Biallelic Alteration and Dysregulation of the Hippo Pathway in Mucinous Tubular and Spindle Cell Carcinoma of the Kidney
Tóm tắt
Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma (RCC) with distinctive morphologic and cytogenetic features. Here, we carry out whole-exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n = 22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSG) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes, whereas other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion. Mutations in the context of recurrent chromosomal losses amounted to biallelic alterations in these TSGs. As a readout of Hippo pathway inactivation, a majority of cases (90%) exhibited increased nuclear YAP1 protein expression. Taken together, nearly all cases of MTSCC exhibit some evidence of Hippo pathway dysregulation.
Significance: MTSCC is a rare and relatively recently described subtype of RCC. Next-generation sequencing of a multi-institutional MTSCC cohort revealed recurrent chromosomal losses and somatic mutations in the Hippo signaling pathway genes leading to potential YAP1 activation. In virtually all cases of MTSCC, there was evidence of Hippo pathway dysregulation, suggesting a common mechanistic basis for this disease. Cancer Discov; 6(11); 1258–66. ©2016 AACR.
This article is highlighted in the In This Issue feature, p. 1197
Từ khóa
Tài liệu tham khảo
Cancer Genome Atlas Research Network, 2013, Comprehensive molecular characterization of clear cell renal cell carcinoma, Nature, 499, 43, 10.1038/nature12222
Linehan, 2016, Comprehensive molecular characterization of papillary renal-cell carcinoma, N Engl J Med, 135
Davis, 2014, The somatic genomic landscape of chromophobe renal cell carcinoma, Cancer Cell, 26, 319, 10.1016/j.ccr.2014.07.014
Fine, 2006, Expanding the histologic spectrum of mucinous tubular and spindle cell carcinoma of the kidney, Am J Surg Pathol, 30, 1554, 10.1097/01.pas.0000213271.15221.e3
Reuter, 2014, Best practices recommendations in the application of immunohistochemistry in the kidney tumors: report from the International Society of Urologic Pathology consensus conference, Am J Surg Pathol, 38, e35, 10.1097/PAS.0000000000000258
Cieslik, 2015, The use of exome capture RNA-seq for highly degraded RNA with application to clinical cancer sequencing, Genome Res, 25, 1372, 10.1101/gr.189621.115
Mody, 2015, Integrative clinical sequencing in the management of refractory or relapsed cancer in youth, Jama, 314, 913, 10.1001/jama.2015.10080
Robinson, 2013, Activating ESR1 mutations in hormone-resistant metastatic breast cancer, Nat Genet, 45, 1446, 10.1038/ng.2823
Alexandrov, 2013, Signatures of mutational processes in human cancer, Nature, 500, 415, 10.1038/nature12477
Salah, 2011, Negative regulation of the Hippo pathway by E3 ubiquitin ligase ITCH is sufficient to promote tumorigenicity, Cancer Res, 71, 2010, 10.1158/0008-5472.CAN-10-3516
Schramm, 2015, Mutational dynamics between primary and relapse neuroblastomas, Nat Genet, 47, 872, 10.1038/ng.3349
Liu, 2013, PTPN14 interacts with and negatively regulates the oncogenic function of YAP, Oncogene, 32, 1266, 10.1038/onc.2012.147
Yu, 2015, Hippo pathway in organ size control, tissue homeostasis, and cancer, Cell, 163, 811, 10.1016/j.cell.2015.10.044
Peckova, 2015, Mucinous spindle and tubular renal cell carcinoma: analysis of chromosomal aberration pattern of low-grade, high-grade, and overlapping morphologic variant with papillary renal cell carcinoma, Ann Diagn Pathol, 19, 226, 10.1016/j.anndiagpath.2015.04.004
Udager, 2014, Current and proposed molecular diagnostics in a genitourinary service line laboratory at a tertiary clinical institution, Cancer J, 20, 29, 10.1097/PPO.0000000000000017
Avruch, 2012, Protein kinases of the Hippo pathway: regulation and substrates, Semin Cell Dev Biol, 23, 770, 10.1016/j.semcdb.2012.07.002
Moya, 2014, Discovering the Hippo pathway protein-protein interactome, Cell Res, 24, 137, 10.1038/cr.2014.6
Couzens, 2013, Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions, Sci Signaling, 6, rs15, 10.1126/scisignal.2004712
Wang, 2014, Defining the protein–protein interaction network of the human hippo pathway, Mol Cell Proteomics, 13, 119, 10.1074/mcp.M113.030049
