Abstract
Aim: The present study aimed to assess the association between IGF2/H19 genetic variants and susceptibility to platinum-based chemotherapy in epithelial ovarian cancer (EOC). Methods: A total of 43 platinum-resistant (PR) and 138 platinum-sensitive (PS) EOC patients were recruited in our study. 21 polymorphisms in IGF2/H19 locus were genotyped by Sequenom MassARRAY assay. Results: The frequencies of GG genotype in both rs3842761(C/G) and rs4244809(A/G) were significantly lower in PR group compared with those in PS group (9.76 vs 23.36%, p = 0.049; 9.76 vs 26.09%, p = 0.045; respectively). Compared with the AA genotype, rs4244809 GG genotype was associated with significantly reduced risk of platinum resistance (adjusted OR: 0.30; 95% CI: 0.10–0.91; p = 0.033). Further stratified analyses revealed that the SNPs of rs3842761 and rs4244809 were greatly related to PR risk in FIGO stage III–IV (rs3842761GG/CC+CG: adjusted OR: 0.15; 95% CI: 0.02–1.21; rs4244809 GG/AA+AG: adjusted OR: 0.24; 95% CI: 0.07–0.84; respectively) and serous adenocarcinoma subgroups (rs3842761 GG/CC+CG: adjusted OR: 0.21; 95% CI: 0.05–0.94; rs4244809 GG/AA+AG: adjusted OR: 0.19; 95% CI: 0.04–0.5; respectively), while rs7924316 polymorphism was associated with reduced risk of PR in serous adenocarcinoma subgroup as analyzed by a recessive model (rs7924316 GG/TT+TG: adjusted OR: 0.22; 95% CI: 0.05–0.98). In addition, both TCT haplotypes of rs3741206/rs3842761/rs7924316 and TC haplotype of rs3741206/rs3842761 were associated with elevated risk of PR (for the TCT haplotype of rs3741206/rs3842761/rs7924316: p = 0.049; OR: 1.69; 95% CI: 1.00–2.87; for the TC haplotype of rs3741206/rs3842761: p = 0.044; OR: 1.71; 95% CI: 1.01–2.88). Conclusion: These results suggest that polymorphisms in IGF2/H19 gene locus are associated with PR risk in EOC.
References
- 1 Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N. Engl. J. Med. 334(1), 1–6 (1996).
- 2 . Epithelial ovarian carcinoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann. Oncol. 19(Suppl. 2), ii14–ii16 (2008).
- 3 Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J. Clin. Oncol. 21(17), 3194–3200 (2003).
- 4 Overexpression of an ectopic H19 gene enhances the tumorigenic properties of breast cancer cells. Carcinogenesis 23(11), 1885–1895 (2002).
- 5 Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J. 279(17), 3159–3165 (2012).
- 6 . Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene 26(33), 4877–4881 (2007).
- 7 . Ectopic expressed long non-coding RNA H19 contributes to malignant cell behavior of ovarian cancer. Internat. J. Clin. Experiment. Pathol. 8(9), 10082–10091 (2015).
- 8 Common polymorphism in H19 associated with birthweight and cord blood IGF-II levels in humans. BMC Genet. 6(22),
doi:10.1186/1471-2156-6-22 (2005). - 9 . H19 and IGF-2 allele-specific expression in hepatoblastoma. Br. J. Cancer 82(4), 753–756 (2000).
- 10 . Biallelic expression of the H19 and IGF2 genes in human testicular germ cell tumors. J. Natl Cancer Inst. 86(14), 1070–1075 (1994).
- 11 H19 DMR methylation correlates to the progression of esophageal squamous cell carcinoma through IGF2 imprinting pathway. Clin. Transl. Oncol. 16(4), 410–417 (2014).
- 12 . Altered specificity of IGF2 promoter imprinting during fetal development and onset of Wilms tumor. Oncogene 11(4), 751–756 (1995).
- 13 Upregulation of IGF2 is associated with an acquired resistance for cis-diamminedichloroplatinum in human head and neck squamous cell carcinoma. European Arch. Oto-Rhino-Laryngol. 267(10), 1599–1606 (2010).
