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David Wilson Pediatric Hematology-Oncology

David Wilson Pediatric Hematology-Oncology

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David Wilson Pediatric Hematology-Oncology

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  1. Adrenocortical tumors in childhood Previewing themes in the Cancer Biology course David Wilson Pediatric Hematology-Oncology

  2. The major steroidogenic organs derive from a common pool of progenitors

  3. Organization of the mammalian adrenal gland

  4. Phenotypic plasticity of adrenal steroidogenic cells Cell proliferation occurs in the subcapsular region. Cells in different zones have a common origin; their phenotype depends on environmental cues.

  5. Chimeric adrenal gland derived from injection ofGFP-tagged mouse ES cells into a blastocyst

  6. Clinical case 1 CT scan demonstated a L adrenal tumor, which was completely resected. Pathology consistent with adrenocortical adenoma. Patient is now a healthy teen. • 2-year-old boy with irritability, weight gain, and acne. • Endocrine evaluation reveals high serum cortisol and DHEA-S in the setting of a low serum ACTH. Cushingoid features due to excess glucocorticoids

  7. Clinical case 2 Previously healthy, athletic teenager. 3 mo of unexplained weight gain (particularly facial and abdominal fat). New onset acne. High blood pressure. Endocrine evaluation reveals high serum cortisol and low serum ACTH.

  8. The left adrenal was resected; histopathology showed a large adrenocortical carcinoma.

  9. Adrenocortical neoplasms in humans • Adenoma. 5% of people over the age of 50 have at least one small, non-functioning benign tumor (“incidentaloma”). Benign tumors that secrete hormones are uncommon. • Adrenocortical carcinoma (ACC). These malignant tumors are rare (1 case/million per yr) but carry a poor prognosis because of their propensity to spread before detection. These are usually functional. • The factors that account for the frequent occurrence of adenomas and the low rate of ACC have been the subject of intense investigation over the past decade.

  10. Clinical case 3 • 3-year-old previously healthy female. • 1-2 month history of hair loss. • 10-15% weight loss. • Changes in external genitalia suggestive of inappropriate sex steroid production. • Imaging reveals adrenal gland enlargement.

  11. Rosie

  12. Disruption of the HPG axis leads to sex steroidogenic tumor formation

  13. Two markers of gonadal differentiation, GATA4 and LHR, are expressed in the neoplastic adrenocortical cells of the ferret GATA GATA4 LHR “We thank Rosie Wilson for technical assistance.”

  14. Hair loss reflects ectopic sex steroid production by the ferret adrenal Baldness is seasonal

  15. Shift to long day photoperiod causes an increase in plasma LH levels in ferrets No OVX induced increase in LH

  16. Adrenocorticalneoplasia in various species

  17. GDX-induced adrenocortical neoplasia in mice

  18. Ectopic expression of gonadal markers in the neoplastic adrenocortical tissue An overlooked model of tissue type switching

  19. Genome wide linkage analysis of crosses between DBA2/J and C57Bl/6 mice C57Bl/6 x DBA2/J F1 (B6D2F1) mice, like the parental DBA2/J strain, develop post-GDX tumors with near complete penetrance by 6 mo after surgery, suggesting that tumor predisposition is a dominant trait. Tumor Formation Bernichtein, S. et al. Endocrinology 2008;149:651-661

  20. Conclusions of the linkage analysis GDX-induced adrenocortical neoplasia is a complex trait influenced by multiple genetic loci. Analysis revealed one major locus for tumorigenesison chromosome 8, modulated by epistasis with another locus on chromosome 18. The genes responsible have not been identified.

  21. Summary • Adrenocortical neoplasms are common in humans; range from adenomas to carcinomas. • Functional adrenocortical neoplasms are very common in certain gonadectomized animals, such as goats, ferrets, hamsters, and mice. • GDX-induced adrenocortical tumors express gonadal markers (e.g., GATA4 & LHR) and may produce ectopic sex steroids that cause significant morbidity.

  22. Prevalence of adrenocortical neoplasms in children case 1 girls boys case 2

  23. Prevalence of adrenocortical neoplasms in humans parallels that of brain tumors David Gutmann Josh Rubin What genetic, developmental, and anatomic factors impact tumorigenesis in children vs. adults?

  24. Too much signaling can be a bad thing Bob Heuckeroth Dan Link Role of signaling pathways in tumorigenesis

  25. TP53 R337H mutation and childhood adrenocortical tumors in Brazil

  26. TP53 R337H mutation and childhood adrenocortical tumors in Brazil

  27. Germline and somatic mutations leading to cancer Paul Goodfellow Todd Druley What genetic factors impact tumorigenesis in children vs. adults?

  28. A multipotential stem/progenitor cell is posited to give rise to both corticoid- and sex steroid-producing cells

  29. WNT/b-catenin signaling has been implicated in adrenocortical stem cell maintenance & in tumorigenesis

  30. WNT/b-catenin signaling and the regulation of stem cell proliferation/differentiation using Drosophila models Craig Micchelli

  31. Epigenetic alterations at the IGF2 locus are common in adrenocortical carcinoma

  32. Epigenetic alterations at the IGF2 locus drive stem cell proliferation and inhibit differentiation/apoptosis

  33. Feinberg’s epigenetic progenitor model of cancer • Epigenetic changes precede and heighten risk of cancer in response to oncogenic mutations. • Step 1 is an epigenetic disruption of progenitor cells within an organ or tissue, altered by abnormal regulation of tumor-progenitor genes. This leads to a population of cells ready to cause new growth. • Step 2 involves an initiating mutation within the population of epigenetically disrupted progenitor cells at the earliest stages of new cell growth, such as the rearrangement of chromosomes in the development of leukemia. This mutation normally has been considered the first step in cancer development. • Step 3 is genetic and epigenetic instability, which leads to increased tumor evolution.

  34. Evidence supporting two conceptual models of adrenocorticalneoplasia

  35. Do clonal preexisting epigenetic changes impact the ability of stem cells to respond to LH?

  36. Studies of the emergence of metastatic cells Bill Harbour Studies of ocular melanoma using copy number variation analysis, mRNA and miRNA profiling, and epigenetic profiling to study tumor propagating cell populations within the primary tumor.

  37. ACC is not readily cured by chemotherapy, so novel treatments are needed

  38. New therapies for the treatment of cancer Nancy Bartlett

  39. A multipotential stem/progenitor cell is posited to give rise to both corticoid- and sex steroid-producing cells

  40. Gata4 haploinsufficiency attenuates GDX-induced adrenocortical neoplasia in B6D2F1 mice

  41. Reduced adrenocortical tumor size inGata4 haploinsufficient mice

  42. Relative expression of sex steroidogeneic markers in WT vs.Gata4+/- adrenals