David WilsonPediatric Hematology-Oncology

Adrenocortical tumors in childhood

Previewing themes in the Cancer Biology course

The major steroidogenic organs derive from a common pool of progenitors

Organization of the mammalian adrenal gland

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.

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

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 featuresdue to excess glucocorticoids

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.

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

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.

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.

Rosie

Disruption of the HPG axis leads to sex steroidogenic tumor formation

GATA

Two markers of gonadal differentiation, GATA4 and LHR, are expressed in the neoplastic

adrenocortical cells of the ferret

GATA4 LHR

“We thank Rosie Wilson for technical assistance.”

Hair loss reflects ectopic sex steroid production by the ferret adrenal

Baldness is seasonal

Shift to long day photoperiod causes an increase in plasma LH levels in ferrets

No OVX induced increase in LH

Adrenocortical neoplasia in various species

GDX-induced adrenocortical neoplasia in mice

Ectopic expression of gonadal markers in the neoplastic adrenocortical tissue

An overlooked model of tissue type switching

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

Conclusions of the linkage analysis

• GDX-induced adrenocortical neoplasia is a complex trait influenced by multiple genetic loci.

• Analysis revealed one major locus for tumorigenesis

on chromosome 8, modulated by epistasis with another locus on chromosome 18.

• The genes responsible have not been identified.

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.

Prevalence of adrenocortical neoplasms in children

girls

boys

case 1

case 2

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?

Too much signaling can be a bad thing

Role of signaling pathways in tumorigenesis

Dan LinkBob Heuckeroth

TP53 R337H mutation and childhood adrenocortical tumors in Brazil

TP53 R337H mutation and childhood adrenocortical tumors in Brazil

Germline and somatic mutations leading to cancer

What genetic factors impact tumorigenesis in children vs. adults?

Paul GoodfellowTodd Druley

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

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

WNT/-catenin signaling and the regulation of stem cell proliferation/differentiation using Drosophila models

Craig Micchelli

Epigenetic alterations at the IGF2 locus are common in adrenocortical carcinoma

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

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.

Evidence supporting two conceptual models of adrenocortical neoplasia

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

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.

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

New therapies for the treatment of cancer

Nancy Bartlett

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

Gata4 haploinsufficiency attenuates GDX-induced adrenocortical neoplasia in B6D2F1 mice

Reduced adrenocortical tumor size inGata4 haploinsufficient mice

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