Cervical cancer is a common gynecologic tumor, which poses a great threat to women’s reproductive health and life safety. The incidence rate of cervical cancer is the fourth malignancy in the world (Sung et al., 2021). It has been established that long time infection of type 16 and type 18 human papillomavirus (HPV) is an important risk factor for cervical cancer (Crosbie et al., 2013), and HPV pathogenesis is closely related to DNA damage repair pathway (Spriggs and Laimins, 2017; Mehta and Laimins, 2018; Wallace, 2020). DNA damage repair response is a network of cellular signaling pathways, which can sense, signal and promote the repair of damaged DNA. This damage may be the result of environmental and endogenous activities, including ionizing radiation, ultraviolet radiation and DNA replication errors (Ciccia and Elledge, 2010). Mutations in DNA repair genes usually result in genomic instability, increased risk of congenital diseases and cancer (Eyfjord and Bodvarsdottir, 2005). The core of DNA damage response is ataxia telangiectasia mutation (ATM) and ATM and Rad3 related (ATR) signaling pathways. Therefore, exploring DNA damage repair is of great value for cervical cancer.

Cervical cancer is mainly treated by surgical resection, chemotherapy, radiotherapy or comprehensive treatment. Early cervical cancer patients after standard treatment, the recurrence rate is low, the survival time is longer, but for patients with advanced cervical cancer, the survival time after treatment is often unsatisfactory (Green et al., 2001; Tewari and Monk, 2014). Genetic analysis (2017) could provide prognostic information to guide new biomarkers to prevent metastasis and recurrence of cervical cancer. At the same time, immune infiltration is correlated with the immune response (Shamseddine et al., 2021) and survival (Yang et al., 2019) of cervical cancer patients. In tumor immunotherapy, immune infiltration plays an important role in tumor control and therapeutic response. Understanding the infiltration of immune cells in tumor is a very important index to guide clinical treatment (Fridman et al., 2012; Finotello and Trajanoski, 2018). It will help to better understand the complex anti-tumor response and guide the effective immunotherapy of cervical cancer.

In our study, we estimated the effect of DNA damage repair-related genes on immune function of patients with cervical cancer, and obtained a prognosis model based on DNA damage repair-related genes. It can effectively stratify the prognosis of patients with cervical cancer, guide clinical diagnosis and treatment, and potentially explore the role of immune infiltration and its mechanism.

The mechanism of DNA damage repair in cervical cancer is often thought to be caused by HPV infection (Moody and Laimins, 2009). When HPV infects epithelial cells, a variety of pathways or mechanisms related to DNA damage repair are encouraged to ensure the completion of the virus life cycle. E6 and E7 are the most important proteins in HPV, which can bind and inhibit p53 and pRb respectively (Spriggs and Laimins, 2017; Das et al., 2020). The result is that HPV can activate DNA damage repair mechanism for HPV self-preservation, thus hijacking the unit, which will lead to the secondary inhibition of DNA damage repair. The unit is locked in the G1/S phase to allow HPV replication and prevent the cell cycle regulatory functions that normally occur in the presence of DNA damage. Meanwhile, studies have shown that HPV activates ATM (Moody and Laimins, 2009; Sakakibara et al., 2011) and ATR (Reinson et al., 2013; Hong et al., 2015) pathways and fanconi anemia (Spardy et al., 2007; Hoskins et al., 2012) pathways, which are critical pathways in DNA damage repair network. Because of the unrevealed results of cervical cancer genome map (2017), there has been a strong interest in identifying the target molecular pathways for cervical cancer. New therapeutic methods and clinical trials based on DNA damage repair pathway are gradually carried out. At the same time, NCI clinical trials planning meeting report also discussed relevant aspects with the title of “moving forward in cervical cancer: Enhancing sustainability to DNA repair induction and to DNA damage” (Harkenrider et al., 2020). The analysis process of this study was shown in Graphical Abstract. Gene expression and clinical data required for this study were obtained from TCGA database. In previous studies (Shi et al., 2020; Zhang et al., 2020; Cao et al., 2021; Chen et al., 2021; Peng et al., 2021), many scholars used TGCA gene data to predict the prognosis of patients with cervical cancer. In our study, four DNA damage repair related genes (HAP1, MCM5, RNASEH2A, CETN2) were found to be significantly associated with prognosis and can be incorporated into the nomogram to predict prognosis stratification. This is of positive significance in guiding the prognosis of patients.

