Prediction of lymphovascular space invasion in endometrial cancer using the 55-gene signature selected by DNA microarray analysis

Autoři: Takafumi Watanabe aff001;  Reiko Honma aff002;  Manabu Kojima aff001;  Shinji Nomura aff001;  Shigenori Furukawa aff001;  Shu Soeda aff001;  Shinya Watanabe aff003;  Keiya Fujimori aff001
Působiště autorů: Department of Obstetrics and Gynecology, Fukushima Medical University School of Medicine, Fukushima, Japan aff001;  Nippon Gene Co., Ltd., Chiyoda, Tokyo, Japan aff002;  Medical-Industrial Translational Research Center, Fukushima Medical University School of Medicine, Fukushima, Japan aff003
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223178


Lymphovascular space invasion (LVSI) is considered to be the beginning of lymphogenous and hematogenous metastases. It is strongly related to dissemination, and therefore could be a valuable predictive sign of lymph node metastases and distant spread. Recently, the presence of LVSI in endometrial cancer (EC) has been shown to be an independent prognostic factor. The preoperative diagnosis of LVSI by pathological examination is difficult and LVSI is detected after surgery. The aim of the current study was to explore candidate genes as potential diagnostic biomarkers and determine whether they are predictors of LVSI in patients with EC. A total of 88 surgical specimens obtained from EC patients who had undergone surgical resection at Fukushima Medical University Hospital between 2010 and 2015 were analyzed using DNA microarray. LVSI was significantly associated with poor prognostic factors in EC such as higher tumor grade, lymph node metastasis, deep myometrium invasion, advanced stage and recurrence. Fifty-five candidate genes were significantly differentially expressed between 26 LVSI-positive and 62 LVSI-negative samples. All 88 samples were divided into two groups according to hierarchical clustering of 55 genes. Regarding diagnostic accuracy, sensitivity and negative predictive value were both high (92% and 95%, respectively); further, specificity and positive predictive value were both moderate (63% and 71%, respectively). Our data suggests that the 55-gene signature could contribute to predicting LVSI in EC, and provide clinically important information for better management. The molecular signatures of 55 genes may be also useful for understanding the underlying mechanism of LVSI.

Klíčová slova:

Diagnostic medicine – Gene expression – Histology – Lymph nodes – Metastasis – Microarrays – Surgical and invasive medical procedures – Hierarchical clustering


1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008: Int J Cancer 2010; 127(12): 2893–2917. doi: 10.1002/ijc.25516 21351269

2. Creasman WT, Odicino F, Maisonneuve P, Beller U, Benedet JL, Heintz AP et al. Carcinoma of the corpus uteri. J Epidemiol Biostat 2001; 6(1): 47–86. 11385776

3. Press JZ, Gotlieb WH. Controversies in the treatment of early stage endometrial carcinoma. Obstet Gynecol Int 2012; 2012: 578490. doi: 10.1155/2012/578490 22685466

4. Pecorelli S. Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 2009; 105(2): 103–104. doi: 10.1016/j.ijgo.2009.02.012 19367689

5. Bosse T, Peters EE, Creutzberg CL, Jürgenliemk-Schulz IM, Jobsen JJ, Mens JW et al. Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer—A pooled analysis of PORTEC 1 and 2 trials. Eur J Cancer 2015; 51(13): 1742–1750. doi: 10.1016/j.ejca.2015.05.015 26049688

6. Guntupalli SR, Zighelboim I, Kizer NT, Zhang Q, Powell MA, Thaker PH et al. Lymphovascular space invasion is an independent risk factor for nodal disease and poor outcomes in endometrioid endometrial cancer. Gynecol Oncol 2012; 124(1): 31–35. doi: 10.1016/j.ygyno.2011.09.017 22030404

7. Briët JM, Hollema H, Reesink N, Aalders JG, Mourits MJ, ten Hoor KA, et al. Lymphvascular space involvement: an independent prognostic factor in endometrial cancer. Gynecol Oncol 2005; 96(3): 799–804. doi: 10.1016/j.ygyno.2004.11.033 15721428

