title: A shower of second hit events as the cause of multifocal renal cell carcinoma in tuberous sclerosis complex.
abstract: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by seizures and tumor formation in multiple organs, mainly in the brain, skin, kidney, lung and heart. Renal cell carcinoma (RCC) occurs in ∼3% of TSC patients, and typically develops at age <50. Here we describe genetic findings in two TSC patients with multiple renal tumors, each of whom had the germline mutation TSC2 p.R905Q. The first (female) TSC patient had a left followed by a right nephrectomy at ages 24 and 27. Both kidneys showed multifocal TSC-associated papillary RCC (PRCC). Targeted, next-generation sequencing (NGS) analysis of TSC2 in five tumors (four from the left kidney, one from the right) showed loss of heterozygosity in one tumor, and four different TSC2 point mutations (p.E1351*, p.R1032*, p.R1713H, c.4178_4179delCT) in the other four samples. Only one of the 11 other tumors available from this patient had one of the TSC2 second hit mutations identified. Whole-exome analysis of the five tumors identified a very small number of additional mutated genes, with an average of 3.4 nonsilent coding, somatic mutations per tumor, none of which were seen in >1 tumor. The second (male) TSC patient had bilateral partial nephrectomies (both at age 36), with similar findings of multifocal PRCC. NGS analysis of TSC2 in two of these tumors identified a second hit mutation c.2355+1G>T in one sample that was not seen in other tumors. In conclusion, we report the first detailed genetic analysis of RCCs in TSC patients. Molecular studies indicate that tumors developed independently due to various second hit events, suggesting that these patients experienced a 'shower' of second hit mutations in TSC2 during kidney development leading to this severe phenotype.
authors.affiliation: Division of Pulmonary Medicine and of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Magdalena E
authors.initials: ME
authors.lastname: Tyburczy
authors.affiliation: Children's Memorial Health Institute of Warsaw, Warsaw, Poland.
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Jozwiak
authors.affiliation: Division of Pulmonary Medicine and of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Izabela A
authors.initials: IA
authors.lastname: Malinowska
authors.affiliation: Division of Pulmonary Medicine and of Genetics, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Chekaluk
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.affiliation: Pathology Department, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Chin-Lee
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Division of Genomic Medicine, Helen Diller Family Comprehensive Cancer Center and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Seepo
authors.affiliation: Children's Memorial Health Institute of Warsaw, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Dzik
authors.affiliation: Children's Memorial Health Institute of Warsaw, Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kotulska
authors.affiliation: Division of Pulmonary Medicine and of Genetics, Brigham and Women's Hospital, Boston, MA, USA, dk@rics.bwh.harvard.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Kwiatkowski
mesh_terms: D000293:Adolescent; D000328:Adult; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007668:Kidney / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D014402:Tuberous Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins