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

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Presentation on theme: "A Study of Genetic Susceptibility to Hodgkin’s Lymphoma in a Cohort of Families Cheshire and Merseyside Regional Molecular Genetics Laboratory Abi Rousseau."— Presentation transcript:

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

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

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

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

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

6 Incidence Rare – accounts for 5% of all cancers diagnosed in UK Rare – accounts for 5% of all cancers diagnosed in UK Cancer Research UK figures for 2006: Cancer Research UK figures for 2006: 1611 new cases – incidence 2.7/100, new cases – incidence 2.7/100,000 Bimodal age distribution Bimodal age distribution

7 Causes Environmental Environmental Developed countries show higher incidence than developing countries 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) 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 Impact of environmental risk factors such as smoking and diet – weak and inconsistent evidence Clustering Clustering 31 cases connected by common contacts in Albany, New York (Vianna et al, 1971 & 1972) 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 Lacked control group and results not replicated in similar studies

8 Causes continued Viral Viral Epstein-Barr Virus (EBV) infection in ~50% of cases Epstein-Barr Virus (EBV) infection in ~50% of cases Localised to HRS cells Localised to HRS cells HRS cells arise from B cells that have acquired disadvantageous mutations – rescued from apoptosis by EBV infection 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 3 viral proteins expressed: EBNA1, LMP1 and LMP2A

9 Causes continued Genetic Genetic Reports of familial HL (Robertson et al, 1987) 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 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) Risk of developing HL higher in gender concordant siblings (Grufferman et al, 1977) Increased risk in monozygotic twins (Mack et al, 1995) Increased risk in monozygotic twins (Mack et al, 1995) HL co-occurring with congenital genetic disorders, e.g. LWD HL co-occurring with congenital genetic disorders, e.g. LWD

10 3 families with multiple cases MP HD116 PL HD115 Family 2 JP HD105 JC KK746 IC KK746.1 JC KK746.2 Family 3 HL Family 1 SP HD141 CP HD141.2 EW HD141.1

11 Aims of this study Analyse affected members of each family for copy number variation using oligo arrayCGH Analyse affected members of each family for copy number variation using oligo arrayCGH BlueGnome Cytochip Oligo 4x44K and 2x105K BlueGnome Cytochip Oligo 4x44K and 2x105K 4x44K – 350Kb genome wide backbone 4x44K – 350Kb genome wide backbone 2x105K – 150Kb 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 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 Disrupts 3’ end of OLFM3

13 Family 1 - Discussion OLFM3 OLFM3 Encodes olfactomedin 3, expressed in ocular tissues, brain, kidney and lung Encodes olfactomedin 3, expressed in ocular tissues, brain, kidney and lung May play a role in pathogenesis of glaucoma and other ocular disorders May play a role in pathogenesis of glaucoma and other ocular disorders Does an ocular disorder co-segregate with Hodgkin’s in this family? 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 More clinical information and DNA from further family members required to investigate significance

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

15 Family 2 - Discussion 4q28.1 4q28.1 No genes disrupted No genes disrupted 2 predicted CTCF binding sites 2 predicted CTCF binding sites 18p p predicted CTCF binding site 1 predicted CTCF binding site TGIF – transforming growth interacting factor TGIF – transforming growth interacting factor Represses transcription of EBNA1 (essential for replication of EBV genome) Represses transcription of EBNA1 (essential for replication of EBV genome) EBV- related genetic susceptibility?? EBV- related genetic susceptibility?? Further work required to elucidate targets of the CTCF binding sites Further work required to elucidate targets of the CTCF binding sites

