Effects of Xeroderma pigmentosum group C polymorphism on the likelihood of prostate cancer

Abstract Background Numerous studies have assessed the association between xeroderma pigmentosum complementation group C (XPC) polymorphisms and susceptibility of prostate cancer (PCa); however, the findings remain inconsistent. Methods We performed an updated analysis utilizing data from electronic databases to obtain a more accurate estimation of the relationship between XPC rs2228001 A/C polymorphism and PCa risk. We further used in silico tools to investigate this correlation. Results Totally, 5,305 PCa cases and 6,499 control subjects were evaluated. When all studies pooled together, we detected no positive result (recessive genetic model: OR = 1.14, 95% CI = 0.93‐1.40, P heterogeneity = 0.001, P = .212); nevertheless, the XPC rs2228001 A/C variant was associated with PCa risk in Asian descendants in the subgroup analysis (OR = 1.21, 95% CI = 1.01‐1.43, P heterogeneity = 0.008, P = .034). In silico tools showed that more than 20 proteins can participate in the protein crosstalk with XPC. The expression of XPC was down‐regulated in all Gleason scores of prostate cancer. Conclusions The present study indicated that the XPC rs2228001 A/C variant may be associated with elevated PCa risk in Asian patients.

Studies have shown that genetic factors may play a crucial role in the development of PCa. Down-regulation of DNA repair is a pivotal factor in the progression of PCa. 7 Nucleotide excision repair (NER), a main human DNA repair pathway, is one of the most significant defense mechanism against mutagenic exposure. 8 Xeroderma pigmentosum group C (XPC) is involved in the early damage initiation of NER. 9 The XPC gene located on c3p25 of homo sapiens. 10 Mutation of XPC can alter the capacity of NER and lead to carcinoma of human. 11 The substitution of A to C at position 939 is the most widely studied single nucleotide polymorphisms in XPC. 12 Previous publications demonstrated that the XPC rs2228001 A/C variant may be associated with increased risk for colorectal, bladder, breast, and lung cancer. [13][14][15][16] Association between this XPC variant and PCa likelihood was previously assessed. [17][18][19][20] However, there are vague conclusions about the relationship between XPC rs2228001 A/C polymorphism and PCa susceptibility in different case-controlled studies. Hence, a systematic analysis based on all eligible studies was conducted to further investigate the correlation between the XPC rs2228001 A/C polymorphism and PCa risk. [17][18][19][20][21][22][23][24][25][26][27][28] 2 | ME THODS AND MATERIAL S

| Search strategy
We performed a comprehensive literature search on electronic databases including Web of Science, Cochrane Library, Google Scholar, PubMed, EMBASE, and Chinese Biomedical Database to retrieve all publications on the XPC rs2228001 A/C polymorphism and PCa susceptibility. The search terms were as follows: "XPC OR xeroderma pigmentosum group C," "polymorphism OR single nucleotide polymorphism OR mutation OR variant," and "carcinoma OR tumor OR adenocarcinoma OR cancer." The last search was updated on April 10, 2020. We further screened the supplementary material of accept articles to maximize the search.

| Study selection and inclusion criteria
Two investigators independently searched the studies according to inclusion criteria. The inclusion criteria were as follows: (a) evaluating the association between the XPC rs2228001 A/C polymorphism and PCa risk; (b) including available genotype frequencies to calculate odds ratio; and (c) using a case-control design.

| Exclusion criteria
The exclusion criteria were as follows: (a) Data of control were not available; (b) with no available genotype frequency for the XPC rs2228001 A/C polymorphism; (c) review articles; and (d) duplication with overlapping data from the same authors.

| Data extraction
For every included study, the following information was extracted: name of author, year of publication, control source, ethnicity, genotyping method, PSA level (ng/mL), age range, sample size of case and control, genotyping data of the XPC rs2228001 A/C variant, and Pvalue of Hardy-Weinberg equilibrium (HWE) for case and control.
Any disagreement should be addressed by discussion with a third investigator to achieve a final decision.

| Methods for quantitative synthesis
Odds ratio and 95% confidence interval were adopted to evaluate the correlation between the XPC rs2228001 A/C polymorphism and PCa risk. Four genetic models were employed in the current analy- Moreover, sensitivity analysis was applied to examine the impact of each study on the combined OR P-value of HWE was detected by chi-square test. P-value more than 0.05 indicates an HWE balance.
The subgroup analysis included ethnic types and source of control.

| Study Characteristics
As described in Table 1

| Quantitative synthesis
When all the studies pooled together (Table 2)

| Expression of XPC utilizing in silico analysis
The in silico tool was used to evaluate the expression of XPC in 497 primary tumors and 52 normal tissues. XPC expression was lower in PCa tissues than in the control (P < .001, Figure 4A). The expression of XPC was down-regulated in all Gleason scores of PCa. (P < .05, Figure 3). Furthermore, we investigated whether XPC expression influenced the overall survival and disease-free survival rate in PCa cases. As shown in Figure 4B and Figure  shown in Figure 5B. The PROVEAN score of the XPC rs2228001 A/C variant is 1.667, which indicates that this variant is neutral ( Figure 5C). As shown in Figure 6A, at least 25 genes are involved  Figure 6B). Similar findings were indicated for RBM9 ( Figure 6C) and BRPF1 gene ( Figure 6D). Nevertheless, there are few studies on their connections in present publications. We further used the online String server tools to explore the proteinprotein correlation regarding XPC. As described in Figure 8A, at least 20 proteins participate in the protein crosstalk with XPC.

| Publication bias
We conducted Egger's test and Begg's funnel plot to detect the pub-  Figure 7B. The sensitivity analysis for the XPC variant is shown in Figure 7C. No individual study would influence the pooled OR.  Egger's test, indicating that conclusions of our study were stable and trustworthy.

| D ISCUSS I ON
In conclusion, our study suggested that the XPC rs2228001 A/C variant might contribute to elevated PCa risk in Asian patients.
The expression of XPC was down-regulated in PCa with different Gleason scores. In future, more large-scale and well-designed studies are warranted to confirm our conclusions in more detail.

ACK N OWLED G M ENT
Not applicable.

CO N FLI C T O F I NTE R E S T
The authors declare no competing interests.

E TH I C A L A PPROVA L
Not applicable.

DATA AVA I L A B I L I T Y S TAT E M E N T
All data generated and analyzed during this study are included in this published article. Please contact the author for data requests.