The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

Davis, Caleb; Wang, Min; Yang, Lixing; Cherniack, Andrew D.; Shen, Hui; Buhay, Christian; Kang, Hyojin; Kim, Sang Cheol; Fahey, Catherine C.; Hacker, Kathryn E.; Bhanot, Gyan; Gordenin, Dmitry A.; Chu, Andy; Gunaratne, Preethi H.; Biehl, Michael; Seth, Sahil; Kaipparettu, Benny Abraham; Bristow, Christopher A.; Donehower, Lawrence A.; Wallen, Eric; Smith, Angela; Tickoo, Satish K.; Tamboli, Pheroze; Reuter, Victor E.; Schmidt, Laura S.; Hsieh, James J.; Choueiri, Toni K.; Hakimi, A. Ari; Creighton, Chad J.; Morgan, Margaret; Wheeler, David A.; Gibbs, Richard A.; Signoretti, Sabina; Robertson, A. Gordon; Henske, Elizabeth P.; Kwiatkowski, David J.; Ricketts, Christopher J.; Linehan, W. Marston; Seiler, Michael; Rathmell, W. Kimryn; Laird, Peter W.; Shuch, Brian; Muzny, Donna M.; Chao, Hsu; Dahdouli, Mike; Liu, Xi; Kakkar, Nipun; Reid, Jeffrey G.; Downs, Brittany; Drummond, Jennifer; Morton, Donna; Doddapaneni, Harshavardhan; Lewis, Lora; English, Adam C.; Meng, Qingchang; Kovar, Christie; Wang, Qiaoyan; Hale, Walker; Hawes, Alicia; Kalra, Dipak; Walker, Kimberly; Murray, Bradley A.; Sougnez, Carrie; Saksena, Gordon; Carter, Scott L.; Schumacher, Steven E.; Tabak, Barbara; Zack, Travis I.; Getz, Gad; Beroukhim, Rameen; Gabriel, Stacey; Meyerson, Matthew; Ally, Adrian; Balasundaram, Miruna; Birol, İnanç; Brooks, Denise; Butterfield, Yaron S.N.; Chuah, Eric; Clarke, Amanda; Dhalla, Noreen; Guin, Ranabir; Holt, Robert A.; Kasaian, Katayoon; Lee, Darlene; Li, Haiyan I.; Lim, Emilia L.; Ma, Yussanne; Mayo, Michael; Moore, Richard A.; Mungall, Andrew J.; Schein, Jacqueline E.; Sipahimalani, Payal; Tam, Angela; Thiessen, Nina; Wong, Tina; Jones, Steven J.M.; Marra, Marco A.; Auman, J. Todd; Tan, Donghui; Meng, Shaowu; Jones, Corbin D.; Hoadley, Katherine A.; Mieczkowski, Piotr A.; Mose, Lisle E.; Stuart, Joshua M.; Roach, Jeffrey; Veluvolu, Umadevi; Wilkerson, Matthew D.; Waring, Scot; Buda, Elizabeth; Wu, Junyuan; Bodenheimer, Tom; Hoyle, Alan P.; Simons, Janae V.; Soloway, Mathew G.; Balu, Saianand; Parker, Joel S.; Hayes, D. Neil; Perou, Charles M.; Weisenberger, Daniel J.; Bootwalla, Moiz S.; Triche, Tim; Lai, Phillip H.; Berg, David J. Van Den; Baylin, Stephen B.; Chen, Ken; Coarfa, Cristian; Noble, Michael S.; DiCara, Daniel; Zhang, Hailei; Cho, Juok; Heiman, David I.; Gehlenborg, Nils; Voet, Doug; Lin, Pei; Frazer, Scott; Stojanov, Petar; Liu, Yingchun; Zou, Lihua; Kim, Jaegil; Lawrence, Michael S.; Chin, Lynda; Protopopov, Alexei; Song, Xingzhi; Zhang, Jianhua; Pantazi, Angeliki; Hadjipanayis, Angela; Lee, Eunjung; Luquette, Lovelace J.; Lee, Semin; Parfenov, Michael; Santoso, Netty; Seidman, Jonathan G.; Xu, Andrew Wei; Kucherlapati, Raju; Park, Peter J.; Lee, Junehawk; Roberts, Steven A.; Klimczak, Leszek J.; Fargo, David C.; Lang, Martin; Choi, Yoon–La; Lee, Jake June-Koo; Park, Woong-Yang; Wang, Wenyi; Fan, Yu; Ahn, Jaeil; Akbani, Rehan; Weinstein, John N.; Haussler, David; Ma, Xiaotu; Radenbaugh, Amie; Zhul, Jingchun; Lichtenberg, Tara M.; Zmuda, Erik; Black, Aaron; Hanf, Benjamin; Ramirez, Nilsa C.; Wise, Lisa; Bowen, Jay; Leraas, Kristen; Hall, Tracy Michelle; Gastier‐Foster, Julie M.; Kaelin, William G.; Thorne, Leigh B.; Boice, Lori; Huang, Mei; Vocke, Cathy D.; Peterson, James C.; Worrell, Robert A.; Merino, María J.; Czerniak, Bogdan; Aldape, Kenneth; Wood, Christopher G.; Spellman, Paul T.; Atkins, Michael B.; Cheville, John C.; Thompson, R. Houston; Jensen, Mark A.; Pihl, Todd; Wan, Yunhu; Ayala, Brenda; Baboud, Julien; Velaga, Sudhakar; Walton, Jessica; Liu, Jia; Chudamani, Sudha; Wu, Ye; Sheth, Margi; Shaw, Kenna; Demchok, John A.; Davidsen, Tanja M.; Yang, Liming; Wang, Zhining; Tarnuzzer, Roy; Zhang, Jiashan; Eley, Greg; Felau, Ina; Zenklusen, Jean C.; Hutter, Carolyn M.; Guyer, Mark S.; Ozenberger, Bradley A.; Sofia, Heidi J.

