title: Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma.
abstract: The presence of sarcomatoid features in clear cell renal cell carcinoma (ccRCC) confers a poor prognosis and is of unknown pathogenesis. We performed exome sequencing of matched normal-carcinomatous-sarcomatoid specimens from 21 subjects. Two tumors had hypermutation consistent with mismatch repair deficiency. In the remainder, sarcomatoid and carcinomatous elements shared 42% of somatic single-nucleotide variants (SSNVs). Sarcomatoid elements had a higher overall SSNV burden (mean 90 vs. 63 SSNVs, P = 4.0 × 10(-4)), increased frequency of nonsynonymous SSNVs in Pan-Cancer genes (mean 1.4 vs. 0.26, P = 0.002), and increased frequency of loss of heterozygosity (LOH) across the genome (median 913 vs. 460 Mb in LOH, P < 0.05), with significant recurrent LOH on chromosomes 1p, 9, 10, 14, 17p, 18, and 22. The most frequent SSNVs shared by carcinomatous and sarcomatoid elements were in known ccRCC genes including von Hippel-Lindau tumor suppressor (VHL), polybromo 1 (PBRM1), SET domain containing 2 (SETD2), phosphatase and tensin homolog (PTEN). Most interestingly, sarcomatoid elements acquired biallelic tumor protein p53 (TP53) mutations in 32% of tumors (P = 5.47 × 10(-17)); TP53 mutations were absent in carcinomatous elements in nonhypermutated tumors and rare in previously studied ccRCCs. Mutations in known cancer drivers AT-rich interaction domain 1A (ARID1A) and BRCA1 associated protein 1 (BAP1) were significantly mutated in sarcomatoid elements and were mutually exclusive with TP53 and each other. These findings provide evidence that sarcomatoid elements arise from dedifferentiation of carcinomatous ccRCCs and implicate specific genes in this process. These findings have implications for the treatment of patients with these poor-prognosis cancers.
authors: Department of Genetics, Yale School of Medicine, New Haven, CT 06511; Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06511;
authors: Mark
authors: M
authors: Bi
authors: Department of Genetics, Yale School of Medicine, New Haven, CT 06511; Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06511;
authors: Siming
authors: S
authors: Zhao
authors: Department of Pathology, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095;
authors: Jonathan W
authors: JW
authors: Said
authors: Translational Surgical Pathology Division, National Cancer Institute, Bethesda, MD 20850;
authors: Maria J
authors: MJ
authors: Merino
authors: Department of Pathology, Yale School of Medicine, New Haven, CT 06511;
authors: Adebowale J
authors: AJ
authors: Adeniran
authors: Department of Urology, Yale School of Medicine, New Haven, CT 06511;
authors: Zuoquan
authors: Z
authors: Xie
authors: Department of Urology, Yale School of Medicine, New Haven, CT 06511;
authors: Cayce B
authors: CB
authors: Nawaf
authors: Department of Dermatology, Yale School of Medicine, New Haven, CT 06511;
authors: Jaehyuk
authors: J
authors: Choi
authors: Department of Urology, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095;
authors: Arie S
authors: AS
authors: Belldegrun
authors: Department of Urology, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095;
authors: Allan J
authors: AJ
authors: Pantuck
authors: Department of Medicine, Division of Oncology, Yale School of Medicine, New Haven, CT 06511.
authors: Harriet M
authors: HM
authors: Kluger
authors: Department of Genetics, Yale School of Medicine, New Haven, CT 06511;
authors: Kaya
authors: K
authors: Bilgüvar
authors: Department of Genetics, Yale School of Medicine, New Haven, CT 06511; Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06511; richard.lifton@yale.edu brian.shuch@yale.edu.
authors: Richard P
authors: RP
authors: Lifton
authors: Department of Pathology, University of California, Los Angeles School of Medicine, Los Angeles, CA 90095; richard.lifton@yale.edu brian.shuch@yale.edu.
authors: Brian
authors: B
authors: Shuch
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D054337:Cell Dedifferentiation / Q000235:genetics; D053843:DNA Mismatch Repair / Q000235:genetics; D004268:DNA-Binding Proteins; D059472:Exome; D005260:Female; D016158:Genes, p53; D006801:Humans; D007680:Kidney Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D009857:Oncogenes; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics
chemical_list: C112476:ARID1A protein, human; C400134:BAP1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase
keywords: dedifferentiation; kidney cancer; p53; sarcomatoid; transformation