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01-10-2019 | Salivary Gland Cancer | Original Article

Predictive value of FHIT, p27, and pERK1/ERK2 in salivary gland carcinomas: a retrospective study

Authors: Mathias Fiedler, Patty Renner, Jürgen Schubert, Florian Weber, Arndt Hartmann, Heinrich Iro, Veronika Vielsmeier, Christopher Bohr, Michael Gerken, Torsten E. Reichert, Tobias Ettl

Published in: Clinical Oral Investigations | Issue 10/2019

Abstract

Objectives

The aim of this study was to investigate the predictive value of the biomarkers FHIT, p27, and pERK1/ERK2 in salivary gland carcinomas.

Material and methods

Immunohistochemical staining of FHIT, p27, and pERK1/ERK2 of 265 patients with salivary gland carcinomas was conducted, and associations with clinico-histopathological data, overall survival, and disease-specific survival were examined.

Results

Expression of FHIT (quick score 98.7 vs. 206.4) and p27 (QS 187.3 vs. 244.8) was significantly lower in carcinomas compared to non-tumor control tissue. Loss of FHIT frequently occurred in ACC (55.2%), SDC (68.2%), and SCC (100%). In the totality of tumors, loss of FHIT expression was found in 46.7% (106/227) and was significantly associated with advanced T stage and UICC stage, high-grade histology, loss of p27, PI3K, and survivin. FHIT positivity went along with significantly better overall and disease-specific survival. Negativity of p27 occurred in 28.7% (70/244) of tumors, particularly in SDC (54.4%) and SCC (50%). In the totality of tumors, p27 was associated with advanced patient age, high-grade histology, PI3K, survivin as well as better overall and disease-specific survival (p < 0.05). Positive pERK1/ERK2 expression correlated with positive survivin expression but did not affect overall survival in the totality of tumors. In mucoepidermoid carcinomas, pERK1/ERK2 expression was associated with low-grade malignancy, positive nuclear survivin, and better disease-specific survival.

Conclusions

Loss of FHIT and p27 characterizes aggressive tumor growth and unfavorable prognosis in salivary gland cancer.

Clinical relevance

The results may help to stratify patient-specific therapies according to individual tumor characteristics.

Speight P, Barrett A (2002) Salivary gland tumours. Oral Dis 8:229–240CrossRef

El-Naggar AK (2017) What is new in the World Health Organization 2017 histopathology classification? Curr Treat Options in Oncol 18:43. https://doi.org/10.1007/s11864-017-0469-x CrossRef

Pekarsky Y, Zanesi N, Palamarchuk A, Huebner K, Croce CM (2002) FHIT: from gene discovery to cancer treatment and prevention. Lancet Oncol 3:748–754. https://doi.org/10.1016/s1470-2045(02)00931-2 CrossRefPubMed

Dincer N, Tezel GG, Sungur A, Himmetoglu C, Huebner K, Guler G (2010) Study of FHIT and WWOX expression in mucoepidermoid carcinoma and adenoid cystic carcinoma of salivary gland. Oral Oncol 46:195–199. https://doi.org/10.1016/j.oraloncology.2009.12.003 CrossRefPubMed

Semba S, Trapasso F, Fabbri M, McCorkell KA, Volinia S, Druck T, Iliopoulos D, Pekarsky Y, Ishii H, Garrison PN, Barnes LD, Croce CM, Huebner K (2006) Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential. Oncogene 25:2860–2872. https://doi.org/10.1038/sj.onc.1209323 CrossRefPubMed

Okabe M, Inagaki H, Murase T, Inoue M, Nagai N, Eimoto T (2001) Prognostic significance of p27 and Ki-67 expression in mucoepidermoid carcinoma of the intraoral minor salivary gland. Mod Pathol 14:1008–1014CrossRef

Chu IM, Hengst L, Slingerland JM (2008) The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 8:253–267. https://doi.org/10.1038/nrc2347 CrossRefPubMed

Ben-Izhak O, Akrish S, Gan S, Nagler RM (2009) p27 and salivary cancer. Cancer Immunol Immunother 58:469–473. https://doi.org/10.1007/s00262-008-0547-9 CrossRefPubMed

Handra-Luca A, Ruhin B, Lesty C, Fouret P (2006) P27, SKP2, and extra-cellular signal-related kinase signalling in human salivary gland mucoepidermoid carcinoma. Oral Oncol 42:1005–1010. https://doi.org/10.1016/j.oraloncology.2005.12.022/c CrossRefPubMed

10.

