The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss

English version

Autoři: Bhuvana A. Setty ^aff001; Goodwin G. Jinesh ^aff003; Michael Arnold ^aff004; Fredrik Pettersson ^aff006; Chia-Ho Cheng ^aff006; Ling Cen ^aff006; Sean J. Yoder ^aff007; Jamie K. Teer ^aff006; Elsa R. Flores ^aff008; Damon R. Reed ^aff003; Andrew S. Brohl ^aff003
Působiště autorů: Division of Hematology/Oncology/BMT, Nationwide Children’s Hospital, Columbus, Ohio, United States of America ^aff001; Department of Pediatrics, The Ohio State University Wexner Medical Center Columbus, Ohio, United States of America ^aff002; Chemical Biology and Molecular Medicine Program, Moffitt Cancer Center, Florida, United States of America ^aff003; Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio, United States of America ^aff004; Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America ^aff005; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida, United States of America ^aff006; Molecular Genomics Core Facility, Moffitt Cancer Center, Tampa, Florida, United States of America ^aff007; Department of Molecular Oncology, Moffitt Cancer Center, Tampa, Florida, United States of America ^aff008; Adolescent and Young Adult Program, Moffitt Cancer Center, Tampa, Florida, United States of America ^aff009; Sarcoma Department, Moffitt Cancer Center, Tampa, Florida, United States of America ^aff010
Vyšlo v časopise: The genomic landscape of undifferentiated embryonal sarcoma of the liver is typified by C19MC structural rearrangement and overexpression combined with TP53 mutation or loss. PLoS Genet 16(4): e32767. doi:10.1371/journal.pgen.1008642
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008642

Souhrn

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy. Though the molecular underpinnings of this cancer have been largely unexplored, recurrent chromosomal breakpoints affecting a noncoding region on chr19q13, which includes the chromosome 19 microRNA cluster (C19MC), have been reported in several cases. We performed comprehensive molecular profiling on samples from 14 patients diagnosed with UESL. Congruent with prior reports, we identified structural variants in chr19q13 in 10 of 13 evaluable tumors. From whole transcriptome sequencing, we observed striking expressional activity of the entire C19MC region. Concordantly, in 7 of 7 samples undergoing miRNAseq, we observed hyperexpression of the miRNAs within this cluster to levels >100 fold compared to matched normal tissue or a non-C19MC amplified cancer cell line. Concurrent TP53 mutation or copy number loss was identified in all evaluable tumors with evidence of C19MC overexpression. We find that C19MC miRNAs exhibit significant negative correlation to TP53 regulatory miRNAs and K-Ras regulatory miRNAs. Using RNA-seq we identified that pathways relevant to cellular differentiation as well as mRNA translation machinery are transcriptionally enriched in UESL. In summary, utilizing a combination of next-generation sequencing and high-density arrays we identify the combination of C19MC hyperexpression via chromosomal structural event with TP53 mutation or loss as highly recurrent genomic features of UESL.

Klíčová slova:

Cell fusion – DNA transcription – Hispanic people – Chromosome structure and function – MicroRNAs – Molecular genetics – RNA sequencing – Somatic mutation

Zdroje

1. Shi Y, Rojas Y, Zhang W, Beierle EA, Doski JJ, Goldfarb M, et al. Characteristics and outcomes in children with undifferentiated embryonal sarcoma of the liver: A report from the National Cancer Database. Pediatr Blood Cancer. 2017;64(4). doi: 10.1002/pbc.26272 27781381; PubMed Central PMCID: PMC5333454.

2. Ismail H, Dembowska-Baginska B, Broniszczak D, Kalicinski P, Maruszewski P, Kluge P, et al. Treatment of undifferentiated embryonal sarcoma of the liver in children—single center experience. J Pediatr Surg. 2013;48(11):2202–6. Epub 2013/11/12. doi: 10.1016/j.jpedsurg.2013.05.020 [pii]. 24210186.

3. Stocker JT, Ishak KG. Undifferentiated (embryonal) sarcoma of the liver: report of 31 cases. Cancer. 1978;42(1):336–48. doi: 10.1002/1097-0142(197807)42 : 1<336::aid-cncr2820420151>3.0.co;2-v 208754.

