Expression and clinical significance of PRKDC in lung cancer based on bioinformatics analysis

doi:10.21203/rs.3.rs-1658621/v1

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Expression and clinical significance of PRKDC in lung cancer based on bioinformatics analysis

https://doi.org/10.21203/rs.3.rs-1658621/v1

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Objective: To investigate the expression and prognostic significance of protein kinase DNA activated catalytic subunit (PRKDC) in non-small cell lung cancer (NSCLC).

Methods: oncomine, ualcan, human protein Altas, Kaplan Meier plot and c-bioportal databases were searched to analyze the mRNA expression, protein expression, clinicopathological parameters, prognosis, survival and gene mutation of PRKDC in NSCLC and normal lung tissues.

Results: the overexpression of PRKDC mRNA and protein in pathological tissues was significantly correlated with the stage of lung adenocarcinoma (luad) and lung squamous cell carcinoma (lusc), smoking habits, gender, race and lymph node metastasis, and significantly correlated with the shortening of overall survival rate (OS) of NSCLC patients. At the same time, PRKDC had a high mutation rate in NSCLC（ LUAD:23% ，LUSC:19% ）The patients with luad had shorter OS and disease-free survival Survival rate (DPS) was significantly correlated.

Conclusion: PRKDC may be a biomarker for the prognosis of NSCLC patients.

non small cell lung cancer

PRKDC

bioinformatics

prognosis

markers

On a global scale,lung cancer is one of the major problems affecting human health, and its morbidity and mortality continue to rise^[1,2].According to Globocan, there were 2.09 million new cases of lung cancer in 2018, accounting for 11.6 percent of all cancer cases, and 1.76 million deaths, accounting for 18.4 percent of all cancer deaths^[3].Of all lung cancers, non-small-cell lung carcinoma（NSCLC） account for 85%^[4] , of which 25%-30% are Lung squamous cell carcinoma（LUSC）^[5]and 40%-45% are Lung adenocarcinoma （LUAD）^[6]. Overall, the 5-year survival rate for lung cancer is low, at about 19%^[7], mainly because most patients are diagnosed at an advanced stage and the treatment regimens are ineffective^[8].Studies have shown that certain biomarkers can contribute to the rapid clinical diagnosis of NSCLC^[9] .Therefore, we urgently need to develop a potential prognostic marker for NSCLC, in order to be able to provide new ideas and methods in the early diagnosis and treatment of NSCLC.PRKDC, also known as the human x Ray Repair Cross Complementary Group 7(Xrcc7) , is located on chromosome 8q11^[10]. It is a nuclear protein serine/threonine kinase and plays an important role in the repair of DNA double strand breaks and the maintenance of genomic stability^[11,12].PRKDC mutations have been found to be associated with an increased burden of tumor mutations, inflammation of the tumor microenvironment, and favorable responses to checkpoint inhibitors^[13]. Further analysis showed that the mutation frequency of PRKDC in lung cancer was 9.7% , and the response rate to immunocheckpoint inhibitors was 75% . In Lung Adenocarcinoma (Luad) , PRKDC mutation was significantly associated with high mutation load^[14].In addition, there was a significant negative correlation between the expression of PRKDC encoded DNA-PKcs and the overall survival (Os) and disease-free survival (DFS) in NSCLC patients^[15].The prognosis of PRKDC FOR NSCLC has not been reported.

In this study, we analyzed the expression, mutation and clinical prognosis of PRKDC in NSCLC patients to explore the potential clinical value of PRKDC in NSCLC patients.

1.1 Differential expression and pathological parameter analysis

The expression of PRKDC in NSCLC was obtained from Oncomine（https://www.oncomine.org/） and UALCAN databases, and then the results were visualized by expression spectrum.Oncomine database is a public cancer database and data mining platform based on the analysis, research and visualization of tumor data from network^[16].It can be used to detect PRKDC mRNA expression in more than 20 kinds of tumors and compare with normal tissues. "PRKDC" was used as the key word, and "cancer and normal tissue analysis" was used as the selection parameter: p value < 0.01; Fold Change > 1.5; Gene Rank 10% ; Data type as mRNA.On the basis of the above-mentioned operations, the tumor types were set as Lung Adenocarcinoma/lung squamous Cell Carcinoma, the results of the corresponding research projects were selected respectively, and the corresponding parameters were recorded and displayed in tabular form.

We then analyzed the mRNA expression of PRKDC and its relationship to clinicopathologic parameters such as stage, sex, race, and lymph node metastasis in Luad and LUSC patients using the UALCAN database（http://ualcan.path.uab.ed）^[17].The database uses the data of 31 kinds of tumors in TCGA database（https://cancergenome.nih.gov）, so it can be verified with Oncomine database when differential expression is carried out.

1.2 Overall survival analysis

Kaplan-Meier Plotter database（https://kmplot.com/analysis） combines GEO and TCGA survival data to study more than 54,000 genes and 21 types of cancer, allowing online survival analysis of malignant tumors.In this study, we used this database to analyze the prognostic value of PRKDC in patients with NSCLC.

1.3 Mutation analysis

The cBioPortal database(https: //www.cbioportal.org)^[18]can be used for the interactive exploration of multiple cancer genomics data sets. Its data comes from multiple data platforms, including Tcga, Oncomine, etc. There are many types of genes that are studied, such as somatic mutation, DNA copy number mutation and DNA methylation and so on.In this study, we used the database to analyze the genetic mutation of PRKDC. The data set was "Lung Adenocarcinoma/lung squamous Cell Carcinoma (TCGA, Firehose Legancy) " , the sample was "RNA Seq V2" , z-threshold = ± 1.8, finally, enter the gene name "PRKDC" for retrieval.

1.4 Similar genetic bioinformatics analysis

GEPIA 2.0(http://gepia.cancerpku.cn）^[19]was used to find 100 adjacent genes significantly associated with the PRKDC mutation in NSCLC, and then the protein-protein Interaction network was visualized in the STRING11.0 database (https://string-db.org）^[20]with Interaction score = 0.4 as the screening condition.

In addition, PRKDC and its similar genes were enriched with GO, KEGG and RECTOME in Metascape database（https://david.ncifcrf.gov/summary.jsp）^[21] .

2.1 Overexpression of PRKDC mRNA in NSCLC

We analyzed the mRNA and protein expression of PRKDC from the ONCOMINE（www.oncomine.org）,the UALCAN（http://ualcan.path.uab.edu）and the human protein atlas（https://www.proteinatlas.org）.We measured PRKDC mRNA expression patterns in 20 cancers in the ONCOMINE database and compared them with normal tissues. The results showed that PRKDC was overexpressed in 13 of the 19 Lung Cancer Studies (see figure 1).At the same time, PRKDC mRNA expression was significantly increased in Luad and LUSC samples from multiple datasets.In the Bhattacharjee ^[22] lung dataset, the mRNA expression of PRKDC in the LUAD sample increased 3.022 fold (p = 0.002).Likewise,in the Garber ^[23] , Stearman ^[24] , Landi ^[25] and Hou ^[26]lung dataset ,the mRNA expression of PRKDC increased 1.905-fold (p = 9.00E-04) , 1.836-fold (p = 1.13E-07) , 1.787-fold (p = 3.11E-12) and 1.73-fold (p = 3.09E-09) , respectively.In addition, significant increases in PRKDC mRNA expression were also observed in the LUSC sample.In Bhattacharjee's ^[22]lung dataset, PRKDC mRNA expression increased 8.885-fold (P = 3.87E-06). Similarly, in Talbot^[27] , Garber ^[23] and Hou^[26]lung datasets, the mRNA expression of PRKDC increased 2.484-fold (p = 1.19E-12) , 2.365-fold (p = 1.63E-04) and 2.224-fold (6.45E-13) , respectively (see table 1).PRKDC mRNA expression was again measured using the UALCAN database, which is based on clinical data from the level 3 RNA-seq and TCGA database for 31 cancer types, unlike the ORCOMINE database.The results showed that the mRNA expression of PRKDC was significantly overexpressed in both primary Luad and LUSC tissues (p = 1.62E-12)(see figures 2A and 2B).

Table 1

Relationship between mRNA expression of PRKDC in different lung cancer data sets

	Types of NSCLC VS Lung	Fold Change	P value	t-test	Ref
PRKDC	Lung Adenocarcinoma	3.022	0.002	3.316	Bhattacharjee Lung
	Lung Adenocarcinoma	1.905	0.0009	4.187	Garber Lung
	Lung Adenocarcinoma	1.836	1.13E-07	7.124	Stearman Lung
	Lung Adenocarcinoma	1.787	3.11E-12	7.754	Landi Lung
	Lung Adenocarcinoma	1.730	3.9E-09	6.75	Hou Lung
PRKDC	Lung Squamous cell Carcinoma	8.885	3.87-06E	5.338	Bhattacharjee Lung
	Lung Squamous cell Carcinoma	2.482	1.19E-012	8.775	Talbot Lung
	Lung Squamous cell Carcinoma	2.365	0.000163	4.677	Garber Lung
	Lung Squamous cell Carcinoma	2.224	6.45E-13	10.594	Hou Lung

2.2 Analysis of relationship between clinical pathological parameters and PRKD

UALCAN（http://ualcan.path.uab.edu）was used to analyze the relationship between PRKDC mRNA expression and clinicopathologic parameters of NSCLC patients, including tumor stage, smoking habit, sex, race and lymph node metastasis.In general, patients with advanced cancer tend to have higher mRNA expression at the tumor stage. In patients with Luad and LUSC, the highest mRNA expression of PRKDC was at stage 3(see figures 3A and 3B).In terms of smoking habits, PRKDC mRNA expression tends to be higher as the duration of smoking increases.In LUAD patients, the mRNA expression of PRKDC was significantly higher in smokers and smokers over 15 years than in non-smokers and smokers under 15 years,and there are statistical differences (figure 4A).In patients with LUSC, there was no significant difference in PRKDC mRNA expression between smoking and non-smoking patients, and between patients over 15 years of age and under 15 years of age.For gender differences, the highest mRNA expression of PRKDC was found in male in both Luad and LUSC patients (figure 4B). In terms of racial differences,among patients with Luad and LUSC, the highest mRNA expression levels of PRKDC were found in Asians (see figures 4C and 4D).For lymph node metastasis, PRKDC mRNA expression was highest in patients with Luad at stage N2 and highest in patients with LUSC at stage N1. The highest expression level of PRKDC mRNA was not at stage N3, possibly due to the small sample size (N = 2 in Luad and N = 5 in LUSC)(see figures 4E and 4F) .

In short, these results suggest that PRKDC mRNA expression is significantly correlated with clinicopathologic parameters of NSCLC.

2.3 Prognostic value of PRKDC mRNA expression in NSCLC patients

Kaplan Myer plotter（http://kmplot.com/analysis）was used to analyze the prognostic value of PRKDC mRNA expression in NSCLC patients.The expression of PRKDC mRNA was significantly correlated with the prognosis of NSCLC.The results showed that the high mRNA expression level of PRKDC (HR = 1.76,95% CI: 1.48-2.10, p = 1.4E-10) was significantly associated with poor prognosis (see figure 5).Therefore, PRKDC may be used as a biomarker for predicting survival in NSCLC patients.

2.4 Analysis of PRKDC gene mutation and prognosis

We analyzed the mutations in the PRKDC gene using the CBIOPORTAL database.The results showed that 119 out of 510 Luad patients were found to have the gene change, with a mutation rate of 23% (see figure 6A).Of 484 patients with LUSC sequencing, 90 LUAD patients were found to have gene changes, with a mutation rate of 19% (see figure 6B).In addition, the Kaplan-Meier and log-rank tests showed that the gene alterations in PRKDC were significantly different from those in Luad patients with shorter OS (figure 6C, p = 5.194E-3) and DFS (figure 6D, P = 5.256E-4) ,were not statistically significant compared with patients with LUSC with Short Os (figure 6E, p = 0.0835) and DFS (figure 6F, p = 0.364) .These results suggest that PRKDC has a high mutation rate in NSCLC patients, and PRKDC gene mutation may influence the prognosis of LUAD patients.