Donovan JC, Milic A, Slingerland JM (2001) Constitutive MEK/MAPK activation leads to p27(Kip1) deregulation and antiestrogen resistance in human breast cancer cells. J Biol Chem 276:40888–40895. https://doi.org/10.1074/jbc.M106448200 CrossRefPubMed

11.

Burotto M, Chiou VL, Lee JM, Kohn EC (2014) The MAPK pathway across different malignancies: a new perspective. Cancer 120:3446–3456. https://doi.org/10.1002/cncr.28864 CrossRefPubMedPubMedCentral

12.

Barnes L, Eveson J, Reichart P, Sidransky D (2005) Pathology and genetics of head and neck tumours. World Health Organization classification of Tumours. IARC, Lyon

13.

Ettl T, Schwarz-Furlan S, Haubner F, Müller S, Zenk J, Gosau M, Reichert TE, Zeitler K (2012) The PI3K/AKT/mTOR signalling pathway is active in salivary gland cancer and implies different functions and prognoses depending on cell localisation. Oral Oncol 48:822–830CrossRef

14.

Ettl T, Stiegler C, Zeitler K, Agaimy A, Zenk J, Reichert TE, Gosau M, Kühnel T, Brockhoff G, Schwarz S (2012) EGFR, HER2, survivin, and loss of pSTAT3 characterize high-grade malignancy in salivary gland cancer with impact on prognosis. Hum Pathol 43:921–931CrossRef

15.

Milanes-Yearsley M, Hammond ME, Pajak TF, Cooper JS, Chang C, Griffin T, Nelson D, Laramore G, Pilepich M (2002) Tissue micro-array: a cost and time-effective method for correlative studies by regional and national cancer study groups. Mod Pathol 15:1366–1373. https://doi.org/10.1097/01.MP.0000036345.18944.22 CrossRefPubMed

16.

Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, Rougier P, Lievre A, Landi B, Boige V, Ducreux M, Ychou M, Bibeau F, Bouche O, Reid J, Stone S, Penault-Llorca F (2009) Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol 27:5924–5930. https://doi.org/10.1200/JCO.2008.21.6796 CrossRefPubMed

17.

Cao J, Li W, Xie J, Du H, Tang W, Wang H, Chen X, Xiao W, Li Y (2006) Down-regulation of FHIT inhibits apoptosis of colorectal cancer: mechanism and clinical implication. Surg Oncol 15:223–233. https://doi.org/10.1016/j.suronc.2007.01.006 CrossRefPubMed

18.

Woenckhaus M, Merk J, Stoehr R, Schaeper F, Gaumann A, Wiebe K, Hartmann A, Hofstaedter F, Dietmaier W (2008) Prognostic value of FHIT, CTNNB1, and MUC1 expression in non-small cell lung cancer. Hum Pathol 39:126–136. https://doi.org/10.1016/j.humpath.2007.05.027 CrossRefPubMed

19.

Dumon K, Ishii H, Vecchione A, Trapasso F, Baldassarre G, Chakrani F, Druck T, Rosato E, Williams N, Baffa R, During M, Huebner K, Croce C (2001) Fragile histidine triad expression delays tumor development and induces apoptosis in human pancreatic cancer1. Cancer Res 61:4827–4836PubMed

20.

Huang Q, Liu Z, Xie F, Liu C, Shao F, Zhu CL, Hu S (2014) Fragile histidine triad (FHIT) suppresses proliferation and promotes apoptosis in cholangiocarcinoma cells by blocking PI3K-Akt pathway. ScientificWorldJournal 2014:179698. https://doi.org/10.1155/2014/179698 CrossRefPubMedPubMedCentral

21.

Li F, Yang J, Ramnath N, Javle MM, Tan D (2005) Nuclear or cytoplasmic expression of survivin: what is the significance? Int J Cancer 114:509–512. https://doi.org/10.1002/ijc.20768 CrossRefPubMedPubMedCentral

22.

Zhao P, Meng Q, Liu LZ, You YP, Liu N, Jiang BH (2010) Regulation of survivin by PI3K/Akt/p70S6K1 pathway. Biochem Biophys Res Commun 395:219–224. https://doi.org/10.1016/j.bbrc.2010.03.165 CrossRefPubMed

23.