4. Bisogno G, Pilz T, Perilongo G, Ferrari A, Harms D, Ninfo V, et al. Undifferentiated sarcoma of the liver in childhood: a curable disease. Cancer. 2002;94(1):252–7. Epub 2002/01/30. doi: 10.1002/cncr.10191 [pii]. 11815984.

5. Rajaram V, Knezevich S, Bove KE, Perry A, Pfeifer JD. DNA sequence of the translocation breakpoints in undifferentiated embryonal sarcoma arising in mesenchymal hamartoma of the liver harboring the t(11;19)(q11;q13.4) translocation. Genes Chromosomes Cancer. 2007;46(5):508–13. doi: 10.1002/gcc.20437 17311249.

6. Zhang H, Lei L, Zuppan CW, Raza AS. Undifferentiated embryonal sarcoma of the liver with an unusual presentation: case report and review of the literature. J Gastrointest Oncol. 2016;7(Suppl 1):S100–6. doi: 10.3978/j.issn.2078-6891.2015.020 27034807; PubMed Central PMCID: PMC4783619.

7. O'Sullivan MJ, Swanson PE, Knoll J, Taboada EM, Dehner LP. Undifferentiated embryonal sarcoma with unusual features arising within mesenchymal hamartoma of the liver: report of a case and review of the literature. Pediatr Dev Pathol. 2001;4(5):482–9. Epub 2002/01/10. doi: 10.1007/s10024001-0047-9 11779051.

8. Mathews J, Duncavage EJ, Pfeifer JD. Characterization of translocations in mesenchymal hamartoma and undifferentiated embryonal sarcoma of the liver. Exp Mol Pathol. 2013;95(3):319–24. Epub 2013/10/15. doi: 10.1016/j.yexmp.2013.09.006 [pii]. 24120702.

9. Kleinman CL, Gerges N, Papillon-Cavanagh S, Sin-Chan P, Pramatarova A, Quang DA, et al. Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nat Genet. 2014;46(1):39–44. Epub 2013/12/10. doi: 10.1038/ng.2849 24316981.

10. Jinesh GG, Flores ER, Brohl AS. Chromosome 19 miRNA cluster and CEBPB expression specifically mark and potentially drive triple negative breast cancers. PLoS One. 2018;13(10):e0206008. Epub 2018/10/20. doi: 10.1371/journal.pone.0206008 30335837; PubMed Central PMCID: PMC6193703.

11. Augello C, Colombo F, Terrasi A, Trombetta E, Maggioni M, Porretti L, et al. Expression of C19MC miRNAs in HCC associates with stem-cell features and the cancer-testis genes signature. Dig Liver Dis. 2018;50(6):583–93. Epub 2018/04/21. doi: 10.1016/j.dld.2018.03.026 29673952.

12. Vaira V, Elli F, Forno I, Guarnieri V, Verdelli C, Ferrero S, et al. The microRNA cluster C19MC is deregulated in parathyroid tumours. J Mol Endocrinol. 2012;49(2):115–24. doi: 10.1530/JME-11-0189 22767050.

13. Strub GM, Kirsh AL, Whipple ME, Kuo WP, Keller RB, Kapur RP, et al. Endothelial and circulating C19MC microRNAs are biomarkers of infantile hemangioma. JCI Insight. 2016;1(14):e88856. Epub 2016/09/24. doi: 10.1172/jci.insight.88856 [pii]. 27660822; PubMed Central PMCID: PMC5029419.

14. Flor I, Spiekermann M, Loning T, Dieckmann KP, Belge G, Bullerdiek J. Expression of microRNAs of C19MC in Different Histological Types of Testicular Germ Cell Tumour. Cancer Genomics Proteomics. 2016;13(4):281–9. Epub 2016/07/02. 13/4/281 [pii]. 27365378.

15. Rippe V, Dittberner L, Lorenz VN, Drieschner N, Nimzyk R, Sendt W, et al. The two stem cell microRNA gene clusters C19MC and miR-371-3 are activated by specific chromosomal rearrangements in a subgroup of thyroid adenomas. PLoS One. 2010;5(3):e9485. Epub 2010/03/09. doi: 10.1371/journal.pone.0009485 20209130; PubMed Central PMCID: PMC2831057.

