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Kym Spencer Liverpool Women’s Hospital

High resolution mapping of the X chromosome pseudoautosomal region in two siblings with Hodgkin Lymphoma and Leri-Weill Dyschondrosteosis. Kym Spencer Liverpool Women’s Hospital. Reed-Sternberg cells & Hodgkin cells. Clinical Features. Incidence. Cancer Research UK figures for 2004:

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Kym Spencer Liverpool Women’s Hospital

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  1. High resolution mapping of the X chromosome pseudoautosomal region in two siblings with Hodgkin Lymphoma and Leri-Weill Dyschondrosteosis Kym Spencer Liverpool Women’s Hospital

  2. Reed-Sternberg cells & Hodgkin cells

  3. Clinical Features

  4. Incidence • Cancer Research UK figures for 2004: • 1,519 new cases - 0.5% of all cancers diagnosed. • Incidence of 2.4/100,000 individuals • 2.7/100,000 males • 2.1/100,000 females • Bimodal age of incidence • 15-40 years • >55 years

  5. A genetic cause of HL • Several familial cases of HL reported. • Risk of HL higher in individuals with a family history of the condition. • Higher in siblings. • Highest in gender concordant siblings. • Combination of inherited susceptibility with shared environment? • Male predominance of HL • Horwitz & Weirnik (1999 & 2007) suggest pseudoautosomal link due to recombination mechanism of pseudoautosomal regions.

  6. Leri-Weill Dyschondrosteosis (LWD) Hodgkin Lymphoma (HL) Family L

  7. LWD - Madelung Deformity

  8. p PAR1 PAR2 p q q X Y Pseudoautosomal Regions

  9. Map of PAR1

  10. Leri-Weill Dyschondrosteosis (LWD) Hodgkin Lymphoma (HL) 2 (GW) Family L

  11. Methods • MLPA for SHOX copy number using P018B MLPA kit from MRC Holland • Fluorescent microsatellite analysis • Addition of custom probes into existing MLPA kit • SNP analysis • Microarray analysis

  12. SHOX MLPA

  13. SHOX MLPA

  14. PR55 B α, β, γ or δ PR65 α or β PR61 B’ α, β, γ, δ or ε A PR72/PR130 B’’ or PR48 C PR93/SG2NA or PP2A B’’’ PR110/striatin α or β PPP2R3B • PPP2R3B encodes PR48. • B subunit of the PP2A holoenzyme. • Involved in cell cycle regulation - binds to Cdc6 in mammalian cells and restricts DNA replication. • PP2A is a cell cycle regulator and tumour suppressor. • Consists of A, B and C subunits. • B subunits confer substrate specificity.

  15. Microsatellite Analysis

  16. Microsatellite Analysis

  17. Custom MLPA

  18. Custom MLPA

  19. SNP Analysis

  20. SNP Analysis

  21. CTCF

  22. CTCF • CTCF (CCCTC - binding factor) • Transcriptional regulator through • chromatin remodelling • epigenetic modification • control of transcriptional machinery • insulating promoter interaction with enhancers /silencers • Can bind to a diverse array of DNA sequences using different combinations of its 11 zinc finger domains CTCF zinc finger domain

  23. More SNP analysis

  24. Microarray analysis

  25. Conclusions • Deletion of this CTCF binding site could affect regulation of its target gene. • Could the target be PPP2R3B? • Deregulation of PPP2R3B could result in deregulation of the cell cycle • Another B subunit of PP2A is present at 4p16.1, a region linked to HL in a study by Goldin et al. (2006). • The CTCF binding site could regulate another, more distant gene. • Further studies required.

  26. Map of PAR1

  27. Conclusions • Deletion of this CTCF binding site could affect regulation of its target gene. • Could the target be PPP2R3B? • Deregulation of PPP2R3B could result in deregulation of the cell cycle • Another B subunit of PP2A is present at 4p16.1, a region linked to HL in a study by Goldin et al. (2006). • The CTCF binding site could regulate another, more distant gene. • Further studies required.

  28. Acknowledgements Thanks to the following people for their help: • David Gokhale • Vicky Stinton • G Malcolm Taylor • Ciaron McAnulty • Frances White • Una Maye • Julie Sibbring • Emma McCarthy • Roger Mountford • Andrew Wallace • Simon Thomas • Kevin Baker • Gareth Evans • John Radford • All at Liverpool Molecular Genetics Laboratory for their help, advice, interest and patience. 