2.5 Function prediction and enrichment analysis of PRKDC and similar genes

We searched GEPIA2.0（http://gepia2.cancer-pku.cn)for 100 adjacent genes significantly associated with the PRKDC mutation and constructed a complete network by STRING11.0（https://string-db.org）(figure 7A).In addition, GO and KEGG analyzed the function of PRKDC and its 100 mutated neighboring genes in Metascape（http://www.metascape.org）.See figure 7B-7D,biological Processes such as DNA repair (GO: 0006281) and regulation of DNA metabolic processes (GO: 0051052) are significantly regulated by the PRKDC mutation in LUAD. Cellular components such as the Chromosomal region (GO: 0098687) and the DNA damage site (GO: 0090734) are significantly regulated by the PRKDC mutation in LUAD.In addition, PRKDCA mutations also significantly affected molecular functions, such as impaired DNA binding (GO: 0003684) , DNA replicator binding (GO: 0003688) and so on.In KEGG analysis, 99 pathways including KO04110 cell cycle and KO03030DNA replication were associated with the function of PRKDC in LUAD (figure 7E).

As one of the most important problems in global health care, lung cancer has gradually become the malignant tumor with the highest morbidity and mortality in the world in recent decades.The proportion of NSCLC was more than 85% , and the 5-year survival rate was only 16% in all stages^[28].Therefore, new diagnostic and prognostic biomarkers need to be further studied.The Catalytic Polypeptide (PRKDC) is a DNA repair gene, which encodes DNA-dependent protein kinase (DNA-pccs) and plays a key role in DNA damage reaction (DDR) , Its main function is the double strand break (DSB) reaction and the maintenance of genomic stability. It is an important part of DNA repair mechanism, including DNA double strand break repair and recombination,so DNA repair genes may serve as potential biomarkers for malignant tumors or therapeutic targets^{[29,30,31,32]}.Although several studies have linked PRKDC to adverse outcomes in many tumor types, such as esophageal cancer ^[33] , B cell leukemia ^[34] and colorectal cancer^[35] . However, the role of PRKDC in NSCLC remains to be clarified.This study was to analyze the expression, mutation and prognostic value of PRKDC in NSCLC.

The results showed that overexpression of PRKDC mRNA was found in both primary LUAD and LUSC tissues. The mRNA expression of PRKDC was significantly correlated with tumor stage, smoking habit, sex, race and lymph node metastasis in NSCLC patients.In addition, the high level of PRKDC mRNA expression was significantly associated with a good prognosis in NSCLC patients.At the same time, high mutation rate (23%) was observed in patients with LUAD in the PRKDC gene mutation associated with good OS and DFS in LUAD patients.Finally, the mutation function and pathway of PRKDC and its 100 LUAD patients were analyzed. The results showed that MCM4, Kif14, UBE2V2 were significantly related to the mutation of PRKDC.Biological Processes such as DNA repair (GO: 0006281) , regulation of DNA metabolism (GO: 0051052) , cellular components such as chromosomal regions (GO: 0098687) , DNA damage sites (GO: 0090734) , molecular functions such as damaged DNA binding (GO: 0003684) , DNA replication source binding (GO: 0003688) , etc. .In KEGG analysis, 5 pathways including KO04110 cell cycle and KO03030DNA replication were significantly associated with PRKDC mutations in Luad patients.

The molecular mechanism of PRKDC in the progression of NSCLC is unclear, but the main reason may be its role in DDR.In response to DNA damage stimuli, PRKDC is recruited by DNA double strand breaks, where it forms DNAPK complexes that bind to DNA Ku70/80 heterosomes to facilitate repair of DNA lesions^[36,37,38].At the same time, there is growing evidence that PRKDC overexpression is observed in many human cancers and is associated with lymph node metastasis, treatment resistance, for example, overexpression of PRKDC has been observed in several cancer types, such as liver cancer, lung cancer and Lymphoma, and is associated with more advanced tumor grade and faster progression^{[39,40,41,42]}.Given the strong association between aberrant PRKDC expression and cancer incidence, it may play an important role in promoting tumorigenesis.In addition, PRKDC has been shown to play a key role in regulating cell cycle and chromosome segregation, which may contribute to tumorigenesis.On the other hand, PRKDC has been found to be associated with the late clinical phase and poor prognosis of many tumor types^[43].Expression of PRKDC was found to be elevated in esophageal carcinoma tissue compared with adjacent normal mucosa ^[44]. The high tumornormal expression ratio of PRKDC was associated with an increased risk of non-small-cell lung carcinoma death.The increased expression of PRKDC was observed by staining in high-grade Lymphoma lymph nodes compared with low-grade Lymphoma patients.Similarly, in our study, PRKDC had higher mRNA expression rates in LUAD and LUSC than in normal tissues, and was significantly associated with clinical stages and poor prognosis in NSCLC patients.Defective DNA repair is a common feature of cancer.Recently, Chae et Al. analyzed a comprehensive list of 193 DNA repair genes using large databases such as COSMIC and TCGA.PRKDC has been identified as one of the top ten mutated DNA repair genes in common cancers including lung, breast, liver, colorectal cancer and skin cancers.In addition, Chae et Al. reported a significant increase in the mutation burden in all colorectal cancer patients with the PRKDC mutation^[45].Our results suggest that PRKDC has a high mutation rate in NSCLC patients and is associated with shorter Os and DFS mutations in LUAD patients, suggesting that the PRKDC gene mutation may significantly influence prognosis in LUAD patients.

Our research has some limitations.First, although PRKDC mRNA expression is associated with Os and DPS in NSCLC, the PRKDC gene mutation is associated with shorter Os and DPS in LUAD, which demonstrates the important predictive value of PRKDC in NSCLC and the PRKDC mutation in LUAD.However, all data analysed in our study were retrieved from the online database and further studies are needed to include a larger sample size to validate our findings and explore the clinical application of PRKDC in the treatment of NSCLC.Secondly, we did not assess the potential role of PRKDC in the diagnosis and treatment of NSCLC, so future studies are needed to explore whether PRKDC can be used as a diagnostic marker or therapeutic target.Finally, we did not explore the potential mechanisms of different PRKDC in NSCLC. Future studies are worth investigating the detailed mechanisms between PRKDC and NSCLC.

Overall, our results suggest that PRKDC may be a prognostic biomarker for poor survival of NSCLC and may be helpful in providing more effective and rational treatment for patients with PRKDC.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript

Competing Interests

The authors have no relevant financial or non-financial interests to disclose

Author Contributions

All authors contributed to the study conception and design.Material preparation, data collection and analysis were performed by Yikun Guo and Mengxia Yang,contributed 50% to the article,Xingxing Liu and Yanbin Liu polished the language, contributed 20% to the article,Junyan provided the idea of the article,contributed 30% to the article.All authors read and approved the final manuscript

Competitive interests

The author did not receive the support of any organization for the submitted work.No funds were received to assist in the preparation of the manuscript.No funds were received for the study.No funds, grants or other support were received.The author has no relevant financial or non-financial interests to disclose. The author has no conflict of interest statement relevant to the content of this article. All authors certify that they have no relationship or participation with any organization or entity and have any economic or non-economic interest in the topics or materials discussed in this manuscript. The author has no financial or proprietary interest in any of the materials discussed in this article.

Conflict of Interest

The authors declare that they have no conflict of interest.

Author composition

All authors of this article:Yikun Guo,Mengxia Yang,Xingxing Liu,Yanbin Liu,Jun Yan.Jun Yan is the corresponding author of this article.Mailbox is [email protected].

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Expression and clinical significance of PRKDC in lung cancer based on bioinformatics analysis

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