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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.

Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development