  29. References • Bao L, Zhou M & Cui Y (2007), “CTCFBSDB: a CTCF-binding site database for characterisation of vertebrate genomic insulators”, Nucleic Acids Res, 36: D83-D87 • Belin V, Cusin V, Viot G, Girlich D, Toutain A, Moncla A, Vekemans M, Le Merrer M, Munnich A & Cormier-Daire V (1998), “SHOX mutations in dyschondrosteosis (Leri-Weill Syndrome)”, Nat Genet, 19: 67-69 • Benito-Sanz S, Thomas NS, Huber C, Gorbenko del Blanco D, Aza-Carmona M, Crolla JA, Maloney V, Rappold G, Argente J, Campos-Barros A, Cormier-Daire V & Heath KE (2005), “A Novel Class of Pseudoautosomal Region 1 Deletions Downstream of SHOX Is Associated with Leri-Weill Dyschondrosteosis”, Am J Hum Genet, 77: 533-544 • Benito-Sanz S, Gorbenko del Blanco D, Huber C, Thomas NS, Aza-Carmona M, Bunyan D, Maloney V, Argente J, Cormier-Daire V, Campos-Barros A & Heath KE (2006), “Characterisation of SHOX Deletions in Leri-Weill Dyschondrosteosis (LWD) Reveals Genetic Heterogeneity and No Recombination Hotspots”, Am J Hum Genet, 79: 409-414 • Filippova GN (2008), “Genetics and Epigenetics of the Multifunctional Protein CTCF”, Curr Top Dev Biol, 80: 337-360 • Fukami M, Kato F, Tajima T, Yokoya S & Ogata T (2006), “Transactivation Function of an ~800-bp Evolutionarily Conserved Sequence at the SHOX 3’ Region: Implication for the Downstream Enhancer”, Am J Hum Genet, 78: 167-170 • Gokhale DA, Evans DG, Crowther D, Woll P, Watson CJ, Dearden SP, Fergusson WD, Stevens RF & Taylor GM (1995), “Molecular genetic analysis of a family with a history of Hodgkin’s Disease and Dyschondrosteosis”, Leukemia, 9: 826-833 • Goldin LR, McMaster ML, Ter-Minassian M, Saddlemire S, Harmsen B, Lalonde G & Tucker MA (2006), “A genome screen of families at high risk for Hodgkin lymphoma: evidence for a susceptibility locus on chromosome 4”, J Med Genet, 42: 595-601 • Hoppe RT, Mauch PT, Armitage JO, Diehl V & Weiss LM (2007), “Hodgkin Lymphoma, 2nd Edition” • Horwitz M &.Wiernik PH (1999), “Pseudoautosomal Linkage of Hodgkin Disease”, Am J Hum Genet, 65: 1413–1422. • Horwitz MS & Mealiffe ME (2007), “Further evidence for a pseudoautosomal gene for Hodgkin’s Lymphoma: Reply to ‘The familial risk of Hodgkin’s Lymphoma ranks among the highest in the Swedish Family-Cancer Database’ by Altieri A and Hemminki K”, Leukemia, 21: 351 • Janssens V & Goris J (2001), “Protein Phosphatase 2A: a highly regulated family of serine/threonine pgosphatases implicated in growth and signalling”, Biochem J, 353: 417-439 • Mack TM, Cozen W, Shibata DK, Weiss LM, Nathwani BN, Hernandez AM, Taylor CR, Hamilton AS, Deapen DM, Rappaport EB (1995), “Concordance For Hodgkin’s Disease In Identical Twins Suggesting Genetic Susceptibility To The Young-Adult Form Of The Disease”, N Engl J Med, 332: 413-418 • Shears DJ, Endris V, Gokhale DA, Dearden SP, Radford JA, Rappold GA & Taylor GM (2003), “Pseudoautosomal Linkage of Familial Hodgkin’s Lymphoma: Molecular Analysis of a Unique Family with Leri-Weill Dyschondrosteosis and Hodgkin’s Lymphoma”, B J Haematol, 121: 375-380 • Yan Z, Fedorov S A, Mumby M C & Williams R S (2000), “PR48, a Novel Regulatory Subunit of Protein Phosphatase 2A, Interacts with Cdc6 and Modulates DNA Replication in Human Cells”, Mol Cell Biol, 20: 1021-1029

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