Cervical cancer is regarded as the most common gynecologic cancer in developing countries which ranks third among all cancer types [1, 2, 3]. Recent studies demonstrated that treatment of cervical epithelial atypical hyperplasia, a precancerous of cervical cancer, displays 1% and 0.5% decrease in the incidence and mortality, respectively [4]. The rise in the occurrence of cervical cancer in developing countries is associated with sexual behavior, such as multiple partners, multiple pregnancy with Chlamydia psittaci infection, and HIV-associated immunosuppression, which could increase the risk of HPV infection, therefore promote the occurrence of cervical cancer [5, 6]. The main therapy to treat cervical cancer is surgical operation and radiotherapy combined with chemotherapy [7, 8, 9]. The efficacy of chemoradiation therapy determines their prognosis and survival time among the patients who cannot receive radical operation [10, 11]. It has been established that the sensitivity to chemoradiation therapy for cervical cancer is associated with numerous factors, including immune state, neoplasm staging and genovariation [12, 13]. Among these, gene polymorphism has a close relationship with the efficacy of chemoradiation therapy for cervical cancer [14, 15]. However, the relationship between GSDMB polymorphism and sensitivity to chemoradiation therapy for cervical cancer has been unclarified yet. Therefore, we designed this study to investigate the effect of GSDMB polymorphism on sensitivity to chemoradiation therapy for cervical cancer. Briefly, this study analyzed the GSDMB rs8067378 A$>$G, rs7216389 C$>$T and rs11650680 C$>$T polymorphism combined with haplotype analysis and linkage disequilibrium analysis, and GSDMB gene expression analysis in patients with cervical cancer who are sensitive or non-sensitive to chemoradiation therapy.

Cervical cancer is one of the most common malignant tumors in women. It has been estimated that the five-year survival rate of localized cervical cancer is 91.5%, while metastatic cervical cancer is 16.5% [16]. Cisplatin-based chemotherapy has long been the major treatment for intermediate and advanced cervical cancer. However, the survival rate shows no significant improvement as patients respond differently to chemotherapy. Adding of new therapeutical drugs, such as antiangiogenic agent, can greatly improve the outcome of curative capability [17]. However, the sensitivity of patients to chemoradiation varies because of tumor heterogeneity and individual difference, which directly impact the tumor prognosis and survival of patients [18, 19]. Therefore, identifying factors which are associated with the sensitivity to cervical cancer chemoradiation therapy could contribute to prolong the overall survival of patients. In this study, we analyzed a total 108 cases of cervical cancer after chemoradiation therapy. We discovered that 24% of total patients were CR, while the percentages of PR, SD and PD patients were 33.3%, 29.6% and 12.9% respectively, with an effective ratio of 57.3%. Tumor size and CEA level were significantly different, meanwhile, age, pathology results, stage and histological grade distribution were not changed significantly between sensitive and non-sensitive group. Moreover, no significant correlation was found between age, pathology results, stage, histological grade, and sensitivity to chemoradiation therapy. Instead, tumor size and CEA were correlated with chemoradiation sensitivity. These results suggested that tumor size and CEA level contribute to the sensitivity of patients to chemoradiation therapy rather than age, pathology results, stage and histological grades.