- 14 . Loss of imprinting of the IGF-II and H19 genes in epithelial ovarian cancer. Clin. Cancer Res. 6, 474–479 (2000).
- 15 Association between indel polymorphism in the promoter region of lncRNA GAS5 and the risk of hepatocellular carcinoma. Carcinogenesis 36(10), 1136–1143 (2015).
- 16 Analysis of the association of HOTAIR single nucleotide polymorphism (rs920778) and risk of cervical cancer. APMIS 124(7), 567–573 (2016).
- 17 The association analysis of lncRNA HOTAIR genetic variants and gastric cancer risk in a Chinese population. Oncotarget 6(31), 31255–31262 (2015).
- 18 Association of genetic variants in lncRNA H19 with risk of colorectal cancer in a Chinese population. Oncotarget 7(18), 25470–25477 (2016).
- 19 Tag SNPs in long non-coding RNA H19 contribute to susceptibility to gastric cancer in the Chinese Han population. Oncotarget 6(17), 15311–15320 (2015).
- 20 Hormone-related pathways and risk of breast cancer subtypes in African American women. Breast Cancer Res. Treatment 154(1), 145–154 (2015).
- 21 . Association between Gly1619ARG polymorphism of IGF2R domain 11 (rs629849) and advanced stage of oral cancer. Med. Oncol. 29(2), 682–685 (2012).
- 22 IGF2R genetic variants, circulating IGF2 concentrations and colon cancer risk in African Americans and Whites. Dis. Markers 32(2), 133–141 (2012).
- 23 Insulin-like growth factor 2 gene methylation in peripheral blood mononuclear cells of patients with hepatitis C related cirrhosis or hepatocellular carcinoma. Clin. Res. Hepatol. Gastroenterol. 36(4), 345–351 (2012).
- 24 Association of well-characterized lung cancer lncRNA polymorphisms with lung cancer susceptibility and platinum-based chemotherapy response. Tumor Biol. 37(6), 8349–8358 (2016).
- 25 An association between variants in the IGF2 gene and Beckwith–Wiedemann syndrome: interaction between genotype and epigenotype. Hum. Mol. Genet. 13(2), 247–255 (2004).
- 26 Associations between paternally transmitted fetal IGF2 variants and maternal circulating glucose concentrations in pregnancy. Diabetes 60(11), 3090–3096 (2011).
- 27 Impact of abnormal DNA methylation of imprinted loci on human spontaneous abortion. Reprod. Sci. 25(1), 131–139 (2017).
- 28 High IGF2 expression is associated with poor clinical outcome in human ovarian cancer. Oncol. Rep. 34(2), 936–942 (2015).
- 29 Insulin-like growth factor 2 expression modulates Taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer. Clin. Cancer Res. 16(11), 2999–3010 (2010).
- 30 . Insulin-like growth factor 2 silencing restores taxol sensitivity in drug resistant ovarian cancer. PLoS ONE 9(6), e100165 (2014).
- 31 Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk. Hum. Mol. Genet. 20(11), 2263–2272 (2011).
- 32 LncRNA H19 is a major mediator of doxorubicin chemoresistance in breast cancer cells through a cullin4A-MDR1 pathway. Oncotarget 8(54), 91990–92003 (2017).
- 33 Oncofetal H19 RNA promotes tumor metastasis. Biochim. Biophys. Acta 1843(7), 1414–1426 (2014).
- 34 The essential role of H19 contributing to cisplatin resistance by regulating glutathione metabolism in high-grade serous ovarian cancer. Sci Rep 6, 26093 (2016).
- 35 Analysis of the TGF beta functional pathway in epithelial ovarian carcinoma. Br. J. Cancer 85(5), 687–691 (2001).
- 36 Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science (New York) 330(6001), 228–231 (2010).
- 37 Loss of heterozygosity on 10q23.3 and mutation of the tumor suppressor gene PTEN in benign endometrial cyst of the ovary: possible sequence progression from benign endometrial cyst to endometrioid carcinoma and clear cell carcinoma of the ovary. Cancer Res. 60(24), 7052–7056 (2000).
- 38 Loss of BAF250a (ARID1A) is frequent in high-grade endometrial carcinomas. J. Pathol. 224(3), 328–333 (2011).