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BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Aberrant expression of ALK and EZH2 in Merkel cell carcinoma

Authors: Tuukka Veija, Virve Koljonen, Tom Bohling, Mia Kero, Sakari Knuutila, Virinder Kaur Sarhadi

Published in: BMC Cancer | Issue 1/2017

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Abstract

Background

Distinct characteristic features categorize Merkel cell carcinoma (MCC) into two subgroups according to the Merkel cell polyomavirus infection. Many mutational studies on MCC have been carried out in recent years without identifying a prominent driver mutation. However, there is paucity reporting the expression of cancer genes at the RNA level in MCC tumors. In this study, we studied the RNA expression profiles of 26 MCC tumors, with a goal to identify prospective molecular targets that could improve the treatment strategies of MCC.

Methods

RNA expression of 50 cancer-related genes in 26 MCC tumors was analyzed by targeted amplicon based next-generation sequencing using the Ion Torrent technology and the expression compared with that of normal, non-cancerous skin samples. Sequencing data were processed using Torrent Suite™ Software. Expression profiles of MCV-negative and MCV-positive tumors were compared. Fluorescence in situ hybridization was performed to study ALK rearrangements and immunohistochemistry to study ALK expression in tumor tissue.

Results

ALK, CDKN2A, EZH2 and ERBB4 were overexpressed, and EGFR, ERBB2, PDGFRA and FGFR1 were underexpressed in MCC tumors compared to normal skin. In the MCV-negative tumors, MET, NOTCH1, FGFR3, and SMO were overexpressed and JAK3 and NPM1 were under-expressed compared to the MCV-positive tumors.

