8-OHdG repair is associated with platinum sensitivity in high-grade serous ovarian carcinoma

Objectives: This study investigated 8-OHdG repair-related gene polymorphisms, 8-OHdG concentration and their association with the risk and survival of high-grade serous ovarian carcinoma (HG-SOC). Methods: Germline variants in the 8-OHdG repair pathway were assessed in 350 sporadic HG-SOC patients (HG-SOCs) and 700 healthy controls. The 8-OHdG concentration in leukocyte DNA was measured by ELISA. Cox proportional hazard models and log-rank test were used to conduct the survival analysis. Results: The genotype and allele frequencies of OGG1 c.977C > G, MUTYH c.972G > C, and TP53 codon 72 Arg/Pro were different to those of platinum-sensitive recurrent HG-SOCs and refractory/platinum-resistant recurrent sub HG-SOCs (P = 0.04, 0.05, and 0.03, respectively). The average value of 8-OHdG/106${}^6$ dG was higher in patients with OGG1 c.977G, MUTYH c.972G, or TP53 codon 72 Arg alleles (all P < 0.01). High 8-OHdG concentrations in leukocyte DNA was independently associated with shorter overall survival (OS) (P < 0.01) and progression-free survival (PFS) in HG-SOCs. Conclusion: Functional polymorphisms in the base excision repair (BER) system were associated with increased 8-OHdG concentrations and thus with platinum sensitivity and prognosis in HG-SOCs.

8-OHdG; Genetic polymorphism; Platinum sensitivity; High-grade serous ovar-ian carcinoma

[1] Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA: A Cancer Journal for Clinicians. 2016; 66: 115–132.

[2] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: A Cancer Journal for Clinicians. 2016; 66: 7–30.

[3] Vaughan S, Coward JI, Bast RC, Berchuck A, Berek JS, Brenton JD, et al. Rethinking ovarian cancer: recommendations for improving outcomes. Nature Reviews Cancer. 2011; 11: 719–725.

[4] Kim J, Park EY, Kim O, Schilder JM, Coffey DM, Cho CH, et al. Cell origins of high-grade serous ovarian cancer. Cancers. 2018; 10: 433.

[5] Coleridge SL, Bryant A, Lyons TJ, Goodall RJ, Kehoe S, Morrison J. Chemotherapy versus surgery for initial treatment in advanced ovarian epithelial cancer. Cochrane Database of Systematic Reviews. 2019; 10: CD005343.

[6] Agarwal R, Gourley C, Perren TJ, Reed N, Parkin DE, Carty K, et al. First-line therapy for ovarian cancer with carboplatin followed by paclitaxel-gemcitabine (SCOTROC5): a feasibility study and comparative analysis of the SCOTROC series. European Journal of Cancer. 2010; 46: 2020–2026.

[7] Banerjee S, Rustin G, Paul J, Williams C, Pledge S, Gabra H, et al. A multicenter, randomized trial of flat dosing versus intrapatient dose escalation of single-agent carboplatin as first-line chemotherapy for advanced ovarian cancer: an SGCTG (SCOTROC 4) and ANZGOG study on behalf of GCIG. Annals of Oncology. 2013; 24: 679–687.

[8] Cooke SL, Brenton JD. Evolution of platinum resistance in highgrade serous ovarian cancer. The Lancet Oncology. 2011; 12: 1169–1174.

[9] Cai Z, Chen H, Tao J, Guo W, Liu X, Zheng B, et al. Association of base excision repair gene polymorphisms with esrd risk in a chinese population. Oxidative Medicine and Cellular Longevity. 2012; 2012: 1–10.

[10] Chen X, Liu X, Wang J, Guo W, Sun C, Cai Z, et al. Functional polymorphisms of the hOGG1 gene confer risk to type 2 epithelial ovarian cancer in Chinese. International Journal of Gynecological Cancer. 2012; 21: 1407–1413.

[11] Chen X, Wang J, Guo W, Liu X, Sun C, Cai Z, et al. Two functional variations in 5′-UTR of hoGG1 gene associated with the risk of breast cancer in Chinese. Breast Cancer Research and Treatment. 2011; 127: 795–803.

[12] Lee J, Kim HS, Suh DH, Kim M, Chung HH, Song Y. Ovarian cancer biomarker discovery based on genomic approaches. Journal of Cancer Prevention. 2014; 18: 298–312.

[13] Liu X, Xiao N, Guo W, Wu Y, Cai Z, He Q, et al. The hOGG1 gene 5’-UTR variant c.-53G>C contributes to the risk of gastric cancer but not colorectal cancer in the Chinese population: the functional variation of hOGG1 for gastric cancer risk. Journal of Cancer Research and Clinical Oncology. 2011; 137: 1477–1485.