GSDMB belongs to the Gasdermin protein family, and these gene family members share conserved N- and C-terminal structural domain with a sequence homology of 45% [20, 21]. The Gasdermin protein family has five members in humans, which are termed as GSDMA, GSDMB, GSDMC, GSDMD and GSDME [22, 23]. GSDMB displays broader expression pattern as compared to other GSDM family members by showing higher tissue-specific expression in skin epithelium, gastrointestinal tract and immune cells [24, 25]. Genome-wide association study (GWAS) revealed a close relationship between GSDMB and susceptibility to inflammatory diseases such as Crohn’s disease, asthma, and type I diabetes [26, 27]. A study on GSDMB transgenic mice indicated that GSDMB promotes the development of asthma, and increases airway responsiveness and remodeling [28, 29]. Besides, researchers have found that GSDMB was highly expressed not only in healthy tissues, but also in cancerous tissues from gastric cancer, metrocarcinoma, cervical cancer and breast cancer. GSDMB was located in amplicons which often amplified during the progression of cancer [30]. Therefore, GSDMB might be involved in the occurrence, development and metastasis of cancer. However, the functions of GSDMB are still not studied well. Meanwhile, the effect of GSDMB on sensitivity to chemoradiation therapy in cervical cancer also remains undocumented. This study compared the GSDMB rs8067378 A$>$G, rs7216389 C$>$T and rs11650680 C$>$T polymorphism between sensitive group and non-sensitive group, and discovered the difference of allele distribution at GSDMB rs8067378 A$>$G (p = 0.000) and rs7216389 C$>$T (p = 0.000) sites. Moreover, we also found that the “A” allele frequency of rs8067378 A$>$G and the “C” allele frequency of rs7216389 C$>$T was higher in sensitive group. Genotype distribution of GSDMB rs8067378 A$>$G (p = 0.000), rs7216389 C$>$T (p = 0.000) and rs11650680 C$>$T (p = 0.007) in sensitive group was different from that of non-sensitive group. The frequency of AA in rs8067378 A$>$G, TT in rs7216389 C$>$T and CT in rs11650680 C$>$T was higher in sensitive group. There was significant correlation between GSDMB rs8067378 A$>$G (r = 0.437, p = 0.000), rs7216389 C$>$T (r = –0.274, p = 0.003) polymorphism and sensitivity to chemoradiation therapy in cervical cancer. In a recessive model, distribution of rs8067378 A$>$G was different between sensitive and non-sensitive group, with a lower frequency of AG + GG in sensitive group. A significant difference was observed in the distribution of rs7216389 C$>$T between sensitive and non-sensitive group in a dominant model, and sensitive group has a lower frequency of CC + CT. These results suggested a close relationship between GSDMB rs8067378 A$>$G, rs7216389 C$>$T and rs11650680 C$>$T polymorphism, and efficacy of chemoradiation therapy for cervical cancer. Overall, it was found that cervical cancer patients with specific genotype might be more sensitive to chemoradiation therapy. In clinics, sensitivity of patients to chemoradiation therapy can be assessed in advance by detecting GSDMB rs8067378 A$>$G, rs7216389 C$>$T and rs11650680 C$>$T polymorphism, so as to adjust regimen accordingly to enhance treatment efficacy.

By haplotype analysis and linkage disequilibrium analysis, we found that ATT (p = 0.000), GCC (p = 0.008), GCT (p = 0.000) and GTC (p = 0.004) of GSDMB rs8067378 A$>$G, rs7216389 C$>$T and rs11650680 C$>$T were different between sensitive and non-sensitive group. Linkage disequilibrium was higher in GSDMB rs8067378 A$>$G and rs7216389 C$>$T (D’ = 0.415, r${}^2$ = 0.137). These data indicate that GSDMB rs8067378 A$>$G, rs7216389 C$>$T and rs11650680 C$>$T sites might influence the sensitivity to chemoradiation therapy in cervical cancer through haplotype. People with different haplotype in GSDMB rs8067378 A$>$G, rs7216389 C$>$T and rs11650680 C$>$T might have different sensitivity to chemoradiation therapy.

We further concluded that GSDMB rs8067378 A$>$G polymorphism was associated with GSDMB gene expression (p 0.05). Gene expression level of GSDMB was significantly increased in patients with AG genotype of sensitive group, suggesting that GSDMB polymorphism might affect GSDMB expression, or the impact of GSDMB polymorphism on sensitivity to chemoradiation therapy for cervical cancer might be exerted through modulating gene expression, which needs further study.

The limitations of this study is that the sample size is not large enough to fully confirm the effect of GSDMB rs8067378 A$>$G, rs7216389 C$>$T and rs11650680 C$>$T polymorphism. Moreover, our study validated only one SNP, while other SNPs not included in this study which could also account for alternation of GSDMB expression. To achieve full gene coverage, a number of other tag SNP needed to be covered in further study. Therefore, our genetic study contains one Chinese cohort, and it should be replicated for rs8067378 and a number of other tag SNPs covering GSDMB in other independent ethnicities. However, our conclusion is defensible, and it supports further investigating to reveal the relationship between GSDMB gene and sensitivity to chemoradiation therapy for cervical cancer.

This analysis provides new insights into the genetic causes of cervical cancer and is of great significance for the prevention and treatment of cervical cancer.

NZ, YY and HL designed the research study. NZ performed the research. GHP, HC and QYT provided help and advice on the ELISA experiments. NZ, YY, HKL, QP, HZZ and YBZ analyzed the data. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

All subjects gave their informed consent for inclusion before they participated in the study. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Chenzhou First People’s Hospital (Approval number: QZ6C11 ).

We would like to express our gratitude to all those who helped us during the writing of this manuscript. And thanks to all the peer reviewers for their opinions and suggestions at the same time.

Chenzhou Science and Technology Bureau 2019 (No.zdyf201945).

The authors declare no conflict of interest.