A novel somatic MAPK1 mutation in primary ovarian mixed germ cell tumors

Zou,Yang; Deng,Wei; Wang,Feng; Yu,Xiao‑Hong; Liu,Fa‑Ying; Yang,Bi‑Cheng; Huang,Mei‑Zhen; Guo,Jiu‑Bai; Xie,Qiu‑Hua; He,Ming; Huang,Ou‑Ping

doi:10.3892/or.2015.4402

A novel somatic MAPK1 mutation in primary ovarian mixed germ cell tumors

Authors:
- Yang Zou
- Wei Deng
- Feng Wang
- Xiao‑Hong Yu
- Fa‑Ying Liu
- Bi‑Cheng Yang
- Mei‑Zhen Huang
- Jiu‑Bai Guo
- Qiu‑Hua Xie
- Ming He
- Ou‑Ping Huang
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Affiliations: Key Laboratory of Women's Reproductive Health of Jiangxi, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, P.R. China, Department of Pathology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, P.R. China, Department of Pharmacology and Molecular Therapeutics, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
Published online on: November 5, 2015 https://doi.org/10.3892/or.2015.4402
Pages: 725-730

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Abstract

A recent exome-sequencing study revealed prevalent mitogen-activated protein kinase 1 (MAPK1) p.E322K mutation in cervical carcinoma. It remains largely unknown whether ovarian carcinomas also harbor MAPK1 mutations. As paralogous gene mutations co‑occur frequently in human malignancies, we analyzed here a total of 263 ovarian carcinomas for the presence of MAPK1 and paralogous MAPK3 mutations by DNA sequencing. A previously unreported MAPK1 p.D321N somatic mutation was identified in 2 out of 18 (11.1%) ovarian mixed germ cell tumors, while no other MAPK1 or MAPK3 mutation was detected in our samples. Of note, OCC‑115, the MAPK1‑mutated sample with bilateral cancerous ovaries affected, harbored MAPK1 mutation in the right ovary while retained the left ovary intact, implicating that the genetic alterations underlying ovarian mixed germ cell tumor may be different, even in patients with similar genetic backgrounds and tumor microenvironments. The results of evolutionary conservation and protein structure modeling analysis implicated that MAPK1 p.D321N mutation may be pathogenic. Additionally, mutations in protein phosphatase 2 regulatory subunit α (PPP2R1A), ring finger protein 43 (RNF43), DNA directed polymerase ε (POLE1), ribonuclease type III (DICER1), CCCTC‑binding factor (CTCF), ribosomal protein L22 (RPL22), DNA methyltransferase 3α (DNMT3A), transformation/transcription domain‑associated protein (TRRAP), isocitrate dehydrogenase (IDH)1 and IDH2 were not detected in ovarian mixed germ cell tumors, implicating these genetic alterations may be not associated with MAPK1 mutation in the development of this malignancy. The present study identified a previously unreported MAPK1 mutation in ovarian mixed germ cell tumors for the first time, and this mutation may be actively involved in the tumorigenesis of this disease.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Munkarah A, Chatterjee M and Tainsky MA: Update on ovarian cancer screening. Curr Opin Obstet Gynecol. 19:22–26. 2007. View Article : Google Scholar : PubMed/NCBI
3	Tinelli A, Vergara D, Martignago R, Leo G, Pisanò M and Malvasi A: An outlook on ovarian cancer and borderline ovarian tumors: Focus on genomic and proteomic findings. Curr Genomics. 10:240–249. 2009. View Article : Google Scholar : PubMed/NCBI
4	Lowe KA, Chia VM, Taylor A, O'Malley C, Kelsh M, Mohamed M, Mowat FS and Goff B: An international assessment of ovarian cancer incidence and mortality. Gynecol Oncol. 130:107–114. 2013. View Article : Google Scholar : PubMed/NCBI
5	Davis A, Tinker AV and Friedlander M: 'Platinum resistant' ovarian cancer: What is it, who to treat and how to measure benefit? Gynecol Oncol. 133:624–631. 2014. View Article : Google Scholar : PubMed/NCBI
6	De Luca A, Maiello MR, D'Alessio A, Pergameno M and Normanno N: The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: Role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets. 16(Suppl 2): S17–S27. 2012. View Article : Google Scholar : PubMed/NCBI
7	Steelman LS, Franklin RA, Abrams SL, Chappell W, Kempf CR, Bäsecke J, Stivala F, Donia M, Fagone P, Nicoletti F, et al: Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia. 25:1080–1094. 2011. View Article : Google Scholar : PubMed/NCBI
8	McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, et al: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 1773:1263–1284. 2007. View Article : Google Scholar
9	Holderfield M, Deuker MM, McCormick F and McMahon M: Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer. 14:455–467. 2014. View Article : Google Scholar : PubMed/NCBI
