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A Study of Genetic Susceptibility to Hodgkin’s Lymphoma in a Cohort of Families

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

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  1. A Study of Genetic Susceptibility to Hodgkin’s Lymphoma in a Cohort of Families Abi Rousseau Cheshire and Merseyside Regional Molecular Genetics Laboratory

  2. Cancer of the lymphatic system Broadly subdivided into non-Hodgkin’s and Hodgkin’s Hodgkin’s defined by: Reed-Sternberg cells Hodgkin cells Lymphoma

  3. Cancer of the lymphatic system Broadly subdivided into non-Hodgkin’s and Hodgkin’s Hodgkin’s defined by: Reed-Sternberg cells Hodgkin cells Lymphoma

  4. Cancer of the lymphatic system Broadly subdivided into non-Hodgkin’s and Hodgkin’s Hodgkin’s defined by: Reed-Sternberg cells Hodgkin cells Lymphoma

  5. Lymphodenopathy Other symptoms: Significant weight loss Itchy skin Recurrent fevers Drenching night sweats Fatigue Increased sensitivity to alcohol Clinical Features

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. Family 1 results – 1p21.2 deletion • Disrupts 3’ end of OLFM3

  13. 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

  14. Family 2 results • 4q28.1 duplication • 18p11.31 duplication

  15. 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

  16. Family 3 results – 7q36.3 deletion

  17. 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

  18. 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

  19. 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

  20. 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

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