Renal
angiomyolipoma is a kidney
tumor in the perivascular epithelioid (
PEComa) family that is common in patients with
Tuberous Sclerosis Complex (
TSC) and
Lymphangioleiomyomatosis (
LAM) but occurs rarely sporadically. Though histologically benign, renal
angiomyolipoma can cause life-threatening
hemorrhage and
kidney failure. Both
angiomyolipoma and
LAM have mutations in TSC2 or TSC1. However, the frequency and contribution of other somatic events in
tumor development is unknown. We performed whole exome sequencing in 32 resected
tumor samples (
n = 30 angiomyolipoma, n = 2
LAM) from 15 subjects, including three with
TSC. Two germline and 22 somatic inactivating mutations in TSC2 were identified, and one germline TSC1 mutation. Twenty of 32 (62%) samples showed copy neutral LOH (CN-LOH) in TSC2 or TSC1 with at least 8 different LOH regions, and 30 of 32 (94%) had biallelic loss of either TSC2 or TSC1. Whole exome sequencing identified a median of 4 somatic non-synonymous coding region mutations (other than in TSC2/TSC1), a mutation rate lower than nearly all other
cancer types. Three genes with mutations were known
cancer associated genes (BAP1, ARHGAP35 and SPEN), but they were mutated in a single sample each, and were missense variants with uncertain functional effects. Analysis of sixteen
angiomyolipomas from a
TSC subject showed both second hit point mutations and CN-LOH in TSC2, many of which were distinct, indicating that they were of independent clonal origin. However, three
tumors had two shared mutations in addition to private somatic mutations, suggesting a branching evolutionary pattern of
tumor development following initiating loss of TSC2. Our results indicate that TSC2 and less commonly TSC1 alterations are the primary essential driver event in
angiomyolipoma/
LAM, whereas other somatic mutations are rare and likely do not contribute to
tumor development.