Pheochromocytomas and paragangliomas (PCC/PGL) are tumors of the adrenal medulla or extra-adrenal ganglia, respectively. Most are benign yet still carry high morbidity and mortality due to excessive catecholamine production leading to hypertension, stroke and even death. Approximately one-fourth of PCC/PGLs are malignant, defined by distant metastases. Over one-third of PCC/PGLs have a mutation in one of ten known susceptibility genes, including VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, NF1, RET, TMEM127 and MAX. Whereas the inherited genetics of this disease and their grouping based on expression profiling and methylation status are well described, somatic mutations and genomic aberrations in PCC/PGL, in particular in relationship to inherited mutations and each other are very poorly understood. The TCGA effort in rare tumors will increase our understanding of the somatic profiles of PCC/PGLs. However, the plans include only 50 tumors, and focus on malignant and/or SDHB mutation positive PCC/PGL, a subset of the known disease spectrum.
In Specific Aim 1, we propose a combination of whole exome (in tumor and germline), low coverage (5x) whole genome sequencing (in tumor) and transcriptome sequencing (RNA Seq in tumor) to characterize 30 PCC/PGLs with a lower risk of malignancy, including VHL mutated, and the CIMP-L/0 group, either sporadic (non-SDHx/VHL) or with germline MAPK and PI3K pathway mutations (e.g. RET/NF1), which will complement the TCGA effort. Data analysis will be done across the combined set of 80 TCGA and Penn PCC/PGLs, as we hypothesize that some somatic genetic mutations and genomic aberrations will be common to all PCC/PGLs, despite their differing malignant potential, or occur in sub-sets crossing inherited mutational status. We will validate our findings in 115 independent PCC/PGLs.
In Specific Aim 2 a, we will determine if distinct patterns of somatic mutations and aberrations are associated with clinically aggressive PCC/PGLs compared to clinically benign PCC/PGLs using 125 samples (80 discoveries, 45 validations). We hypothesize that the pattern of somatic mutations and aberrations will differ in PCC/PGL associated with clinically aggressive disease from clinically benign disease. We will perform an exploratory analysis in Specific Aim 2b to determine if the mutational spectrum differs between PCC/PGLs with different known inherited mutations. These studies will enable us to better understand how mutations in such a broad range of susceptibility genes can lead to the same tumor type, and why the rates of malignant potential vary greatly between inherited mutation groups. We are particularly interested in whether PCC/PGL with different known inherited mutations may have distinct mutational spectra providing insights into the mechanisms promoting tumorigenesis and malignant transformation, which would be relevant for all tumor types. Finally, the results of thi study will allow us to substantially further our understanding of the tumor biology of PCC/PGLs, and identify novel targets for therapeutics for PGL/PCL, which are critically needed.

Public Health Relevance

Pheochromocytomas and paragangliomas (PCC/PGLs) are tumors of the autonomic nervous system, one- quarter of which are malignant. However, even benign tumors have high morbidity due to the secretion of catecholamines and tumor location. Of all tumor types, they have the greatest proportion associated with inherited mutations. Despite our understanding of their inherited genetics, we know very little about somatic genetic and genomic aberrations, which would guide our understanding of tumor biology, and assist in the identification of therapeutics for these tumors. Additionally, because we know what the initiating event (inherited mutation) is for PCC/PGLs, these analyses may provide information to guide our understanding of somatic profiles of genomic and genetic aberrations in more common solid tumors, as it may point to an initiating event in tumors with similar profiles, for which no initiating event has been identified.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA185953-01
Application #
8692202
Study Section
Special Emphasis Panel (ZCA1-SRLB-4 (J1))
Program Officer
Nelson, Stefanie A
Project Start
2014-09-12
Project End
2016-08-31
Budget Start
2014-09-12
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$187,050
Indirect Cost
$70,144
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104