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Common Biological Basis of Childhood Cancer: Need to focus on all cancers, not just leukemia

Common Biological Basis of Childhood Cancer: Need to focus on all cancers, not just leukemia. Joshua D. Schiffman, MD Associate Professor, Pediatrics & Oncological Sciences Center for Children’s Cancer Research (C3R) November 12, 2012.

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Common Biological Basis of Childhood Cancer: Need to focus on all cancers, not just leukemia

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  1. Common Biological Basis of Childhood Cancer: Need to focus on all cancers, not just leukemia Joshua D. Schiffman, MD Associate Professor, Pediatrics & Oncological Sciences Center for Children’s Cancer Research (C3R) November 12, 2012

  2. What is the burden of cancer in children in the United States? • Overall rate: 165 cases per 1,000,000 children <20 years • ~12,400 children <20 years diagnosed each year • 1 in 315 chance of developing cancer Source: SEER Pediatric Cancer Monograph; SEER Cancer Statistics Review

  3. 1% of all cancers Source: SEER Cancer Statistics Review

  4. Cancer Cell types • Most adult cancers are carcinomas • Epithelial origin • In contrast, most childhood cancers are: • Leukemias/lymphomas • Blastomas→ Embryonal cells • Sarcomas → Mesenchymal origin Source:http://www.ncbi.nlm.nih.gov/About/primer/genetics_cell.html

  5. Aren’t kids just little adults?

  6. “It has been established firmly that, for children, classification of tumors should be based on morphology rather than, as in adults, the primary site of origin.”

  7. Pediatric Cancer Subtypes

  8. Source: SEER Pediatric Cancer Monograph

  9. Source: SEER Pediatric Cancer Monograph

  10. Source: SEER Pediatric Cancer Monograph

  11. Source: SEER Cancer Statistics Review

  12. Male to female ratio of childhood cancer rates Source: Gurney et al, 2005

  13. Hereditary Cancer Risk in Pediatric Oncology Follow-up Clinic • 370 survivors/families over 2 years, screened for family history, demographics, and tumor characteristics • 29% (n=109) identified as candidates for further cancer genetics evaluation • Family history early onset or related malignancy (61%) • Cancer strongly associated with hereditary cancer (18%) • Medical history suggesting genetic diagnosis (16%) Knapke et al. Pediatr Blood Cancer (2011)

  14. Pediatric cancers that merit genetics evaluation • Retinoblastoma (RB1) • Bilateral Wilms Tumor (WT1) • Adrenocortical carcinoma (TP53) • Choroid Plexus Tumor (TP53) • Rhabdomyosarcoma < 3 yo (TP53) • Osteosarcoma < 5-10 yo (TP53) • Medullary thyroid cancer (RET) • Atypical teratoid and malignant rhabdoid tumor (SMARCB1/INI1/SNF5) • Hepatoblastoma (APC) • GIST(SDHA,-B,-C,-D) • Pheochromocytoma / paraganglioma (VHL, NF1, RET, SDHA,-B,-C,-D,-AF2) • Retinal/cerebellar hemangioblastoma (VHL) • Endolymphatic sac tumors (VHL) • Optic pathway tumor (NF1) • Acoustic or vestibular schwannomas (NF2) • Basal Cell Carcinoma / Medulloblastoma (PTCH) • Bilateral Neuroblastoma (ALK, PHOX2B)

  15. Hallmarks of Cancer Hanahan & Weinberg. Cell. (2011)

  16. Acute Childhood Leukemia • Most common pediatric malignancy • 3,250 new diagnoses/yr in United States • Relapsed leukemia leading cause of mortality in pediatric cancer Source: SEER Pediatric Cancer Monograph

  17. Translocations in Acute Lymphoblastic Leukemia (ALL) Source: Greaves, 2002

  18. Cytogenetic Subtypes of Pediatric ALL (B and T-cell) Mullighan. J Clin Invest. (2012)

  19. Genome-Wide Copy Number:FFPE Bone Marrow Aspirate Clots Precursor B-cell ALL, N=60 = Gain = Loss Blood (ASH 2009);114:1589, Blood (ASH 2010);116;273 & 275

  20. Mullighan. J Clin Invest. (2012)

  21. Recurrent genetic lesions in Acute Myeloid Leukemia (AML) Rubnitz and Inaba. Br J Haematol. (2012)

  22. Rubnitz and Inaba. Br J Haematol. (2012)

  23. Classification of Embryonal Childhood Brain Tumors Taylor et al. ACTA Neuropathol. (2011)

  24. Taylor et al. ACTA Neuropathol. (2011)

  25. Taxonomy of soft tissue sarcoma Taylor et al. Nat Rev Cancer. (2011)

  26. Another way to slice the (genomic) pie • Balanced translocation-associated sarcoma • Genome stable • Complex genotype-karyotype sarcoma • Genome unstable

  27. Another way to slice the (genomic) pie Bone Sarcoma: BCOR-CCNB3 Pierron et al. Nat Genet. (2012) Rushton and López-Terrada. Cancer Biomark. (2010) Taylor et al. Nat Rev Cancer. (2011)

  28. Another way to slice the (genomic) pie Taylor et al. Nat Rev Cancer. (2011)

  29. Racial and Clinical Disparity in Ewing’s Sarcoma Incidence

  30. Neuroblastoma: Embryonal tumor Rushton and López-Terrada. Cancer Biomark. (2010)

  31. Hepatoblastoma (HBL): another Embryonal Tumor

  32. Classical Cytogenetics and HBL • Numerical aberrations • Trisomy 2, 8, 20 • Structural aberrations • Translocations @1q12, 1q21 • Duplications of 1q • Loss of materials on reciprocal chromosomes

  33. Hallmarks of Cancer Hanahan & Weinberg. Cell. (2011)

  34. Summary • Distinct genomic and molecular pathways to childhood cancer • May still have underlying common cancer pathways (Hanahan & Weinberg) • Need to consider the above when designing I4C research questions • Discussion!

  35. Thank you! Joshua.Schiffman@hci.utah.edu

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