16. Bortolin-Cavaille ML, Dance M, Weber M, Cavaille J. C19MC microRNAs are processed from introns of large Pol-II, non-protein-coding transcripts. Nucleic Acids Res. 2009;37(10):3464–73. Epub 2009/04/03. doi: 10.1093/nar/gkp205 19339516; PubMed Central PMCID: PMC2691840.

17. Malnou EC, Umlauf D, Mouysset M, Cavaille J. Imprinted MicroRNA Gene Clusters in the Evolution, Development, and Functions of Mammalian Placenta. Front Genet. 2018;9 : 706. Epub 2019/02/05. doi: 10.3389/fgene.2018.00706 30713549; PubMed Central PMCID: PMC6346411.

18. Holland AJ, Cleveland DW. Chromoanagenesis and cancer: mechanisms and consequences of localized, complex chromosomal rearrangements. Nature Medicine. 2012;18(11):1630–8. doi: 10.1038/nm.2988 23135524

19. Forment JV, Kaidi A, Jackson SP. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nature Reviews Cancer. 2012;12(10):663–70. doi: 10.1038/nrc3352 22972457

20. Shen MM. Chromoplexy: a new category of complex rearrangements in the cancer genome. Cancer Cell. 2013;23(5):567–9. doi: 10.1016/j.ccr.2013.04.025 23680143; PubMed Central PMCID: PMC3673705.

21. Tsuchiya N, Izumiya M, Ogata-Kawata H, Okamoto K, Fujiwara Y, Nakai M, et al. Tumor Suppressor miR-22 Determines p53-Dependent Cellular Fate through Post-transcriptional Regulation of p21. Cancer Research. 2011;71(13):4628–39. doi: 10.1158/0008-5472.CAN-10-2475 21565979

22. Fornari F, Milazzo M, Galassi M, Callegari E, Veronese A, Miyaaki H, et al. p53/mdm2 Feedback Loop Sustains miR-221 Expression and Dictates the Response to Anticancer Treatments in Hepatocellular Carcinoma. Molecular Cancer Research. 2014;12(2):203–16. doi: 10.1158/1541-7786.MCR-13-0312-T 24324033

23. Borzi C, Calzolari L, Centonze G, Milione M, Sozzi G, Fortunato O. mir-660-p53-mir-486 Network: A New Key Regulatory Pathway in Lung Tumorigenesis. Int J Mol Sci. 2017;18(1). doi: 10.3390/ijms18010222 28124991; PubMed Central PMCID: PMC5297851.

24. Bou Kheir T, Futoma-Kazmierczak E, Jacobsen A, Krogh A, Bardram L, Hother C, et al. miR-449 inhibits cell proliferation and is down-regulated in gastric cancer. Molecular Cancer. 2011;10(1):29. doi: 10.1186/1476-4598-10-29 21418558

25. Zhao W, Shen W-W, Cao X-M, Ding W-Y, Yan L-P, Gao L-J, et al. Novel mechanism of miRNA-365-regulated trophoblast apoptosis in recurrent miscarriage. Journal of cellular and molecular medicine. 2017;21(10):2412–25. Epub 04/10. doi: 10.1111/jcmm.13163 28393453.

26. Bouamar H, Jiang D, Wang L, Lin A-P, Ortega M, Aguiar RCT. MicroRNA 155 Control of p53 Activity Is Context Dependent and Mediated by Aicda and Socs1. Molecular and Cellular Biology. 2015;35(8):1329–40. doi: 10.1128/MCB.01446-14 25645925

27. Slattery ML, Mullany LE, Wolff RK, Sakoda LC, Samowitz WS, Herrick JS. The p53-signaling pathway and colorectal cancer: Interactions between downstream p53 target genes and miRNAs. Genomics. 2018. doi: 10.1016/j.ygeno.2018.05.006 29860032; PubMed Central PMCID: PMC6274615.

28. Yang S, Guo H, Wei B, Zhu S, Cai Y, Jiang P, et al. Association of miR-502-binding site single nucleotide polymorphism in the 3′-untranslated region of SET8 and TP53 codon 72 polymorphism with non-small cell lung cancer in Chinese population. Acta Biochimica et Biophysica Sinica. 2013;46(2):149–54. doi: 10.1093/abbs/gmt138 24374662

29. Jiang Y, Duan Y, Zhou H. MicroRNA-27a directly targets KRAS to inhibit cell proliferation in esophageal squamous cell carcinoma. Oncol Lett. 2015;9(1):471–7. doi: 10.3892/ol.2014.2701 25436011; PubMed Central PMCID: PMC4246996.