Sarli L, Bottarelli L, Azzoni C, Campanini N, Di Cola G, Barilli AL, Marchesi F, Mazzeo A, Salvemini C, Morari S, Di Mauro D, Donadei E, Necchi F, Roncoroni L, Bordi C (2006) Loss of p27 expression and microsatellite instability in sporadic colorectal cancer. Surg Oncol 15:97–106. https://doi.org/10.1016/j.suronc.2006.09.002 CrossRefPubMed

24.

Handra-Luca A, Bilal H, Bertrand J-C, Fouret P (2003) Extra-cellular signal-regulated ERK-1/ERK-2 pathway activation in human salivary gland Mucoepidermoid carcinoma. Am J Pathol 163:957–967. https://doi.org/10.1016/s0002-9440(10)63455-4 CrossRefPubMedPubMedCentral

25.

Deschenes-Simard X, Kottakis F, Meloche S, Ferbeyre G (2014) ERKs in cancer: friends or foes? Cancer Res 74:412–419. https://doi.org/10.1158/0008-5472.CAN-13-2381 CrossRefPubMed

26.

Milde-Langosch K, Bamberger AM, Rieck G, Grund D, Hemminger G, Muller V, Loning T (2005) Expression and prognostic relevance of activated extracellular-regulated kinases (ERK1/2) in breast cancer. Br J Cancer 92:2206–2215. https://doi.org/10.1038/sj.bjc.6602655 CrossRefPubMedPubMedCentral

27.

Lujan B, Hakim S, Moyano S, Nadal A, Caballero M, Diaz A, Valera A, Carrera M, Cardesa A, Alos L (2010) Activation of the EGFR/ERK pathway in high-grade mucoepidermoid carcinomas of the salivary glands. Br J Cancer 103:510–516. https://doi.org/10.1038/sj.bjc.6605788 CrossRefPubMedPubMedCentral

28.

Chen X, Duan N, Zhang C, Zhang W (2016) Survivin and tumorigenesis: molecular mechanisms and therapeutic strategies. J Cancer 7:314–323. https://doi.org/10.7150/jca.13332 CrossRefPubMedPubMedCentral

29.

Ettl T, Baader K, Stiegler C, Muller M, Agaimy A, Zenk J, Kuhnel T, Gosau M, Zeitler K, Schwarz S, Brockhoff G (2012) Loss of PTEN is associated with elevated EGFR and HER2 expression and worse prognosis in salivary gland cancer. Br J Cancer 106:719–726. https://doi.org/10.1038/bjc.2011.605 CrossRefPubMedPubMedCentral

30.

Ettl T, Schwarz S, Kleinsasser N, Hartmann A, Reichert TE, Driemel O (2008) Overexpression of EGFR and absence of C-KIT expression correlate with poor prognosis in salivary gland carcinomas. Histopathology 53:567–577. https://doi.org/10.1111/j.1365-2559.2008.03159.x CrossRefPubMed

31.

Ach T, Zeitler K, Schwarz-Furlan S, Baader K, Agaimy A, Rohrmeier C, Zenk J, Gosau M, Reichert TE, Brockhoff G, Ettl T (2013) Aberrations of MET are associated with copy number gain of EGFR and loss of PTEN and predict poor outcome in patients with salivary gland cancer. Virchows Arch 462:65–72. https://doi.org/10.1007/s00428-012-1358-0 CrossRefPubMed

Title: Predictive value of FHIT, p27, and pERK1/ERK2 in salivary gland carcinomas: a retrospective study
Authors: Mathias Fiedler
Patty Renner
Jürgen Schubert
Florian Weber
Arndt Hartmann
Heinrich Iro
Veronika Vielsmeier
Christopher Bohr
Michael Gerken
Torsten E. Reichert
Tobias Ettl
Publication date: 01-10-2019
Publisher: Springer Berlin Heidelberg
Keywords: Salivary Gland Cancer
Salivary Gland Cancer
Published in: Clinical Oral Investigations / Issue 10/2019
Print ISSN: 1432-6981
Electronic ISSN: 1436-3771
DOI: https://doi.org/10.1007/s00784-019-02809-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Predictive value of FHIT, p27, and pERK1/ERK2 in salivary gland carcinomas: a retrospective study

Abstract

Objectives

Material and methods

Results

Conclusions

Clinical relevance

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Objectives

Material and methods

Results

Conclusions

Clinical relevance

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