Conclusions

High expression of ALK, CDKN2A and EZH2 was recorded in MCC tumors. No ALK fusion was seen by FISH analysis. Overexpression of EZH2 suggests its potential as a drug target in MCC.
Appendix
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Literature
1.
Cardoso JC, Teixeira V, Tchernev G, Wollina U. Merkel cell carcinoma: a review and update on aetiopathogenesis, diagnosis and treatment approaches. Wien Med Wochenschr. 2013;163(15-16):359–67.
2.
3.
Bhatia K, Goedert JJ, Modali R, Preiss L, Ayers LW. Merkel cell carcinoma subgroups by Merkel cell polyomavirus DNA relative abundance and oncogene expression. Int J Cancer. 2010;126(9):2240–6.PubMedPubMedCentral
4.
Iwasaki T, Matsushita M, Kuwamoto S, Kato M, Murakami I, Higaki-Mori H, Nakajima H, Sano S, Hayashi K. Usefulness of significant morphologic characteristics in distinguishing between Merkel cell polyomavirus-positive and Merkel cell polyomavirus-negative Merkel cell carcinomas. Hum Pathol. 2013;44(9):1912–7.CrossRefPubMed
5.
Martin B, Poblet E, Rios JJ, Kazakov D, Kutzner H, Brenn T, Calonje E. Merkel cell carcinoma with divergent differentiation: histopathological and immunohistochemical study of 15 cases with PCR analysis for Merkel cell polyomavirus. Histopathology. 2013;62(5):711–22.CrossRefPubMed
6.
Leroux-Kozal V, Lévêque N, Brodard V, Lesage C, Dudez O, Makeieff M, Kanagaratnam L, Diebold M. Merkel cell carcinoma: histopathological and prognostic features according to the immunohistochemical expression of Merkel cell polyomavirus large T antigen correlated with viral load. Hum Pathol. 2015;46(3):443–53.CrossRefPubMed
7.
Veija T, Sahi H, Koljonen V, Bohling T, Knuutila S, Mosakhani N. miRNA-34a underexpressed in Merkel cell polyomavirus-negative Merkel cell carcinoma. Virchows Arch. 2014;466(3):289–95.CrossRefPubMed
8.
Shuda M, Feng H, Kwun HJ, Rosen ST, Gjoerup O, Moore PS, Chang Y. T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus. Proc Natl Acad Sci U S A. 2008;105(42):16272–7.CrossRefPubMedPubMedCentral
9.
Veija T, Sarhadi VK, Koljonen V, Bohling T, Knuutila S. Hotspot mutations in polyomavirus positive and negative Merkel cell carcinomas. Cancer Genet. 2016;209(1–2):30–5.CrossRefPubMed
10.
Goh G, Walradt T, Markarov V, Blom A, Riaz N, Doumani R, Stafstrom K, Moshiri A, Yelistratova L, Levinsohn J, Chan TA, Nghiem P, Lifton RP, Choi J. Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy. Oncotarget. 2016;7(3):3403–15.PubMed
11.
Harms PW, Vats P, Verhaegen ME, Robinson DR, Wu YM, Dhanasekaran SM, Palanisamy N, Siddiqui J, Cao X, Su F, Wang R, Xiao H, Kunju LP, Mehra R, Tomlins SA, Fullen DR, Bichakjian CK, Johnson TM, Dlugosz AA, Chinnaiyan AM. The distinctive mutational spectra of Polyomavirus-negative Merkel cell carcinoma. Cancer Res. 2015;75(18):3720–7.CrossRefPubMedPubMedCentral
12.
Erstad DJ, Jr JC. Mutational analysis of merkel cell carcinoma. Cancers (Basel). 2014;6(4):2116–36.CrossRef
13.
Wong SQ, Waldeck K, Vergara IA, Schroder J, Madore J, Wilmott JS, Colebatch AJ, De Paoli-Iseppi R, Li J, Lupat R, Semple T, Arnau GM, Fellowes A, Leonard JH, Hruby G, Mann GJ, Thompson JF, Cullinane C, Johnston M, Shackleton M, Sandhu S, Bowtell DD, Johnstone RW, Fox SB, McArthur GA, Papenfuss AT, Scolyer RA, Gill AJ, Hicks RJ, Tothill RW. UV-associated mutations underlie the etiology of MCV-negative Merkel cell carcinomas. Cancer Res. 2015;75(24):5228–34.CrossRefPubMed
14.
Sihto H, Kukko H, Koljonen V, Sankila R, Bohling T, Joensuu H. Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst. 2009;101(13):938–45.CrossRefPubMed
15.
16.
Tuononen K, Sarhadi VK, Wirtanen A, Ronty M, Salmenkivi K, Knuuttila A, Remes S, Telaranta-Keerie AI, Bloor S, Ellonen P, Knuutila S. Targeted resequencing reveals ALK fusions in non-small cell lung carcinomas detected by FISH, immunohistochemistry, and real-time RT-PCR: a comparison of four methods. Biomed Res Int. 2013;2013:757490.CrossRefPubMedPubMedCentral
17.
Filtenborg-Barnkob BE, Bzorek M. Expression of anaplastic lymphoma kinase in Merkel cell carcinomas. Hum Pathol. 2013;44(8):1656–64.CrossRefPubMed
18.
Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro DN, Saltman DL, Look AT. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science. 1994;263(5151):1281–4.CrossRefPubMed