Alder, 2014, Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation, Cell Rep, 9, 261, 10.1016/j.celrep.2014.08.046
Yimlamai, 2014, Hippo pathway activity influences liver cell fate, Cell, 157, 1324, 10.1016/j.cell.2014.03.060
Kanazawa, 2011, Hepatocyte nuclear factor 4 alpha is associated with mesenchymal–epithelial transition in developing kidneys of C57BL/6 mice, J Vet Med Sci, 73, 601, 10.1292/jvms.10-0493
Kanazawa, 2010, Hepatocyte nuclear factor 4 alpha is related to survival of the condensed mesenchyme in the developing mouse kidney, Dev Dyn, 239, 1145, 10.1002/dvdy.22276
Mele, 2015, Human genomics. The human transcriptome across tissues and individuals., Science, 348, 660, 10.1126/science.aaa0355
Kanazawa, 2009, Expression of hepatocyte nuclear factor 4alpha in developing mice, Anat Histol Embryol, 38, 34, 10.1111/j.1439-0264.2008.00889.x
Suh, 2006, The expression profiles of nuclear receptors in the developing and adult kidney, Mol Endocrinol, 20, 3412, 10.1210/me.2006-0312
Saadettin, 1996, Human renal cell carcinogensis is accompanied by a coordinate loss of the tissue specific transcription factors HNF4A and HNF1A, Cancer Lett, 101, 205, 10.1016/0304-3835(96)04136-5
Cheval, 2012, Of mice and men: divergence of gene expression patterns in kidney, PloS One, 7, e46876, 10.1371/journal.pone.0046876
Lee, 2015, Deep sequencing in microdissected renal tubules identifies nephron segment-specific transcriptomes, J Am Soc Nephrol, 26, 2669, 10.1681/ASN.2014111067
Srigley, 2002, Phenotypic, molecular and utrastructural studies of a novel low grade renal epithelial neoplasm possibly related to the loop of Henle, Mod Pathol, 15
Bonilla, 2016, Genomic analysis identifies new drivers and progression pathways in skin basal cell carcinoma, Nat Genet, 48, 398, 10.1038/ng.3525
Rakozy, 2002, Low-grade tubular-mucinous renal neoplasms: morphologic, immunohistochemical, and genetic features, Mod Pathol, 15, 1162, 10.1097/01.MP.0000031709.40712.46
Harms, 2015, The distinctive mutational spectra of polyomavirus-negative Merkel cell carcinoma, Cancer Res, 75, 3720, 10.1158/0008-5472.CAN-15-0702
Mehra, 2014, Primary urethral clear-cell adenocarcinoma: comprehensive analysis by surgical pathology, cytopathology, and next-generation sequencing, Am J Pathol, 184, 584, 10.1016/j.ajpath.2013.11.023
Robinson, 2015, Integrative clinical genomics of advanced prostate cancer, Cell, 161, 1215, 10.1016/j.cell.2015.05.001
Koboldt, 2012, VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing, Genome Res, 22, 568, 10.1101/gr.129684.111
Li, 2009, The sequence alignment/map format and SAMtools, Bioinformatics, 25, 2078, 10.1093/bioinformatics/btp352
Wang, 2010, ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data, Nucleic Acids Res, 38, e164, 10.1093/nar/gkq603
Lonigro, 2011, Detection of somatic copy number alterations in cancer using targeted exome capture sequencing, Neoplasia, 13, 1019, 10.1593/neo.111252
Dobin, 2013, STAR: ultrafast universal RNA-seq aligner, Bioinformatics, 29, 15, 10.1093/bioinformatics/bts635
Dobin, 2015, Mapping RNA-seq reads with STAR, Current Protocols Bioinformat, 51, 11 4 1, 10.1002/0471250953.bi1114s51
Liao, 2013, The Subread aligner: fast, accurate and scalable read mapping by seed-and-vote, Nucleic Acids Res, 41, e108, 10.1093/nar/gkt214
Ritchie, 2015, limma powers differential expression analyses for RNA-sequencing and microarray studies, Nucleic Acids Res, 43, e47, 10.1093/nar/gkv007
Smyth, 2004, Linear models and empirical Bayes methods for assessing differential expression in microarray experiments, Stat Appl Genet Mol Biol, 3, Article3, 10.2202/1544-6115.1027
Law, 2014, voom: Precision weights unlock linear model analysis tools for RNA-seq read counts, Genome Biol, 15, R29, 10.1186/gb-2014-15-2-r29
Chen, 2016, Multilevel genomics-based taxonomy of renal cell carcinoma, Cell Rep, 14, 2476, 10.1016/j.celrep.2016.02.024
Hoyer, 2004, Non-negative matrix factorization with sparseness constraints, J Mach Learning Res, 5, 1457
Newton, 2007, Random-set methods identify distinct aspects of the enrichment signal in gene-set analysis, Ann Appl Stat, 85