Molecular determinants for lymph node metastasis in clinically early-stage endometrial cancer

Bou Zgheib,Nadim; Marchion,Douglas  C.; Bush,Stephen  H.; Judson,Patricia  L.; Wenham,Robert  M.; Apte,Sachin  M.; Lancaster,Johnathan  M.; Gonzalez‑Bosquet,Jesus

doi:10.3892/ol.2015.3883

Molecular determinants for lymph node metastasis in clinically early-stage endometrial cancer

Authors:
- Nadim Bou Zgheib
- Douglas C. Marchion
- Stephen H. Bush
- Patricia L. Judson
- Robert M. Wenham
- Sachin M. Apte
- Johnathan M. Lancaster
- Jesus Gonzalez‑Bosquet
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Affiliations: Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA, Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa Hospital and Clinics, Iowa, IA 52242, USA
Published online on: November 6, 2015 https://doi.org/10.3892/ol.2015.3883
Pages: 323-329

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Abstract

Patients with occult lymph node metastasis in endometrioid-type endometrial cancer (EC) are prone to the development of recurrences and have worse outcomes compared with patients without lymph node metastasis. In the current study, the aim was to identify molecular parameters associated with lymph node metastasis in EC clinically early‑stage disease. A univariate analysis of differentially expressed genes, proteins and clinicopathological parameters (including myometrial invasion and tumor grade) was performed, comparing EC patients with and without lymph node metastasis (n=262 patients from The Cancer Genome Atlas). Significant parameters were introduced in a multivariate model and a gene expression pathway analysis. Lymph node metastasis was associated with expression of 268 unique genes (P<0.001), 19 unique proteins (P<0.05), tumor grade and myometrial invasion in univariate analysis. Multivariate analysis demonstrated 10 genes independently associated with lymph node metastasis and 4 independently associated proteins. Myometrial invasion was the only independent clinicopathological parameter associated with lymph node status. The enrichment pathway analysis demonstrated that expression of epidermal growth factor receptor, Bcl2 antagonist of cell death and phosphatase and tensin homolog pathways were significantly involved in lymph node metastasis (P≤0.001). A gene expression signature to predict lymph node status in EC was created for future validation. Few studies have focused on the association between EC's molecular characteristics and nodal metastasis. Defining molecular risk factors for EC lymphatic nodal metastasis may help to individualize treatment and improve patient outcomes.