19.
Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–6.CrossRefPubMed
20.
Liu J, Jin H, Tian H, Lian G, Chen S, Li J, Zhang X, Ma D. Anaplastic lymphoma kinase protein expression predicts micrometastases and prognosis for patients with hepatocellular carcinoma. Oncol Lett. 2016;11(1):213–23.PubMed
21.
Sihto H, Kukko H, Koljonen V, Sankila R, Bohling T, Joensuu H. Merkel cell polyomavirus infection, large T antigen, retinoblastoma protein and outcome in Merkel cell carcinoma. Clin Cancer Res. 2011;17(14):4806–13.CrossRefPubMed
22.
PDQ Cancer Genetics Editorial Board. Genetics of Skin Cancer (PDQ(R)). Health Professional Version. In: Edited by Anonymous. PDQ Cancer Information Summaries. Bethesda (MD). 2002.
23.
Cohen PR, Tomson BN, Elkin SK, Marchlik E, Carter JL, Kurzrock R. Genomic portfolio of Merkel cell carcinoma as determined by comprehensive genomic profiling: implications for targeted therapeutics. Oncotarget. 2016;26;7(17):23454–67.
24.
Romagosa C, Simonetti S, Lopez-Vicente L, Mazo A, Lleonart ME, Castellvi J. Ramon y Cajal S: p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011;30(18):2087–97.CrossRefPubMed
25.
Masumoto N, Fujii T, Ishikawa M, Saito M, Iwata T, Fukuchi T, Susumu N, Mukai M, Kubushiro K, Tsukazaki K, Nozawa S. P16 overexpression and human papillomavirus infection in small cell carcinoma of the uterine cervix. Hum Pathol. 2003;34(8):778–83.CrossRefPubMed
26.
Zouheir Y, Fechtali T, Elgnaoui N. Human Papillomavirus genotyping and p16(INK4a) expression in cervical lesions: a combined test to avoid cervical cancer progression. J Cancer Prev. 2016;21(2):121–5.CrossRefPubMedPubMedCentral
27.
McCluggage WG, Kennedy K, Busam KJ. An immunohistochemical study of cervical neuroendocrine carcinomas: Neoplasms that are commonly TTF1 positive and which may express CK20 and P63. Am J Surg Pathol. 2010;34(4):525–32.CrossRefPubMed
28.
Sahi H, Savola S, Sihto H, Koljonen V, Bohling T, Knuutila S. RB1 gene in Merkel cell carcinoma: hypermethylation in all tumors and concurrent heterozygous deletions in the polyomavirus-negative subgroup. APMIS. 2014;122(12):1157–66.
29.
Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006;439(7078):871–4.CrossRefPubMed
30.
31.
Zingg D, Debbache J, Schaefer SM, Tuncer E, Frommel SC, Cheng P, Arenas-Ramirez N, Haeusel J, Zhang Y, Bonalli M, McCabe MT, Creasy CL, Levesque MP, Boyman O, Santoro R, Shakhova O, Dummer R, Sommer L. The epigenetic modifier EZH2 controls melanoma growth and metastasis through silencing of distinct tumour suppressors. Nat Commun. 2015;6:6051.CrossRefPubMed
32.
Tasher D, Dalal I. The genetic basis of severe combined immunodeficiency and its variants. Appl Clin Genet. 2012;5:67–80.PubMedPubMedCentral
33.
Colombo E, Alcalay M, Pelicci PG. Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases. Oncogene. 2011;30(23):2595–609.CrossRefPubMed
34.
Yun JP, Miao J, Chen GG, Tian QH, Zhang CQ, Xiang J, Fu J, Lai PB. Increased expression of nucleophosmin/B23 in hepatocellular carcinoma and correlation with clinicopathological parameters. Br J Cancer. 2007;96(3):477–84.CrossRefPubMedPubMedCentral
35.
Nozawa Y, Van Belzen N, Van der Made AC, Dinjens WN, Bosman FT. Expression of nucleophosmin/B23 in normal and neoplastic colorectal mucosa. J Pathol. 1996;178(1):48–52.CrossRefPubMed
36.
Mosakhani N, Raty R, Tyybakinoja A, Karjalainen-Lindsberg ML, Elonen E, Knuutila S. MicroRNA profiling in chemoresistant and chemosensitive acute myeloid leukemia. Cytogenetic Genome Research. 2013;141(4):272–6.CrossRefPubMed
37.
Nouri K, Moll JM, Milroy LG, Hain A, Dvorsky R, Amin E, Lenders M, Nagel-Steger L, Howe S, Smits SH, Hengel H, Schmitt L, Munk C, Brunsveld L, Ahmadian MR. Biophysical characterization of Nucleophosmin interactions with human immunodeficiency virus rev and herpes simplex virus US11. PLoS One. 2015;10(12):e0143634.CrossRefPubMedPubMedCentral
Metadata
Title
Aberrant expression of ALK and EZH2 in Merkel cell carcinoma
Authors
Tuukka Veija
Virve Koljonen
Tom Bohling
Mia Kero
Sakari Knuutila
Virinder Kaur Sarhadi
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3233-5

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