[14] Sun C, Chen H, Guo W, Zhang K, Qi Q, Gu X, et al. A common mutation of the MYH gene is associated with increased DNA oxidation and age-related diseases. Free Radical Biology & Medicine. 2010; 48: 430–436.

[15] Sun C, Liu X, Zhang H, Guo W, Cai Z, Chen H, et al. Functional polymorphism of hOGG1 gene is associated with type 2 diabetes mellitus in Chinese population. Molecular and Cellular Endocrinology. 2010; 325: 128–134.

[16] Xie H, Xia K, Rong H, Chen X. Genetic polymorphism in hOGG1 is associated with triple-negative breast cancer risk in Chinese Han women. Breast. 2014; 22: 707–712.

[17] Xu X, Wang Y, Guo W, Zhou Y, Lv C, Chen X, et al. The significance of the alteration of 8-OHdG in serous ovarian carcinoma. Journal of Ovarian Research. 2014; 6: 74.

[18] Zhu M, Chen X, Zhang H, Xiao N, Zhu C, He Q, et al. AluYb8 insertion in the MUTYH gene and risk of early-onset breast and gastric cancers in the Chinese population. Asian Pacific Journal of Cancer Prevention. 2012; 12: 1451–1455.

[19] Hao W, Xu X, Shi H, Zhang C, Chen X. No association of TP53 codon 72 and intron 3 16-bp duplication polymorphisms with breast cancer risk in Chinese Han women: new evidence from a population-based case-control investigation. European Journal of Medical Research. 2018; 23: 47.

[20] Lambrechts S, Smeets D, Moisse M, Braicu EI, Vanderstichele A, Zhao H, et al. Corrigendum to “Genetic heterogeneity after firstline chemotherapy in high-grade serous ovarian cancer”. European Journal of Cancer. 2016; 60: 226.

[21] Kumar A, Le N, Santos J, Hoskins P. Chemotherapy is of value in second line and beyond, relapsed high-grade, serous epithelial ovarian cancer: an analysis of outcomes obtained with oral etoposide. American Journal of Clinical Oncology. 2019; 41: 379–384.

[22] Böhm S, Faruqi A, Said I, Lockley M, Brockbank E, Jeyarajah A, et al. Chemotherapy response score: development and validation of a system to quantify histopathologic response to neoadjuvant chemotherapy in tubo-ovarian high-grade serous carcinoma. Journal of Clinical Oncology. 2015; 33: 2457–2463.

[23] Steffensen KD, Smoter M, Waldstrøm M, Grala B, Bodnar L, Stec R, et al. Resistance to first line platinum paclitaxel chemotherapy in serous epithelial ovarian cancer: the prediction value of ERCC1 and Tau expression. International Journal of Oncology. 2014; 44: 1736–1744.

[24] Koti M, Siu A, Clément I, Bidarimath M, Turashvili G, Edwards A, et al. A distinct pre-existing inflammatory tumour microenvironment is associated with chemotherapy resistance in high-grade serous epithelial ovarian cancer. British Journal of Cancer. 2015; 112: 1215–1222.

[25] Lambrechts S, Smeets D, Moisse M, Braicu EI, Vanderstichele A, Zhao H, et al. Genetic heterogeneity after first-line chemotherapy in high-grade serous ovarian cancer. European Journal of Cancer. 2016; 53: 51–64.

[26] Liu Y, Yasukawa M, Chen K, Hu L, Broaddus RR, Ding L, et al. Association of somatic mutations of adamts genes with chemotherapy sensitivity and survival in high-grade serous ovarian carcinoma. JAMA Oncology. 2016; 1: 486–494.

[27] Sohn I, Jung WY, Sung CO. Somatic hypermutation and outcomes of platinum based chemotherapy in patients with high grade serous ovarian cancer. Gynecologic Oncology. 2012; 126: 103–108.

[28] Bell D, Berchuck A, Birrer M, Chien J, Cramer DW, Dao F, et al. Integrated genomic analyses of ovarian carcinoma. Nature. 2011; 474: 609–615.

[29] Palozza P, Serini S, Di Nicuolo F, Boninsegna A, Torsello A, Maggiano N, et al. Beta-Carotene exacerbates DNA oxidative damage and modifies p53-related pathways of cell proliferation and apoptosis in cultured cells exposed to tobacco smoke condensate. Carcinogenesis. 2004; 25: 1315–1325.

