Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1

BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma. MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed. RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype. CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.

Measuring energy spectra of TeV gamma-ray emission from the Cygnus region of our galaxy with Milagro

High energy gamma rays can provide fundamental clues to the origins of cosmic rays. In this thesis, TeV gamma-ray emission from the Cygnus region is studied. Previously the Milagro experiment detected five TeV gamma-ray sources in this region and a significant excess of TeV gamma rays whose origin is still unclear. To better understand the diffuse excess the separation of sources and diffuse emission is studied using the latest and most sensitive data set of the Milagro experiment. In addition, a newly developed technique is applied that allows the energy spectrum of the TeV gamma rays to be reconstructed using Milagro data. No conclusive statement can be made about the spectrum of the diffuse emission from the Cygnus region because of its low significance of 2.2 σ above the background in the studied data sample. The entire Cygnus region emission is best fit with a power law with a spectral index of α=2.40 (68% confidence interval: 1.35-2.92) and a exponential cutoff energy of 31.6 TeV (10.0-251.2 TeV). In the case of a simple power law assumption without a cutoff energy the best fit yields a spectral index of α=2.97 (68% confidence interval: 2.83-3.10). Neither of these best fits are in good agreement with the data. The best spectral fit to the TeV emission from MGRO J2019+37, the brightest source in the Cygnus region, yields a spectral index of α=2.30 (68% confidence interval: 1.40-2.70) with a cutoff energy of 50.1 TeV (68% confidence interval: 17.8-251.2 TeV) and a spectral index of α=2.75 (68% confidence interval: 2.65-2.85) when no exponential cutoff energy is assumed. According to the present analysis, MGRO J2019+37 contributes 25% to the differential flux from the entire Cygnus at 15 TeV.