doi:10.1016/j.ccr.2014.07.014

Cited by 701 publications

(679 citation statements)

References 45 publications

Supporting

Mentioning

622

Contrasting

Unclassified

Order By: Relevance

“…However, in addition, the T>C mutations exhibit transcriptional strand bias, potentially indicating that some of these mutations arise from adducts subject to transcription coupled repair 9 . The signature 5 mutation rate is high in kidney clear cell and papillary cancers, which are thought to originate from kidney proximal tubular epithelium which absorbs metabolites, but low in kidney chromophobe tumours, which may arise from cells of the cortical collecting duct 10 . This raises the possibility that continuous exposure to a ubiquitous metabolic mutagen, which is actively reabsorbed in the kidney proximal tubule resulting in an elevated exposure in these cells, may underlie signature 5.…”

Section: Resultsmentioning

confidence: 99%

Clock-like mutational processes in human somatic cells

et al. 2015

View full text Add to dashboard Cite

During the course of a lifetime somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This study provides the first survey of clock-like mutational processes operative in human somatic cells.

show abstract

Section: Resultsmentioning

confidence: 99%

Clock-like mutational processes in human somatic cells

et al. 2015

View full text Add to dashboard Cite

show abstract

“…1B). These tumors were considered to have hypermutation based on prior definitions (31,32) and evidence of mismatch repair deficiency. Consistent with this classification, one hypermutated tumor had a heterozygous somatic truncating mutation at R389 in mutS homolog 2 (MSH2) in both carcinomatous and sarcomatoid elements with sarcomatoidspecific LOH at this locus and a sarcomatoid-specific heterozygous E1085K mutation in polymerase e (POLE).…”

Section: Resultsmentioning

confidence: 99%

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

Zhao

Said

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

View full text Add to dashboard Cite

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 PanCancer 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 ATrich 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.

show abstract

“…The most frequently mutated genes in somatic chRCC are TP53 (32% of tumours) and PTEN (9% of tumours) 28,35 . Wilms tumours are often associated with developmental syndromes such as Wilms tumour, aniridia, genitourinary abnormalities, mental retardation (WAGR) syndrome, and with deletions of chromosome 11 36 .…”

Section: Epidemiology and Genetics Of Renal Cancermentioning

confidence: 99%

The epigenetic landscape of renal cancer

2016

View full text Add to dashboard Cite

| The majority of kidney cancers are associated with mutations in the von Hippel-Lindau gene and a small proportion are associated with infrequent mutations in other well characterized tumour-suppressor genes. In the past 15 years, efforts to uncover other key genes involved in renal cancer have identified many genes that are dysregulated or silenced via epigenetic mechanisms, mainly through methylation of promoter CpG islands or dysregulation of specific microRNAs. In addition, the advent of next-generation sequencing has led to the identification of several novel genes that are mutated in renal cancer, such as PBRM1, BAP1 and SETD2, which are all involved in histone modification and nucleosome and chromatin remodelling. In this Review, we discuss how altered DNA methylation, microRNA dysregulation and mutations in histone-modifying enzymes disrupt cellular pathways in renal cancers.

show abstract

The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

Cited by 701 publications

References 45 publications

Clock-like mutational processes in human somatic cells

Clock-like mutational processes in human somatic cells

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

The epigenetic landscape of renal cancer

Contact Info

Product

Resources

About