A subgroup of lymphangioleiomyomatosis with no TSC mutations identified

Lymphangioleiomyomatosis (LAM) is a rare disease characterized by infiltration of the lungs by neoplastic cells with smooth muscle and melanocytic differentiation. Dissemination of LAM cells cause progressive cystic destruction of the lungs, leading to respiratory insufficiency and death. LAM occurs either sporadically (S‐LAM) or in association with tuberous sclerosis (TSC). TSC is caused by mutations in the genes coding for tuberin ( TSC2 ) and hamartin ( TSC1 ), which dimerize and inhibit the mTOR pathway of cell growth and proliferation. LAM was thus thought to follow a two‐hit model leading to complete inactivation of TSC2 (or TSC1 ) in LAM cells. In this study, we sequenced TSC2 and TSC1 genes in lung samples from 10 S‐LAM patients. Laser capture microdissection was used to isolate LAM cell clusters, and deep sequencing was performed to detect mutations with greater sensitivity than was previously possible. We identified TSC2 mutations in 8 out of the 10 cases of S‐LAM. Four of these cases bore 2‐hit TSC2 inactivating mutations. Each of the other 4 cases, however, displayed a single mutation which was restricted to a small fraction of LAM cells. More importantly, no TSC2 or TSC1 mutations were identified in 2 of our 10 S‐LAM cases. Our findings are consistent with the existence of a form of S‐LAM unassociated with mutations in TSC2 or TSC1 and that of LAM cells lacking TSC2 mutations. Funded by NHLBI. KB is ALA Dalsemer Scholar