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1	Siegel R, Maj Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE and Heller PB: Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer. 60:2035–2041. 1987. View Article : Google Scholar : PubMed/NCBI
3	Morrow CP, Bundy BN, Kurman RJ, Creasman WT, Heller P, Homesley HD and Graham JE: Relationship between surgical-pathological risk factors and outcome in clinical stage I and II carcinoma of the endometrium: A gynecologic oncology group study. Gynecol Oncol. 40:55–65. 1991. View Article : Google Scholar : PubMed/NCBI
4	Faught W, Krepart GV, Lotocki R and Heywood M: Should selective paraaortic lymphadenectomy be part of surgical staging for endometrial cancer? Gynecol Oncol. 55:51–55. 1994. View Article : Google Scholar : PubMed/NCBI
5	Kim YB and Niloff JM: Endometrial carcinoma: Analysis of recurrence in patients treated with a strategy minimizing lymph node sampling and radiation therapy. Obstet Gynecol. 82:175–180. 1993.PubMed/NCBI
6	Orr JW Jr, Holimon JL and Orr PF: Stage I corpus cancer: Is teletherapy necessary? Am J Obstet Gynecol. 176:777–788; discussion 788–779. 1997. View Article : Google Scholar : PubMed/NCBI
7	Homesley HD, Kadar N, Barrett RJ and Lentz SS: Selective pelvic and periaortic lymphadenectomy does not increase morbidity in surgical staging of endometrial carcinoma. Am J Obstet Gynecol. 167:1225–1230. 1992. View Article : Google Scholar : PubMed/NCBI
8	Abu-Rustum NR, Alektiar K, Iasonos A, Lev G, Sonoda Y, Aghajanian C, Chi DS and Barakat RR: The incidence of symptomatic lower-extremity lymphedema following treatment of uterine corpus malignancies: A 12-year experience at memorial Sloan-Kettering cancer center. Gynecol Oncol. 103:714–718. 2006. View Article : Google Scholar : PubMed/NCBI
9	Cheng WF, Chen CA, Lee CN, Chen TM, Huang KT, Hsieh CY and Hsieh FJ: Preoperative ultrasound study in predicting lymph node metastasis for endometrial cancer patients. Gynecol Oncol. 71:424–427. 1998. View Article : Google Scholar : PubMed/NCBI
10	La Fianza A, Di Maggio EM, Preda L, Coscia D, Tateo S and Campani R: Clinical usefulness of CT in the treatment of stage I endometrial carcinoma. Radiol Med. 93:567–571. 1997.PubMed/NCBI
11	Frei KA, Kinkel K, Bonél HM, Lu Y, Zaloudek C and Hricak H: Prediction of deep myometrial invasion in patients with endometrial cancer: Clinical utility of contrast-enhanced MR imaging-a meta-analysis and Bayesian analysis. Radiology. 216:444–449. 2000. View Article : Google Scholar : PubMed/NCBI
12	Cancer Genome Atlas Research Network. Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, Shen H, Robertson AG, Pashtan I, Shen R, et al: Integrated genomic characterization of endometrial carcinoma. Nature. 497:67–73. 2013. View Article : Google Scholar : PubMed/NCBI
13	Ohga T, Koike K, Ono M, Makino Y, Itagaki Y, Tanimoto M, Kuwano M and Kohno K: Role of the human Y box-binding protein YB-1 in cellular sensitivity to the DNA-damaging agents cisplatin, mitomycin C and ultraviolet light. Cancer Res. 56:4224–4228. 1996.PubMed/NCBI
14	Abal M, Llauradó M, Doll A, Monge M, Colas E, González M, Rigau M, Alazzouzi H, Demajo S, Castellví J, et al: Molecular determinants of invasion in endometrial cancer. Clin Transl Oncol. 9:272–277. 2007. View Article : Google Scholar : PubMed/NCBI
15	Colas E, Perez C, Cabrera S, Pedrola N, Monge M, Castellvi J, Eyzaguirre F, Gregorio J, Ruiz A, Llaurado M, et al: Molecular markers of endometrial carcinoma detected in uterine aspirates. Int J Cancer. 129:2435–2444. 2011. View Article : Google Scholar : PubMed/NCBI
16	Sun P, Xia S, Lal B, Eberhart CG, Quinones-Hinojosa A, Maciaczyk J, Matsui W, Dimeco F, Piccirillo SM, Vescovi AL and Laterra J: DNER, an epigenetically modulated gene, regulates glioblastoma-derived neurosphere cell differentiation and tumor propagation. Stem Cells. 27:1473–1486. 2009. View Article : Google Scholar : PubMed/NCBI
17	Dewdney SB, Rimel BJ, Thaker PH, Thompson DM Jr, Schmidt A, Huettner P, Mutch DG, Gao F and Goodfellow PJ: Aberrant methylation of the X-linked ribosomal S6 kinase RPS6KA6 (RSK4) in endometrial cancers. Clin Cancer Res. 17:2120–2129. 2011. View Article : Google Scholar : PubMed/NCBI
18	Bartman AE, Buisine MP, Aubert JP, Niehans GA, Toribara NW, Kim YS, Kelly EJ, Crabtree JE and Ho SB: The MUC6 secretory mucin gene is expressed in a wide variety of epithelial tissues. J Pathol. 186:398–405. 1998. View Article : Google Scholar : PubMed/NCBI
19	Herbst RS: Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys. 59:21–26. 2004. View Article : Google Scholar : PubMed/NCBI
20	Konecny GE, Santos L, Winterhoff B, Hatmal M, Keeney GL, Mariani A, Jones M, Neuper C, Thomas B, Muderspach L and Riehle D: HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer. Br J Cancer. 100:89–95. 2009. View Article : Google Scholar : PubMed/NCBI
21	Ise T, Nagatani G, Imamura T, Kato K, Takano H, Nomoto M, Izumi H, Ohmori H, Okamoto T, Ohga T, et al: Transcription factor Y-box binding protein 1 binds preferentially to cisplatin-modified DNA and interacts with proliferating cell nuclear antigen. Cancer Res. 59:342–346. 1999.PubMed/NCBI
22	Albitar L, Pickett G, Morgan M, Wilken JA, Maihle NJ and Leslie KK: EGFR isoforms and gene regulation in human endometrial cancer cells. Mol Cancer. 9:1662010. View Article : Google Scholar : PubMed/NCBI
23	Chon HS, Marchion DC, Xiong Y, Chen N, Bicaku E, Stickles XB, Bou Zgheib N, Judson PL, Hakam A, Gonzalez-Bosquet J, et al: The BCL2 antagonist of cell death pathway influences endometrial cancer cell sensitivity to cisplatin. Gynecol Oncol. 124:119–124. 2012. View Article : Google Scholar : PubMed/NCBI
24	Tashiro H, Blazes MS, Wu R, Cho KR, Bose S, Wang SI, Li J, Parsons R and Ellenson LH: Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res. 57:3935–3940. 1997.PubMed/NCBI