8. Nofech-Mozes S, Ackerman I, Ghorab Z, Ismiil N, Thomas G, Covens A et al. Lymphovascular invasion is a significant predictor for distant recurrence in patients with early-stage endometrial endometrioid adenocarcinoma. Am J Clin Pathol 2008; 129(6): 912–917. doi: 10.1309/CP3HGX7H753QQU8T 18480008

9. Mohammed RA, Martin SG, Gill MS, Green AR, Paish EC, Ellis IO. Improved methods of detection of lymphovascular invasion demonstrate that it is the predominant method of vascular invasion in breast cancer and has important clinical consequences. Am J Surg Pathol 2007; 31(12): 1825–1833. doi: 10.1097/PAS.0b013e31806841f6 18043036

10. Tada T, Honma R, Imai JI, Saze Z, Kogure M, Marubashi S et al. A novel gene expression scoring system for accurate diagnosis of basaloid squamous cell carcinoma of the esophagus. Int J Oncol 2017; 51(3): 877–886. doi: 10.3892/ijo.2017.4075 28731134

11. Miura A, Honma R, Togashi T, Yanagisawa Y, Ito E, Imai J et al. Differential responses of normal human coronary artery endothelial cells against multiple cytokines comparatively assessed by gene expression profiles. FEBS Lett 2006; 580(30): 6871–6879. doi: 10.1016/j.febslet.2006.11.041 17157299

12. Mi H, Poudel S, Muruganujan A, Casagrande JT, Thomas PD. PANTHER version 10: expanded protein families and functions, and analysis tools. Nucleic Acids Res 2016; 44(D1): D336–342. doi: 10.1093/nar/gkv1194 26578592

13. Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD et al. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 2004; 92(3): 744–751. doi: 10.1016/j.ygyno.2003.11.048 14984936

14. Cohn DE, Horowitz NS, Mutch DG, Kim SM, Manolitsas T, Fowler JM. Should the presence of lymphvascular space involvement be used to assign patients to adjuvant therapy following hysterectomy for unstaged endometrial cancer? Gynecol Oncol 2002; 87(3): 243–246. doi: 10.1006/gyno.2002.6825 12468320

15. Koskas M, Bassot K, Graesslin O, Aristizabal P, Barranger E, Clavel-Chapelon F et al. Impact of lymphovascular space invasion on a nomogram for predicting lymph node metastasis in endometrial cancer. Gynecol Oncol 2013; 129(2): 292–297. doi: 10.1016/j.ygyno.2013.02.027 23480871

16. dos Reis R, Burzawa JK, Tsunoda AT, Hosaka M, Frumovitz M, Westin SN et al. Lymphovascular Space Invasion Portends Poor Prognosis in Low-Risk Endometrial Cancer. Int J Gynecol Cancer 2015; 25(7): 1292–1299. doi: 10.1097/IGC.0000000000000490 26067863

17. Kamal M, Burmeister C, Zhang Z, Munkarah A, Elshaikh MA. Obesity and Lymphovascular Invasion in Women with Uterine Endometrioid Carcinoma. Anticancer Res 2015; 35(7): 4053–4057. 26124354

18. Lino-Silva LS, de Leon DC, Salcedo-Hernandez RA, Cavazos-Saman C, Pérez-Montiel MD. A high body mass index is not a worse prognostic factor for endometrial carcinoma in a predominantly obese population. Clin Transl Oncol 2013; 15(3): 243–247. doi: 10.1007/s12094-012-0906-z 22855188

19. Mannelqvist M, Stefansson IM, Bredholt G, Hellem Bø T, Oyan AM, Jonassen I et al. Gene expression patterns related to vascular invasion and aggressive features in endometrial cancer. Am J Pathol 2011; 178(2): 861–871. doi: 10.1016/j.ajpath.2010.10.040 21281818

