Abstract
The objective of this study was to examine B-cell CLL/lymphoma 6 (BCL6) expression in human eutopic endometrium across the menstrual cycle in women with and without endometriosis and to establish a cutoff for future studies. This design was a series of case-control studies in tertiary University teaching hospitals. We examined BCL6 expression by messenger RNA and immu-nohistochemically in prospectively collected samples in both the proliferative (P) and the secretory phases. BCL6 is minimally increased in the mid-secretory phase of the menstrual cycle compared to the P phase in normal patients. BCL6 protein expression was significantly higher in the secretory phase of patients with endometriosis (n = 29) versus fertile controls without endometriosis at laparoscopy (n = 20; P <.0001). Normal fertile controls (n = 28) recruited for endometrial biopsy also had low levels of secretory phase BCL6 expression compared to women with unexplained infertility (Ul; n = I 19). A receiving-operator characteristic analysis of these data revealed an area under the curve of 94% (95% confidence interval 85%-100%; P <.0001) with an HSCORE cutoff of 1.4 to differentiate cases with and without endometriosis. Using this cutoff value, BCL6 was positive in 88% of cases with Ul. Laparoscopic examination of a subset of 65 patients confirmed abnormalities in 98% of cases; 61 (93.8%) were found to have endometriosis, 3 (4.6%) with hydrosalpinx, and I (1.5%) with a normal pelvis. These data suggest that BCL6 is a promising candidate as a Single diagnostic biomarker for detection of endometriosis in women with otherwise Ul and may be associated with endometrial dysfunction, including progesterone resistance.
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References
Large MJ, Demayo FJ. The regulation of embryo implantation and endometrial decidualization by progesterone receptor signal-ing. Mol Cell Endocrinol. 2012;358(2):155–165.
Optimal evaluation of the infertile female. Fertil Steril. 2006;86(5 suppl 1):S264–S267.
Kutteh WH. Novel strategies for the management of recurrent pregnancy loss. Semin Reprod Med. 2015;33(3):161–168.
Nakagawa K, Ohgi S, Horikawa T, Kojima R, Ito M, Saito H. Laparoscopy should be strongly considered for women with unex-plained infertility. J Obstet Gynaecol Res. 2007;33(5):665–670.
Tsuji I, Ami K, Miyazaki A, Hujinami N, Hoshiai H. Benefit of diagnostic laparoscopy for patients with unexplained infertility and normal hysterosalpingography findings. Tohoku J Exp Med. 2009;219(1):39–42.
Bonneau C, Chanelles O, Sifer C, Poncelet C. Use of laparoscopy in unexplained infertility. Eur J Obstet Gynecol Reprod Biol. 2012;163(1):57–61.
McKinnon BD, Bertschi D, Bersinger NA, Mueller MD. Inflam-mation and nerve fiber interaction in endometriotic pain. Trends Endocrinol Metab. 2015;26(1):1–10.
Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389–2398.
Holoch KJ, Lessey BA. Endometriosis and infertility. Clin Obstet Gynecol. 2010;53(2):429–438.
Stratton P. The tangled web of reasons for the delay in diagnosis of endometriosis in women with chronic pelvic pain:will the suffering end? Fertil Steril. 2006;86(5):1302–1304; discussion 17.
Yoimg SL, Lessey BA. Progesterone fimction in human endome-trium:clinical perspectives. Semin Reprod Med. 2010;28(1):5–16.
Allavena G, Carrarelli P, Del Bello B, Luisi S, Petraglia F, Maellaro E. Autophagy is upregulated in ovarian endometriosis:a possible interplay with p53 and heme oxygenase-1. Fertil Steril. 2015;103(5):1244–1251.e1.
Phan RT and Dalla-Favera R. The BCL6 proto-oncogene sup-presses p53 expression in germinal-centre B cells. Nature. 2004;432(7017):635–639.
Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity. 2000;13(2):199–212.
Arguni E, Arima M, Tsuruoka N, Sakamoto A, Hatano M, Toku-hisa T. JunD/AP-1 and STAT3 are the major enhancer molecules for high Bcl6 expression in germinal center B cells. Int Immunol. 2006;18(7):1079–1089.
Kim BG, Yoo JY, Kim TH, et al.. Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis. Hum Reprod. 2015;30(5):1069–1078.
Wu L, Guo L, Liang Y, Liu X, Jiang L, Wang L. Curcumin suppresses stem-like traits of lung Cancer cells via inhibiting the JAK2/STAT3 signaling pathway. Oncol Rep. 2015;34(6):3311–3317.
Carro MS, Lim WK, Alvarez MJ, et al.. The transcriptional net-work for mesenchymal transformation of brain tumours. Nature. 2010;463(7279):318–325.
Ye BH, Lista F, Lo Coco F, et al.. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science. 1993;262(5134):747–750.
Lossos IS, Jones CD, Zehnder JL, Levy R. A polymorphism in the BCL-6 gene is associated with follicle center lymphoma. Leuk lymphoma. 2001;42(6):1343–1350.
Ci W, Polo JM, Cerchietti L, et al.. The BCL6 transcriptional program features repression of multiple oncogenes in primary B cells and is deregulated in DLBCL. Blood. 2009;113(22):5536–5548.
Peh SC, Gan GG, Lee LK, Eow Gl. Clinical relevance of CD10, BCL-6 and multiple myeloma-1 expression in diffuse large B-cell lymphomas in Malaysia. Pathol Int. 2008;58(9):572–579.
Yao D, Cai GH, Chen J, Ling R, Wu SX, Li YP. Prognostic value of p53 alterations in human osteosarcoma:a meta analysis. Int J Clin Exp Pathol. 2014;7(10):6725–6733.
Li X, Large MJ, Creighton CJ, et al.. COUP-TFII regulates human endometrial stromal genes involved in inflammation. Mol Endo-crinol. 2013;27(12):2041–2054.
Lin SC, Li YH, Wu MH, et al.. Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis. J Clin Endocrinol Metab. 2014;99(3):E427–E437.
Franasiak JM, Holoch KJ, Yuan L, Schammel DP, Young SL, Lessey BA. Prospective assessment of midsecretory endometrial leukemia inhibitor factor expression versus alphanubeta3 testing in women with unexplained infertility. Fertil Steril. 2014;101(6):1724–1731.
Noyes RW, Hertig AI, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1(1):3–25.
The Revised American Society for Reproductive Medicine Classification of endometriosis: 1996. Fertil Steril. 1997;67(5):822–829.
Cooper TG, Noonan E, von Eckardstein S, et al.. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16(3):231–245.
Arnold JT, Kaufman DG, Seppala M, Lessey BA. Endometrial stromal cells regulate epithelial cell growth in vitro:a new co-culture model. Hum Reprod. 2001;16(5):836–845.
Plante BJ, Lessey BA, Taylor RN, et al.. G protein-coupled estro-gen receptor (GPER) expression in normal and abnormal endo-metrium. Reprod Sci. 2012;19(7):684–693.
Roemer KL, Young SL, Savaris RF. Characterization of GABI expression over the menstrual cycle in women with and without polycystic ovarian Syndrome provides a new insight into its pathophysiology. J Clin Endocrinol Metab. 2014;99(11):E2162–E2168.
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 2008;3(6):1101–1108.
Budwit-Novotny DA, McCarty KS, Cox EB, et al.. Immunohisto-chemical analyses of estrogen receptor in endometrial adenocar-cinoma using a monoclonal antibody. Cancer Res. 1986;46(10):5419–5425.
Jekel JF, Elmore JG, Katz DL. Jekel’s Epidemiology, Biostatistics, Preventive Medicine, and Public Health. Ist ed. Philadelphia, PA: W.B. Saunders; 1996, p.xiii, 405 p.
Obuchowski NA, Lieber ML, Wians FH Jr. ROC curves in clinical chemistry:uses, misuses, and possible Solutions. Clin Chem. 2004;50(7):1118–1125.
Agic A, Xu H, Finas D, Banz C, Diedrich K, Hornung D. Is endometriosis associated with systemic subclinical inflammation? Gynecol Obstet Invest. 2006;62(3):139–147.
Buyalos RP, Funari VA, Azziz R, Watson JM, Martinez-Maza O. Elevated interleukin-6 levels in peritoneal fluid of patients with pelvic pathology. Fertil Steril. 1992;58(2):302–306.
Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohi J, Simon C. The follicular and endoerine environment in women with endometriosis:local and systemic cytokine produetion. Fertil Steril. 1998;70(3):425–431.
D’Hooghe TM, Debrock S, Hill JA, Meuleman C. Endometriosis and subfertility:is the relationship resolved? Semin Reprod Med. 2003;21(2):243–254.
Meyer WR, Castelbaum AJ, Somkuti S, et al.. Hydrosalpinges adversely affect markers of endometrial receptivity. Hum Reprod. 1997;12(7):1393–1398.
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Evans-Hoeker, E., Lessey, B.A., Jeong, J.W. et al. Endometrial BCL6 Overexpression in Eutopic Endometrium of Women With Endometriosis. Reprod. Sci. 23, 1234–1241 (2016). https://doi.org/10.1177/1933719116649711
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DOI: https://doi.org/10.1177/1933719116649711