30. Kim JS, Kim EJ, Lee S, Tan X, Liu X, Park S, et al. MiR-34a and miR-34b/c have distinct effects on the suppression of lung adenocarcinomas. Exp Mol Med. 2019;51(1):9. doi: 10.1038/s12276-018-0203-1 30700696; PubMed Central PMCID: PMC6353903.

31. Islam F, Gopalan V, Vider J, Lu C-t, Lam AKY. MiR-142-5p act as an oncogenic microRNA in colorectal cancer: Clinicopathological and functional insights. Experimental and Molecular Pathology. 2018;104(1):98–107. doi: 10.1016/j.yexmp.2018.01.006 29337244

32. Langsch S, Baumgartner U, Haemmig S, Schlup C, Schäfer SC, Berezowska S, et al. miR-29b Mediates NF-κB Signaling in KRAS-Induced Non–Small Cell Lung Cancers. Cancer Research. 2016;76(14):4160–9. doi: 10.1158/0008-5472.CAN-15-2580 27199349

33. Shi L, Middleton J, Jeon Y-J, Magee P, Veneziano D, Laganà A, et al. KRAS induces lung tumorigenesis through microRNAs modulation. Cell Death & Disease. 2018;9(2):219. doi: 10.1038/s41419-017-0243-9 29440633

34. Hu W, Chan CS, Wu R, Zhang C, Sun Y, Song JS, et al. Negative regulation of tumor suppressor p53 by microRNA miR-504. Mol Cell. 2010;38(5):689–99. doi: 10.1016/j.molcel.2010.05.027 20542001; PubMed Central PMCID: PMC2900922.

35. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol Cell. 2007;26(5):731–43. doi: 10.1016/j.molcel.2007.05.017 17540598.

36. Wang N, Zhu M, Tsao SW, Man K, Zhang Z, Feng Y. MiR-23a-mediated inhibition of topoisomerase 1 expression potentiates cell response to etoposide in human hepatocellular carcinoma. Mol Cancer. 2013;12(1):119. doi: 10.1186/1476-4598-12-119 24103454; PubMed Central PMCID: PMC3856574.

37. Park S-Y, Lee JH, Ha M, Nam J-W, Kim VN. miR-29 miRNAs activate p53 by targeting p85α and CDC42. Nature Structural &Amp; Molecular Biology. 2008;16 : 23. doi: 10.1038/nsmb.1533 https://www.nature.com/articles/nsmb.1533#supplementary-information. 19079265

38. Suh SS, Yoo JY, Nuovo GJ, Jeon YJ, Kim S, Lee TJ, et al. MicroRNAs/TP53 feedback circuitry in glioblastoma multiforme. Proc Natl Acad Sci U S A. 2012;109(14):5316–21. doi: 10.1073/pnas.1202465109 22431589; PubMed Central PMCID: PMC3325690.

39. Liu F, Di Wang X. miR-150-5p represses TP53 tumor suppressor gene to promote proliferation of colon adenocarcinoma. Sci Rep. 2019;9(1):6740. doi: 10.1038/s41598-019-43231-5 31043658; PubMed Central PMCID: PMC6494853.

40. Apellaniz-Ruiz M, Segni M, Kettwig M, Gluer S, Pelletier D, Nguyen VH, et al. Mesenchymal Hamartoma of the Liver and DICER1 Syndrome. N Engl J Med. 2019;380(19):1834–42. Epub 2019/05/09. doi: 10.1056/NEJMoa1812169 31067372.

41. Naito J, Kaji H, Sowa H, Hendy GN, Sugimoto T, Chihara K. Menin suppresses osteoblast differentiation by antagonizing the AP-1 factor, JunD. J Biol Chem. 2005;280(6):4785–91. Epub 2004/11/26. doi: 10.1074/jbc.M408143200 15563473.

42. Zhang K, Wang M, Li Y, Li C, Tang S, Qu X, et al. The PERK-EIF2alpha-ATF4 signaling branch regulates osteoblast differentiation and proliferation by PTH. Am J Physiol Endocrinol Metab. 2019;316(4):E590–E604. Epub 2019/01/23. doi: 10.1152/ajpendo.00371.2018 30668150.

