes or
regulatory elements for Hodgkin’s lymphoma
susceptibility
Family 1 results – 1p21.2 deletion

Disrupts 3’ end of OLFM3
Family 1 - Discussion
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OLFM3
Encodes olfactomedin 3, expressed in ocular tissues,
brain, kidney and lung
 May play a role in pathogenesis of glaucoma and
other ocular disorders

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Does an ocular disorder co-segregate with
Hodgkin’s in this family?
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More clinical information and DNA from further
family members required to investigate significance
Family 2 results
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4q28.1 duplication
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18p11.31 duplication
Family 2 - Discussion
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4q28.1
No genes disrupted
 2 predicted CTCF binding sites

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18p11.31
1 predicted CTCF binding site
 TGIF – transforming growth interacting factor

Represses transcription of EBNA1 (essential for
replication of EBV genome)
 EBV- related genetic susceptibility??
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Further work required to elucidate targets of the
CTCF binding sites
Family 3 results – 7q36.3 deletion
Discussion – Family 3

CNPY1
Interacts with FGFR1 and ACTRII
 FGFR1 upregulated in various cancers
 Reduction of canopy1 would lead to downregulation
of FGFR1
 ACTRII loss of function mutations – colorectal
cancer

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More clinical information and DNA from
further family members required to investigate
significance
Summary
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HL is rare and familial HL accounts for only a
small proportion of cases
Familial HL may be genetic, viral, environmental or
a combination
Hodgkin’s likely to be heterogeneous
In each family disruption of a gene or CTCF
binding site has been identified
Findings need to be confirmed by another method
Further studies required
Acknowledgments
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Liverpool Molecular
Genetics
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David Gokhale
Vicky Stinton
Roger Mountford
Kym Spencer
Katrina Smith
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Anna Topping
Una Maye
G Malcolm Taylor
Adiba Hussain
BlueGnome Ltd
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William Ferguson
Cancer Immunogenetics
Group, Manchester

Liverpool Cytogenetics
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NGRL, Manchester
David Chrimes
Sheffield Cytogenetics

Simon Webster
References
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