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A Study of Genetic Susceptibility to Hodgkin’s Lymphoma in a Cohort of Families. Abi Rousseau. Cheshire and Merseyside Regional Molecular Genetics Laboratory. Cancer of the lymphatic system Broadly subdivided into non-Hodgkin’s and Hodgkin’s Hodgkin’s defined by: Reed-Sternberg cells
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A Study of Genetic Susceptibility to Hodgkin’s Lymphoma in a Cohort of Families Abi Rousseau Cheshire and Merseyside Regional Molecular Genetics Laboratory
Cancer of the lymphatic system Broadly subdivided into non-Hodgkin’s and Hodgkin’s Hodgkin’s defined by: Reed-Sternberg cells Hodgkin cells Lymphoma
Cancer of the lymphatic system Broadly subdivided into non-Hodgkin’s and Hodgkin’s Hodgkin’s defined by: Reed-Sternberg cells Hodgkin cells Lymphoma
Cancer of the lymphatic system Broadly subdivided into non-Hodgkin’s and Hodgkin’s Hodgkin’s defined by: Reed-Sternberg cells Hodgkin cells Lymphoma
Lymphodenopathy Other symptoms: Significant weight loss Itchy skin Recurrent fevers Drenching night sweats Fatigue Increased sensitivity to alcohol Clinical Features
Incidence • 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
Causes • Environmental • 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 • 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 • Viral • 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 • Genetic • Reports of familial HL (Robertson et al, 1987) • 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
Family 1 Family 2 MP HD116 CP HD141.2 SP HD141 EW HD141.1 JP HD105 PL HD115 Family 3 IC KK746.1 JC KK746.2 JC KK746 3 families with multiple cases HL
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 • 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 • OLFM3 • Encodes olfactomedin 3, expressed in ocular tissues, brain, kidney and lung • May play a role in pathogenesis of glaucoma and other ocular disorders • Does an ocular disorder co-segregate with Hodgkin’s in this family? • More clinical information and DNA from further family members required to investigate significance
Family 2 results • 4q28.1 duplication • 18p11.31 duplication
Family 2 - Discussion • 4q28.1 • No genes disrupted • 2 predicted CTCF binding sites • 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?? • Further work required to elucidate targets of the CTCF binding sites
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 • More clinical information and DNA from further family members required to investigate significance
Summary • 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
Liverpool Molecular Genetics David Gokhale Vicky Stinton Roger Mountford Kym Spencer Katrina Smith Liverpool Cytogenetics Anna Topping Una Maye NGRL, Manchester William Ferguson Cancer Immunogenetics Group, Manchester G Malcolm Taylor Adiba Hussain BlueGnome Ltd David Chrimes Sheffield Cytogenetics Simon Webster Acknowledgments
References • Au W.Y. et al. (2004). Hodgkin’s lymphoma in Chinese migrants to British Columbia: a 25 year survey. Annals of Oncology 15: 626-630 • Vianna N.J. et al (1972). Hodgkin’s disease: Cases with features of a community outbreak. Annals of Internal Medicine, 77(2): 169-180 • Küppers R (2009). The biology of hodgkin’s lymphoma. Nature Reviews Cancer 9(1): 15-27 • Robertson S.J. et al (1987. Familial Hodgkin’s Disease. Cancer 59: 1314-1319 • Razis D.V. et al (1959). Familial Hodgkin’s disease: its significance and implications. Annals of Internal Medicine 51: 933-971 • Grufferman S. et al (1977). Hodgkin’s disease in siblings. NEJM 296: 248-250 • Mack T.M. et al (1995). Concordance for Hodgkin’s disease in identical twins suggesting genetic susceptibility to the young-adult form of the disease. NEJM 332: 413-418 • Gokhale D.A. et al (1995). Molecular genetic analysis of a family with a history of Hodgkin’s disease and dyschrondrosteosis. Leukemia 9: 826-833 • Bao L. et al (2007). CTCFBSDB: a CTCF-binding site database for characterisation of vertebrate genomic insulators. Nucleic Acids Research 36: D83-D87 • Goldin L.R. et al (2005). A genome screen of families at high risk for Hodgkin lymphoma: evidence for a susceptibility gene on chromosome 4. Journal of Medical Genetics 42: 595-601 • Joos S. et al (2000). Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Research 60: 549-552 • Torrado M. et al (2002). Optimedin: a novel olfactomedin-related protein that interacts with myocilin. Human Molecular Genetics 11: 1291-1301 • Liang C.L. et al (2000). Transcription of Epstein-Barr virus-encoded nuclear antigen 1 promoter Qp is repressed by transforming growth factor-beta via Smad4 binding element in human BL cells. Virology 277(1): 184-192 • Hirate Y. et al (2006). Canopy1, a novel regulator of FGF signalling around the midbrain-hindbrain boundary in zebrafish. Current Biology 16: 421-427 • Olaru A. et al (2003). Loss of heterozygosity and mutational analyses of the ACTRII gene locus in human colorectal tumors. Laboratory Investigation 83(12): 1867-1871