20. Mínguez B, Hoshida Y, Villanueva A, Toffanin S, Cabellos L, Thung S et al. Gene-expression signature of vascular invasion in hepatocellular carcinoma. J Hepatol 2011; 55(6): 1325–1331. doi: 10.1016/j.jhep.2011.02.034 21703203

21. Stegmeier F, Rape M, Draviam VM, Nalepa G, Sowa ME, Ang XL et al. Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. Nature 2007; 446(7138): 876–881. doi: 10.1038/nature05694 17443180

22. Townsley FM, Aristarkhov A, Beck S, Hershko A, Ruderman JV. Dominant-negative cyclin-selective ubiquitin carrier protein E2-C/UbcH10 blocks cells in metaphase. Proc Natl Acad Sci U S A 1997; 94(6): 2362–2367. doi: 10.1073/pnas.94.6.2362 9122200

23. Aleskandarany MA, Sonbul SN, Mukherjee A, Rakha EA. Molecular Mechanisms Underlying Lymphovascular Invasion in Invasive Breast Cancer. Pathobiology 2015; 82(3–4): 113–123. doi: 10.1159/000433583 26330352

24. Gu X. Li B, Jiang M, Fang M, Ji J, Wang A, Wang M et al. RNA sequencing reveals differentially expressed genes as potential diagnostic and prognostic indicators of gallbladder carcinoma. Oncotarget 2015; 6(24): 20661–20671. doi: 10.18632/oncotarget.3861 25970782

25. Kuroda T, Yasuda S, Nakashima H, Takada N, Matsuyama S, Kusakawa S et al. Identification of a Gene Encoding Slow Skeletal Muscle Troponin T as a Novel Marker for Immortalization of Retinal Pigment Epithelial Cells. Sci Rep 2017 15; 7(1): 8163. doi: 10.1038/s41598-017-08014-w 28811571

26. Lawrenson K, Pakzamir E, Liu B, Lee JM, Delgado MK, Duncan K et al. Molecular Analysis of Mixed Endometrioid and Serous Adenocarcinoma of the Endometrium. PLoS One 2015; 10(7): e0130909. doi: 10.1371/journal.pone.0130909 26132201

27. Zhou X, Wang H, Wang X. Preoperative CA125 and fibrinogen in patients with endometrial cancer: a risk model for predicting lymphovascular space invasion. J Gynecol Oncol 2017; 28(2): e11. doi: 10.3802/jgo.2017.28.e11 27894164

28. Risinger JI, Maxwell GL, Chandramouli GV, Jazaeri A, Aprelikova O, Patterson T et al. Microarray analysis reveals distinct gene expression profiles among different histologic types of endometrial cancer. Cancer Res 2003; 63(1): 6–11. 12517768

29. Zorn KK, Bonome T, Gangi L, Chandramouli GV, Awtrey CS, Gardner GJ et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res 2005; 11(18): 6422–6430. doi: 10.1158/1078-0432.CCR-05-0508 16166416

30. Mhawech-Fauceglia P, Wang D, Kesterson J, Clark K, Monhollen L, Odunsi K et al. Microarray analysis reveals distinct gene expression profiles among different tumor histology, stage and disease outcomes in endometrial adenocarcinoma. PLoS One 2010; 5(11): e15415. doi: 10.1371/journal.pone.0015415 21079744

31. Yoshida E, Terao Y, Hayashi N, Mogushi K, Arakawa A, Tanaka Y et al. Promoter-level transcriptome in primary lesions of endometrial cancer identified biomarkers associated with lymph node metastasis. Sci Rep 2017; 7(1): 14160. doi: 10.1038/s41598-017-14418-5 29074988

32. Colas E, Perez C, Cabrera S, Pedrola N, Monge M, Castellvi J et al. Molecular markers of endometrial carcinoma detected in uterine aspirates. Int J Cancer 2011; 129(10): 2435–2444. doi: 10.1002/ijc.25901 21207424

33. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer 1987; 60 (8 Suppl): 2035–2041. doi: 10.1002/1097-0142(19901015)60:8+<2035::aid-cncr2820601515>;2-8 3652025

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