10	Wang Y, Kaiser CE, Frett B and Li HY: Targeting mutant KRAS for anticancer therapeutics: A review of novel small molecule modulators. J Med Chem. 56:5219–5230. 2013. View Article : Google Scholar : PubMed/NCBI
11	Tsai JH, Huang WC, Jhuang JY, Jeng YM, Cheng ML, Chiu HY, Kuo KT and Liau JY: Frequent activating HRAS mutations in trichilemmoma. Br J Dermatol. 171:1073–1077. 2014. View Article : Google Scholar : PubMed/NCBI
12	Trietsch MD, Spaans VM, ter Haar NT, Osse EM, Peters AA, Gaarenstroom KN and Fleuren GJ: CDKN2A(p16) and HRAS are frequently mutated in vulvar squamous cell carcinoma. Gynecol Oncol. 135:149–155. 2014. View Article : Google Scholar : PubMed/NCBI
13	Ojesina AI, Lichtenstein L, Freeman SS, Pedamallu CS, Imaz-Rosshandler I, Pugh TJ, Cherniack AD, Ambrogio L, Cibulskis K, Bertelsen B, et al: Landscape of genomic alterations in cervical carcinomas. Nature. 506:371–375. 2014. View Article : Google Scholar : PubMed/NCBI
14	Bell DBA, Birrer M, Chien J, Cramer D, Dao F, Dhir R, DiSaia P, Gabra H, Glenn P, Godwin A, et al Cancer Genome Atlas Research Network: Integrated genomic analyses of ovarian carcinoma. Nature. 474:609–615. 2011. View Article : Google Scholar
15	Wang F, Zou Y, Liu FY, Yu XH, Huang H, Zhang N, Qi YY, Liu RF, Liu XY, Chen J, et al: Infrequent mutations of the PPP2R1A and PPP2R1B genes in patients with ovarian cancer. Mol Med Rep. 7:1826–1830. 2013.PubMed/NCBI
16	Zou Y, Wang F, Liu FY, Huang MZ, Li W, Yuan XQ, Huang OP and He M: RNF43 mutations are recurrent in Chinese patients with mucinous ovarian carcinoma but absent in other subtypes of ovarian cancer. Gene. 531:112–116. 2013. View Article : Google Scholar : PubMed/NCBI
17	Zou Y, Liu FY, Liu H, Wang F, Li W, Huang MZ, Huang Y, Yuan XQ, Xu XY, Huang OP, et al: Frequent POLE1 p.S297F mutation in Chinese patients with ovarian endometrioid carcinoma. Mutat Res. 761:49–52. 2014. View Article : Google Scholar : PubMed/NCBI
18	Zou Y, Huang MZ, Liu FY, Yang BC, Wang LQ, Wang F, Yu XH, Wan L, Wan XD, Xu XY, et al: Absence of DICER1, CTCF, RPL22, DNMT3A, TRRAP, IDH1 and IDH2 hotspot mutations in patients with various subtypes of ovarian carcinomas. Biomed Rep. 3:33–37. 2015.
19	Guex N and Peitsch MC: SWISS-MODEL and the Swiss- PdbViewer: An environment for comparative protein modeling. Electrophoresis. 18:2714–2723. 1997. View Article : Google Scholar
20	Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, et al: Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet. 44:1006–1014. 2012. View Article : Google Scholar : PubMed/NCBI
21	Muzny DMBM, Chang K, Dinh HH, Drummond JA, Fowler G, Kovar CL, Lewis LR, Morgan MB, Newsham IF, Reid JG, et al Cancer Genome Atlas Network: Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487:330–337. 2012. View Article : Google Scholar
22	Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, et al Australian Pancreatic Cancer Genome Initiative: Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 491:399–405. 2012. View Article : Google Scholar : PubMed/NCBI
23	Landau DA, Carter SL, Stojanov P, McKenna A, Stevenson K, Lawrence MS, Sougnez C, Stewart C, Sivachenko A, Wang L, et al: Evolution and impact of subclonal mutations in chronic lymphocytic leukemia. Cell. 152:714–726. 2013. View Article : Google Scholar : PubMed/NCBI
24	Goyal LD, Kaur S and Kawatra K: Malignant mixed germ cell tumour of ovary - an unusual combination and review of literature. J Ovarian Res. 7(91)2014. View Article : Google Scholar
25	Heravi-Moussavi A, Anglesio MS, Cheng SW, Senz J, Yang W, Prentice L, Fejes AP, Chow C, Tone A, Kalloger SE, et al: Recurrent somatic DICER1 mutations in nonepithelial ovarian cancers. N Engl J Med. 366:234–242. 2012. View Article : Google Scholar
26	Witkowski L, Carrot-Zhang J, Albrecht S, Fahiminiya S, Hamel N, Tomiak E, Grynspan D, Saloustros E, Nadaf J, Rivera B, et al: Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet. 46:438–443. 2014. View Article : Google Scholar : PubMed/NCBI
27	Ryland GL, Hunter SM, Doyle MA, Rowley SM, Christie M, Allan PE, Bowtell DD, Gorringe KL and Campbell IG; Australian Ovarian Cancer Study Group: RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. J Pathol. 229:469–476. 2013. View Article : Google Scholar
28	Boyd J, Luo B, Peri S, Wirchansky B, Hughes L, Forsythe C and Wu H: Whole exome sequence analysis of serous borderline tumors of the ovary. Gynecol Oncol. 130:560–564. 2013. View Article : Google Scholar : PubMed/NCBI
29	Pickering CR, Zhang J, Yoo SY, Bengtsson L, Moorthy S, Neskey DM, Zhao M, Ortega Alves MV, Chang K, Drummond J, et al: Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov. 3:770–781. 2013. View Article : Google Scholar : PubMed/NCBI