[30] Reisman D, McFadden JW, Lu G. Loss of heterozygosity and p53 expression in Pterygium. Cancer Letters. 2004; 206: 77–83.

[31] Seidl H, Kreimer-Erlacher H, Bäck B, Soyer HP, Höfler G, Kerl H, et al. Ultraviolet exposure as the main initiator of p53 mutations in basal cell carcinomas from psoralen and ultraviolet a-treated patients with psoriasis. The Journal of Investigative Dermatology. 2001; 117: 365–370.

[32] Coskunpinar E, Yildiz P, Aynaci E, Turna A, Musteri Oltulu Y, Hekimoglu E, et al. Investigation of some DNA repair genes association in non small cell lung cancer. Cellular and Molecular Biology. 2016; 61: 57–62.

[33] Eom S, Yim D, Lee C, Choe K, An JY, Lee KY, et al. Interactions between paraoxonase 1 genetic polymorphisms and smoking and their effects on oxidative stress and lung cancer risk in a Korean population. PLoS ONE. 2016; 10: e0119100.

[34] Dai X, Deng S, Wang T, Qiu G, Li J, Yang B, et al. Associations between 25 lung cancer risk-related SNPs and polycyclic aromatic hydrocarbon-induced genetic damage in coke oven workers. Cancer Epidemiology, Biomarkers & Prevention. 2016; 23: 986–996.

[35] Savic-Radojevic A, Djukic T, Simic T, Pljesa-Ercegovac M, Dragicevic D, Pekmezovic T, et al. GSTM1-null and GSTA1-low activity genotypes are associated with enhanced oxidative damage in bladder cancer. Redox Report. 2013; 18: 1–7.

[36] Mahjabeen I, Masood N, Baig RM, Sabir M, Inayat U, Malik FA, et al. Novel mutations of OGG1 base excision repair pathway gene in laryngeal cancer patients. Familial Cancer. 2013; 11: 587–593.

[37] Bashashati A, Ha G, Tone A, Ding J, Prentice LM, Roth A, et al. Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling. The Journal of Pathology. 2013; 231: 21–34.

[38] Brachova P, Mueting SR, Carlson MJ, Goodheart MJ, Button AM, Mott SL, et al. TP53 oncomorphic mutations predict resistance to platinum‑ and taxane‑based standard chemotherapy in patients diagnosed with advanced serous ovarian carcinoma. International Journal of Oncology. 2015; 46: 607–618.

[39] Gadducci A, Di Cristofano C, Zavaglia M, Giusti L, Menicagli M, Cosio S, et al. P53 gene status in patients with advanced serous epithelial ovarian cancer in relation to response to paclitaxel- plus platinum-based chemotherapy and long-term clinical outcome. Anticancer Research. 2006; 26: 687–693.

[40] Bergamaschi D, Gasco M, Hiller L, Sullivan A, Syed N, Trigiante G, et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell. 2003; 3: 387–402.

[41] Kohno T, Shinmura K, Tosaka M, Tani M, Kim SR, Sugimura H, et al. Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA. Oncogene. 1998; 16: 3219–3225.

[42] Thigpen T. A rational approach to the management of recurrent or persistent ovarian carcinoma. Clinical Obstetrics and Gynecology. 2012; 55:114–130.

[43] Friedlander M, Trimble E, Tinker A, Alberts D, Avall-Lundqvist E, Brady M, et al. Clinical trials in recurrent ovarian cancer. International Journal of Gynecological Cancer. 2011; 21: 771–775.

[44] Berns EMJJ, Bowtell DD. The changing view of high-grade serous ovarian cancer. Cancer Research. 2012; 72: 2701–2704.

[45] Bromley AB, Altman AD, Chu P, Nation JG, Nelson GS, Ghatage P, et al. Architectural patterns of ovarian/pelvic high-grade serous carcinoma. International Journal of Gynecological Pathology. 2012; 31: 397–404.

[46] Jervis S, Song H, Lee A, Dicks E, Harrington P, Baynes C, et al. A risk prediction algorithm for ovarian cancer incorporating BRCA1, BRCA2, common alleles and other familial effects. Journal of Medical Genetics. 2015; 52: 465–475.

[47] Osorio A, Milne RL, Kuchenbaecker K, Vaclová T, Pita G, Alonso R, et al. DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers. PLoS Genetics. 2014; 10: e1004256.

[48] Benitez-Buelga C, Vaclová T, Ferreira S, Urioste M, Inglada-Perez L, Soberón N, et al. Molecular insights into the OGG1 gene, a cancer risk modifier in BRCA1 and BRCA2 mutations carriers. Oncotarget. 2017; 7: 25815–25825.