Abstract
Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder. Patients with NF1 have mono-allelic loss of the tumor suppressor gene NF1 in their germline, which predisposes them to develop a wide array of benign lesions. Intriguingly, recent sequencing efforts revealed that the NF1 gene is frequently mutated in multiple malignant tumors not typically associated with NF1 patients, suggesting that NF1 heterozygosity is refractory to at least some cancer types. In two orthogonal mouse models representing tumors associated with NF1 (neurofibroma and malignant peripheral nerve sheath tumor) and non-NF1-related tumors (papilloma and squamous cell carcinoma), we serendipitously discover that an NF1heterozygosity microenvironment accelerates the formation of benign tumors but impairs further progression to malignancy. Analysis of benign and malignant tumors commonly associated with NF1 patients, as well as those with high NF1 gene mutation frequency, reveals an antagonistic role for NF1 heterozygosity in tumor initiation and malignant transformation and helps to reconciliate the role of the NF1 gene in both NF1 and non-NF1 patient contexts. Our novel framework to study the role of NF1 in tumorigenesis integrates the concept of NF1 as a tumor predisposition gene and we have uncovered mechanisms underlying the impairment of cancer progression by tumor microenvironment cells harboring tumor suppressor genes in the haploinsufficient state, such as NF1 heterozygosity, may translate into novel therapeutic strategies.
Highlights
Necklace sign as a marker of pulmonary disease severity in tuberous sclerosis complex DJ Pithadia2,1, AM Treichel1, V Gopalakrishnan2, J Moss2 and T Darling1 1 Dermatology, USUHS, Bethesda, Maryland, United States and 2 NHLBI, NIH, Bethesda, Maryland, United States Acrochordons are prevalent in the general population and may signify insulin resistance
Initial cyst burden, determined computationally using chest CT scans, was higher in patients with the necklace sign (13.2%, n1⁄416) versus those without (7.21%, n1⁄443) (p1⁄40.044). These results suggest that the necklace sign may aid in identification of tuberous sclerosis complex (TSC) patients at risk for developing more severe LAM earlier in life and that interindividual variability in mechanistic target of rapamycin (mTOR) signaling may influence TSC-associated tumorigenesis
Emotional triggers to pain in a patient with cutaneous leiomyomas associated with Reed syndrome Y Farid and EN Mostow Northeast Ohio Medical University, Rootstown, Ohio, United States A 39 y/o man presented with hundreds of painful, flesh-colored
Summary
Necklace sign as a marker of pulmonary disease severity in tuberous sclerosis complex DJ Pithadia2,1, AM Treichel1, V Gopalakrishnan2, J Moss2 and T Darling1 1 Dermatology, USUHS, Bethesda, Maryland, United States and 2 NHLBI, NIH, Bethesda, Maryland, United States Acrochordons are prevalent in the general population and may signify insulin resistance. Multiple acrochordons on the neck, known as the necklace sign, have been observed in tuberous sclerosis complex (TSC), a genetic disorder characterized by tumors in multiple organs.
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