43. Ichihara-Tanaka K, Kadomatsu K, Kishida S. Temporally and Spatially Regulated Expression of the Linker Histone H1fx During Mouse Development. J Histochem Cytochem. 2017;65(9):513–30. Epub 2017/08/03. doi: 10.1369/0022155417723914 28766996; PubMed Central PMCID: PMC5582669.

44. Izzo A, Kamieniarz K, Schneider R. The histone H1 family: specific members, specific functions? Biol Chem. 2008;389(4):333–43. Epub 2008/01/23. doi: 10.1515/BC.2008.037 18208346.

45. Lee DY, Sugden B. The LMP1 oncogene of EBV activates PERK and the unfolded protein response to drive its own synthesis. Blood. 2008;111(4):2280–9. doi: 10.1182/blood-2007-07-100032 18042799; PubMed Central PMCID: PMC2234060.

46. Maurya PK, Mishra A, Yadav BS, Singh S, Kumar P, Chaudhary A, et al. Role of Y Box Protein-1 in cancer: As potential biomarker and novel therapeutic target. J Cancer. 2017;8(10):1900–7. Epub 2017/08/19. doi: 10.7150/jca.17689 28819388; PubMed Central PMCID: PMC5556654.

47. Kapur RP, Berry JE, Tsuchiya KD, Opheim KE. Activation of the chromosome 19q microRNA cluster in sporadic and androgenetic-biparental mosaicism-associated hepatic mesenchymal hamartoma. Pediatr Dev Pathol. 2014;17(2):75–84. doi: 10.2350/13-12-1415-OA.1 24555441.

48. Fornari F, Milazzo M, Chieco P, Negrini M, Marasco E, Capranico G, et al. In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2. J Pathol. 2012;227(3):275–85. Epub 2012/01/21. doi: 10.1002/path.3995 22262409.

49. Delorme-Axford E, Donker RB, Mouillet J-F, Chu T, Bayer A, Ouyang Y, et al. Human placental trophoblasts confer viral resistance to recipient cells. Proceedings of the National Academy of Sciences. 2013;110(29):12048–53. doi: 10.1073/pnas.1304718110 23818581

50. Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM, et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes & Development. 2013;27(13):1447–61. doi: 10.1101/gad.219642.113 23824538

51. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754–60. doi: 10.1093/bioinformatics/btp324 Epub 2009 May 18. 19451168

52. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–8. doi: 10.1038/ng.806 Epub 2011 Apr 10. 21478889

53. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44(W1):W90–7. doi: 10.1093/nar/gkw377 27141961; PubMed Central PMCID: PMC4987924.

54. Chen K, Wallis JW, McLellan MD, Larson DE, Kalicki JM, Pohl CS, et al. BreakDancer: an algorithm for high-resolution mapping of genomic structural variation. Nat Methods. 2009;6(9):677–81. doi: 10.1038/nmeth.1363 19668202; PubMed Central PMCID: PMC3661775.

55. Fan X, Abbott TE, Larson D, Chen K. BreakDancer: Identification of Genomic Structural Variation from Paired-End Read Mapping. Curr Protoc Bioinformatics. 2014;45 : 15 6 1–1. doi: 10.1002/0471250953.bi1506s45 25152801; PubMed Central PMCID: PMC4138716.

56. Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Kallberg M, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016;32(8):1220–2. doi: 10.1093/bioinformatics/btv710 26647377.

57. Okonechnikov K, Imai-Matsushima A, Paul L, Seitz A, Meyer TF, Garcia-Alcalde F. InFusion: Advancing Discovery of Fusion Genes and Chimeric Transcripts from Deep RNA-Sequencing Data. PLoS One. 2016;11(12):e0167417. doi: 10.1371/journal.pone.0167417 27907167; PubMed Central PMCID: PMC5132003 shares in the company. A patent application (WO2013038010) was filed by Lexogen for the SENSE mRNA-Seq library preparation method and kit. For this study, RNA was extracted and mRNASeq libraries were prepared at Lexogen, and the company funded the NGS run. Lexogen imposes no kind of restriction on the sharing of data and materials. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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