NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation

Jean-Philippe Brosseau, Chung-Ping Liao, Yong Wang, Vijay Ramani, Travis Vandergriff, Michelle Lee, Amisha Patel, Kiyoshi Ariizumi and Lu Q. Le ()
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Jean-Philippe Brosseau: University of Texas Southwestern Medical Center
Chung-Ping Liao: University of Texas Southwestern Medical Center
Yong Wang: University of Texas Southwestern Medical Center
Vijay Ramani: University of Texas Southwestern Medical Center
Travis Vandergriff: University of Texas Southwestern Medical Center
Michelle Lee: University of Texas Southwestern Medical Center
Amisha Patel: University of Texas Southwestern Medical Center
Kiyoshi Ariizumi: University of Texas Southwestern Medical Center
Lu Q. Le: University of Texas Southwestern Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Neurofibromatosis type 1 (NF1) is an autosomal genetic disorder. Patients with NF1 are associated with 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 NF1- and non-NF1-related tumors, we discover that an Nf1+/− 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.

Date: 2018
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DOI: 10.1038/s41467-018-07452-y

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