title: Whole Exome Sequencing Identifies TSC1/TSC2 Biallelic Loss as the Primary and Sufficient Driver Event for Renal Angiomyolipoma Development.
abstract: 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.
authors: Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Krinio
authors: K
authors: Giannikou
authors: Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Izabela A
authors: IA
authors: Malinowska
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Trevor J
authors: TJ
authors: Pugh
authors: Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Rachel
authors: 0000-0002-6718-142X
authors: R
authors: Yan
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Yuen-Yi
authors: YY
authors: Tseng
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Coyin
authors: C
authors: Oh
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Jaegil
authors: J
authors: Kim
authors: Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Magdalena E
authors: ME
authors: Tyburczy
authors: Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Yvonne
authors: Y
authors: Chekaluk
authors: Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Yang
authors: Y
authors: Liu
authors: Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Nicola
authors: N
authors: Alesi
authors: Tufts New England Medical Center, Boston, Massachusetts, United States of America.
authors: Geraldine A
authors: GA
authors: Finlay
authors: Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors: Chin-Lee
authors: CL
authors: Wu
authors: Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors: Sabina
authors: S
authors: Signoretti
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Matthew
authors: M
authors: Meyerson
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Gad
authors: G
authors: Getz
authors: Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Jesse S
authors: 0000-0002-6795-6336
authors: JS
authors: Boehm
authors: Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: Elizabeth P
authors: 0000-0001-7978-6699
authors: EP
authors: Henske
authors: Division of Pulmonary and Critical Care Medicine and of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.|Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America.
authors: David J
authors: DJ
authors: Kwiatkowski
mesh_terms: D000328:Adult; D018207:Angiomyolipoma / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity / Q000235:genetics; D018192:Lymphangioleiomyomatosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins