Discovery of the prognostic marker in the whole blood sample of gestational trophoblastic neoplasia beyond immunohistochemical tissue markers: mdm2

Gestational trophoblastic disease (GTD) is an abnormal trophoblastic proliferation disease that may show malignant progression. Despite reports on the clinical and laboratory parameters for the projection of GTD, there is still a lack of histopathologic or genetic prognostic markers for patients with higher risks of malignant progression and high-risk gestational trophoblastic neoplasia. The primary aim of this study was to identify a marker other than tissue markers for evaluating the progression potential of GTD to gestational trophoblastic neoplasia (GTN). The secondary aim was to determine the tissue marker capacity to detect the progression to neoplasia. The study design was a case-control. The data of 81 patients diagnosed with GTD and 23 control were assessed. Their detailed obstetric and gynecological history were recorded, and their whole blood sample was obtained for genetic evaluation of the mouse double minute 2 (mdm2) gene expression. We also evaluated the curettage specimens for p53, c-erythroblastic oncogene B-2 (c-erbB-2), and ki67 protein expression. The expression of p53 expression was significantly increased in GTD patients and significantly higher in the GTN progressing group than in the spontaneous remission group. Although blood mdm2 gene was significantly different between the low and high-risk GTN subgroups, its expression was not different between the GTD or GTN groups. Additionally, a significant increase in c-erbB-2 was observed in the GTN group. Mdm2 might be a promising blood prognostic factor throughout the course of GTD. p53 and c-erbB-2 might be used as predictive indicators for the early diagnosis of GTN progression. Altogether, these markers may help identify patients with high risks of malignant progression, guide earlier aggressive treatment and increase treatment outcomes.

mdm2; p53; c-erbB-2; Ki67; Gestational trophoblastic disease; Gestational trophoblastic neoplasia

[1] Horowitz NS, Eskander RN, Adelman MR, Burke W. Epidemiology, diagnosis, and treatment of gestational trophoblastic disease: a society of Gynecologic Oncology evidenced-based review and recommendation. Gynecologic Oncology. 2021; 163: 605–613.

[2] Ngan HYS, Seckl MJ, Berkowitz RS, Xiang Y, Golfier F, Sekharan PK, et al. Update on the diagnosis and management of gestational trophoblastic disease. International Journal of Gynaecology and Obstetrics. 2018; 143: 79–85.

[3] Novak E. Berek & Novak’s gynecology. 14th edn. Lippincott Williams & Wilkins: Philadelphia, PA. 2007.

[4] FIGO Oncology Committee. FIGO staging for gestational trophoblastic neoplasia 2000. FIGO Oncology Committee. International Journal of Gynaecology and Obstetrics. 2002; 77: 285–287.

[5] Wang S, Zhao Y, Aguilar A, Bernard D, Yang C. Targeting the MDM2-p53 protein-protein interaction for new cancer therapy: progress and challenges. Cold Spring Harbor Perspectives in Medicine. 2017; 7: a026245.

[6] Ingaramo MC, Sánchez JA, Dekanty A. Regulation and function of p53: a perspective from Drosophila studies. Mechanisms of Development. 2018; 154: 82–90.

[7] Petitjean A, Achatz MIW, Borresen-Dale AL, Hainaut P, Olivier M. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene. 2007; 26: 2157–2165.

[8] Cohen M, Meisser A, Haenggeli L, Irminger-Finger I, Bischof P. Status of p53 in first-trimester cytotrophoblastic cells. Molecular Human Reproduction. 2007; 13: 111–116.

[9] Bittenbring J, Parisot F, Wabo A, Mueller M, Kerschenmeyer L, Kreuz M, et al. MDM2 gene SNP309 T/G and p53 gene SNP72 G/C do not influence diffuse large B-cell non-Hodgkin lymphoma onset or survival in central European Caucasians. BMC Cancer. 2008; 8: 116.

[10] Missaoui N, Landolsi H, Mestiri S, Essakly A, Abdessayed N, Hmissa S, et al. Immunohistochemical analysis of c-erbB-2, Bcl-2, p53, p21WAF 1/Cip1, p63 and Ki-67 expression in hydatidiform moles. Pathology, Research and Practice. 2019; 215: 446–452.

[11] Xu Z, Ford BD. Upregulation of erbB receptors in rat brain after middle cerebral arterial occlusion. Neuroscience Letters. 2005; 375: 181–186.

[12] Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. Journal of Cellular Physiology. 2000; 182: 311–322.

[13] Ngu S, Chan KKL. Management of chemoresistant and quiescent gestational trophoblastic disease. Current Obstetrics and Gynecology Reports. 2014; 3: 84–90.

[14] Sun P, Wu Q, Ruan G, Zheng X, Song Y, Zhun J, et al. Expression patterns of maspin and mutant p53 are associated with the development of gestational trophoblastic neoplasia. Oncology Letters. 2016; 12: 3135–3142.

[15] Cheung AN, Srivastava G, Chung LP, Ngan HY, Man TK, Liu YT, et al. Expression of the p53 gene in trophoblastic cells in hydatidiform moles and normal human placentas. The Journal of Reproductive Medicine. 1994; 39: 223–227.

[16] Cheung AN, Shen DH, Khoo US, Wong LC, Ngan HY. P21WAF1/CIP1 expression in gestational trophoblastic disease: correlation with clinico-pathological parameters, and Ki67 and p53 gene expression. Journal of Clinical Pathology. 1998; 51: 159–162.

[17] Fukunaga M, Katabuchi H, Nagasaka T, Mikami Y, Minamiguchi S, Lage JM. Interobserver and intraobserver variability in the diagnosis of hydatidiform mole. The American Journal of Surgical Pathology. 2005; 29: 942–947.

[18] Fulop V, Mok SC, Genest DR, Gati I, Doszpod J, Berkowitz RS. p53, p21, Rb and mdm2 oncoproteins. Expression in normal placenta, partial and complete mole, and choriocarcinoma. The Journal of Reproductive Medicine. 1998; 43: 119–127.

[19] Fulop V, Mok SC, Genest DR, Szigetvari I, Cseh I, Berkowitz RS. c- myc, c-erbB-2, c-fms and bcl-2 oncoproteins. Expression in normal placenta, partial and complete mole, and choriocarcinoma. The Journal of Reproductive Medicine. 1998; 43: 101–110.

[20] Yang X, Zhang Z, Jia C, Li J, Yin L, Jiang S. The relationship between expression of c-ras, c-erbB-2, nm23, and p53 gene products and development of trophoblastic tumor and their predictive significance for the malignant transformation of complete hydatidiform mole. Gynecologic Oncology. 2002; 85: 438–444.

[21] Hasanzadeh M, Sharifi N, Farazestanian M, Nazemian SS, Madani Sani F. Immunohistochemistry study of P53 and C-erbB-2 Expression in trophoblastic tissue and their predictive values in diagnosing malignant progression of simple molar pregnancy. Iranian Journal of Cancer Prevention. 2016; 9: e4115.

[22] Yazaki-Sun S, Daher S, de Souza Ishigai MM, Alves MT, Mantovani TM, Mattar R. Correlation of c-erbB-2 oncogene and p53 tumor suppressor gene with malignant transformation of hydatidiform mole. The Journal of Obstetrics and Gynaecology Research. 2006; 32: 265–272.

[23] Mak VCY, Lee L, Siu MKY, Wong OGW, Lu X, Ngan HYS, et al. Downregulation of ASPP1 in gestational trophoblastic disease: correlation with hypermethylation, apoptotic activity and clinical outcome. Modern Pathology. 2011; 24: 522–532.

[24] Chan K, Wong ES, Wong IT, Cheung CL, Wong OG, Ngan HY, et al. Overexpression of iASPP is required for autophagy in response to oxidative stress in choriocarcinoma. BMC Cancer. 2019; 19: 953.

[25] Zhang H, Siu MK, Jiang L, Mak VC, Ngan HY, Cheung AN. Overexpression of the Parkinson disease protein DJ-1 and its regulator PTEN in gestational trophoblastic disease. International Journal of Gynecological Pathology. 2010; 29: 468–475.

[26] Cheung AN, Shen DH, Khoo US, Chiu MP, Tin VP, Chung LP, et al. Immunohistochemical and mutational analysis of p53 tumor suppressor gene in gestational trophoblastic disease: correlation with mdm2, proliferation index, and clinicopathologic parameters. International Journal of Gynecological Cancer. 1999; 9: 123–130.

[27] Lertkhachonsuk R, Tantbirojn P, Paiwattananupant K. PTEN and MDM2 expression in the prediction of postmolar gestational trophoblastic neoplasia. The Journal of Reproductive Medicine. 2012; 57: 333–340.

[28] Wang Y, Cao Y, Sun Y. Expression of c-erbB2 in gestational trophoblastic disease and its clinical significance. Journal of Huazhong University of Science and Technology. 2002; 22: 123–125.

[29] Jelincic D, Hudelist G, Singer CF, Bauer M, Horn LC, Bilek K, et al. Clinicopathologic profile of gestational trophoblastic disease. Wiener klinische Wochenschrift. 2003; 115: 29–35.

[30] Tuncer ZS, Vegh GL, Fulop V, Genest DR, Mok SC, Berkowitz RS. Expression of epidermal growth factor receptor-related family products in gestational trophoblastic diseases and normal placenta and its relationship with development of postmolar tumor. Gynecologic Oncology. 2000; 77: 389–393.

[31] Nagib RM, M A Zaki M, Wageh A, Abdelrazik M. Can Ki67 and caspase predict molar progression? Fetal and Pediatric Pathology. 2019; 38: 444–448.

[32] Kar A, Mishra C, Biswal P, Kar T, Panda S, Naik S. Differential expression of cyclin E, p63, and Ki-67 in gestational trophoblastic disease and its role in diagnosis and management: a prospective case-control study. Indian Journal of Pathology and Microbiology. 2019; 62: 54–60.

[33] Chen Y, Shen D, Gu Y, Zhong P, Xie J, Song Q. The diagnostic value of Ki-67, P53 and P63 in distinguishing partial Hydatidiform mole from hydropic abortion. Wiener klinische Wochenschrift. 2012; 124: 184–187.

[34] Hasanzadeh M, Sharifi N, Esmaieli H, Daloee MS, Tabari A. Immunohis-tochemical expression of the proliferative marker Ki67 in hydatidiform moles and its diagnostic value in the progression to gestational trophoblastic neoplasia. The Journal of Obstetrics and Gynaecology Research. 2013; 39: 572–577.