The screened key genes also deserve our attention. HAP1 (Huntingtin Associated Protein 1) (Zhao et al., 2021) is a Protein Coding gene. Huntington’s disease (HD) was a neurodegenerative disease characterized by loss of striatal neurons, caused by the expansion of polyglutamine beams in the HD protein Huntington protein. The gene encoding a protein interacting with Huntington protein, two cytoskeletal proteins (dynactin and centromere autoantigen protein 1) and tyrosine kinase substrate regulated by hepatocyte growth factor. Interactions with cytoskeletal proteins and kinase substrates indicate that the protein plays a role in vesicle trafficking or organelle transport. Two distinct roles played in cell defense against oxidative stress. A recognized role was to repair all kinds of injuries induced by spontaneous hydrolysis or reactive oxygen species (ROS) in DNA. This function had been described in detail, and the role of amino acid residues in a single active site had been defined. The second function was to regulate the DNA binding activity of a group of nuclear factors, which was related to the pathway of gene damage (Friedberg et al., 2000; Wu and Zhou, 2009). MCM5 (Li et al., 2021) was a member of the MCM family of chromatin binding proteins, which could interact with at least two other members of the family. The encoding proteins were up-regulated in the cell cycle from G0 to G1/S, and may be involved in cell cycle regulation. During the initiation of replication, the eukaryotic replicon was assembled around the CMG helicase at the starting point of replication. Once assembled, CMG shall remain stable with the replication fork until the two fork converges from the adjacent starting point, or the single fork meets the terminal or template discontinuity of the linear chromosome. Among them, the ubiquitination of CMG was inhibited before replication termination to prevent replication fork collapse. This inhibition was mediated by replication fork DNA. Recent study (Jenkyn-Bedford et al., 2021) could have shown that the leucine rich repeat domains of Dia2 and LRR1 are different in structure, but bind to a common site on CMG, including MCM3 and MCM5 zinc finger domains, and LRR-MCM interaction was crucial for the decomposition of replicas, and it is crucial that it is duplicated to exclude DNA chain closure, which lay a structural foundation for inhibiting CMG ubiquitination before termination. Down regulated expression in three negative breast cancer could affect prognosis and chemotherapy sensitivity (Sheng et al., 2021), which could also be seen in other cancers (Lu et al., 2021). RNASEH2A (RNase H2 subunit A) was a protein encoding gene, and its RNASEH2A related diseases include Aicardi-Goutieres syndrome and Aicardi-Goutieres syndrome, associated with cancer progression and cell cycle (Marsili et al., 2021). In our study, it was related to the overall survival rate of cervical cancer, which was consistent with previous studies (Huang et al., 2021), and this gene plays a similar role in lung cancer (Zhang et al., 2021) and breast cancer (Chen et al., 2020). CETN2 belonged to the calcium binding protein family and is the structural component of centrosome. Studies (Mullee and Morrison, 2016; Semer et al., 2019) had shown that CEN2 was a transcriptional co activator, which could reshape the epigenetic landscape of promoters. In previous cancer research, it had received some attention as a potential biomarker (Anurag et al., 2018; Lu et al., 2020).

Traditionally, individual based models are often used to develop predictive and prognostic biomarkers, which requires understanding each patient’s response to treatment and clinical outcomes. In contrast, our method is “unsupervised”, which relies on gene damage related gene expression profiles to reveal the potential structure of the immune landscape in tumors, and also takes into account the immune characteristics. In the future, biomarkers may be developed in combination with the inherent characteristics of the immune landscape. It is conceivable that the stratified model, which first stratified patients into subgroups, and then applied individual based risk stratification, can be used to predict biologically relevant clinical outcomes. The concept of “subtype specific” biomarkers has been successfully applied to improve the prognosis of many kinds of cancers (Hu et al., 2021; Ahearn et al., 2022; Zhang et al., 2022). Therefore, integrating subtype analysis and individual based models may be a promising method to develop clinically relevant biomarkers.

We also explored different immune infiltrating environments between the molecular subsets determined according to the DNA damage repair-related genes (Figure 4). DNA damage repair mechanism can induce innate immune response, resulting in the production of interferon and the potential attenuation of cell proliferation, which is an important way to stimulate immune regulation (Paludan, 2015; Nakad and Schumacher, 2016; Bednarski and Sleckman, 2019). A previous study (Wang et al., 2019) analyzed the proportion of immune cells in cervical cancer and identified the immune cells associated with prognosis. In addition, the mutation load of tumor is also the key internal factor that affects tumor response to immunotherapy (Gasser et al., 2017; Havel et al., 2019). There are many pathways or gene expression related to DNA damage in the work network, which can affect gene instability and affect immunity (Kretschmer et al., 2015; Galsky et al., 2018; Bednarski and Sleckman, 2019; Tuli et al., 2019). The molecular subtypes (F1 and F2) we explored the DNA damage repair-related genes may have potential applications in the search for immunotherapy or immunological checkpoints.

Through TCGA, we developed a nomogram with clinical application value based on DNA damage repair-related genes, which can better guide clinical prognosis stratification. At the same time, we explored the relationship between DNA damage repair-related genes and immune infiltration characteristics, and made a preliminary inquiry into the immune infiltration of cervical cancer. Of course, the effect of DNA damage repair-related genes on the prognosis and immunity of cervical cancer needs further experimental study.