16 Family 3 results – 7q36.3 deletion

17 Discussion – Family 3 CNPY1 CNPY1 Interacts with FGFR1 and ACTRII Interacts with FGFR1 and ACTRII FGFR1 upregulated in various cancers FGFR1 upregulated in various cancers Reduction of canopy1 would lead to downregulation of FGFR1 Reduction of canopy1 would lead to downregulation of FGFR1 ACTRII loss of function mutations – colorectal cancer ACTRII loss of function mutations – colorectal cancer More clinical information and DNA from further family members required to investigate significance 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 HL is rare and familial HL accounts for only a small proportion of cases Familial HL may be genetic, viral, environmental or a combination Familial HL may be genetic, viral, environmental or a combination Hodgkin’s likely to be heterogeneous Hodgkin’s likely to be heterogeneous In each family disruption of a gene or CTCF binding site has been identified In each family disruption of a gene or CTCF binding site has been identified Findings need to be confirmed by another method Findings need to be confirmed by another method Further studies required Further studies required

19 Acknowledgments Liverpool Molecular Genetics Liverpool Molecular Genetics David Gokhale David Gokhale Vicky Stinton Vicky Stinton Roger Mountford Roger Mountford Kym Spencer Kym Spencer Katrina Smith Katrina Smith Liverpool Cytogenetics Liverpool Cytogenetics Anna Topping Anna Topping Una Maye Una Maye NGRL, Manchester William Ferguson Cancer Immunogenetics Group, Manchester G Malcolm Taylor Adiba Hussain BlueGnome Ltd David Chrimes Sheffield Cytogenetics Simon Webster

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: Au W.Y. et al. (2004). Hodgkin’s lymphoma in Chinese migrants to British Columbia: a 25 year survey. Annals of Oncology 15: Vianna N.J. et al (1972). Hodgkin’s disease: Cases with features of a community outbreak. Annals of Internal Medicine, 77(2): Vianna N.J. et al (1972). Hodgkin’s disease: Cases with features of a community outbreak. Annals of Internal Medicine, 77(2): Küppers R (2009). The biology of hodgkin’s lymphoma. Nature Reviews Cancer 9(1): Küppers R (2009). The biology of hodgkin’s lymphoma. Nature Reviews Cancer 9(1): Robertson S.J. et al (1987. Familial Hodgkin’s Disease. Cancer 59: Robertson S.J. et al (1987. Familial Hodgkin’s Disease. Cancer 59: Razis D.V. et al (1959). Familial Hodgkin’s disease: its significance and implications. Annals of Internal Medicine 51: Razis D.V. et al (1959). Familial Hodgkin’s disease: its significance and implications. Annals of Internal Medicine 51: Grufferman S. et al (1977). Hodgkin’s disease in siblings. NEJM 296: Grufferman S. et al (1977). Hodgkin’s disease in siblings. NEJM 296: 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: 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: Gokhale D.A. et al (1995). Molecular genetic analysis of a family with a history of Hodgkin’s disease and dyschrondrosteosis. Leukemia 9: Gokhale D.A. et al (1995). Molecular genetic analysis of a family with a history of Hodgkin’s disease and dyschrondrosteosis. Leukemia 9: Bao L. et al (2007). CTCFBSDB: a CTCF-binding site database for characterisation of vertebrate genomic insulators. Nucleic Acids Research 36: D83-D87 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: 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: Joos S. et al (2000). Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Research 60: Joos S. et al (2000). Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Research 60: Torrado M. et al (2002). Optimedin: a novel olfactomedin-related protein that interacts with myocilin. Human Molecular Genetics 11: Torrado M. et al (2002). Optimedin: a novel olfactomedin-related protein that interacts with myocilin. Human Molecular Genetics 11: 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): 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): Hirate Y. et al (2006). Canopy1, a novel regulator of FGF signalling around the midbrain-hindbrain boundary in zebrafish. Current Biology 16: Hirate Y. et al (2006). Canopy1, a novel regulator of FGF signalling around the midbrain-hindbrain boundary in zebrafish. Current Biology 16: Olaru A. et al (2003). Loss of heterozygosity and mutational analyses of the ACTRII gene locus in human colorectal tumors. Laboratory Investigation 83(12): Olaru A. et al (2003). Loss of heterozygosity and mutational analyses of the ACTRII gene locus in human colorectal tumors. Laboratory Investigation 83(12):


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