Inherited Mutations in Chinese Men With Prostate Cancer

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  • 1 Department of Urology, Fudan University Shanghai Cancer Center, Shanghai;
  • | 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai;
  • | 3 Department of Urology, and
  • | 4 Institute of Urology, West China Hospital, Sichuan University, Chengdu;
  • | 5 Department of Urology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou;
  • | 6 Department of Surgery, and
  • | 7 SH Ho Urology Center, Chinese University of Hong Kong, Hong Kong;
  • | 8 Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou; and
  • | 9 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China.

Background: Although China accounts for 7.8% of worldwide new prostate cancer (PCa) cases and 14.5% of new deaths according to GLOBOCAN 2020, the risk of PCa associated with germline mutations is poorly defined, hampered in part by lack of nationwide evidence. Here, we sequenced 19 PCa predisposition genes in 1,836 Chinese patients with PCa and estimated disease risk associated with inherited mutations. Patients and Methods: Patients were recruited from 4 tertiary cancer centers (n=1,160) and a commercial laboratory (n=676). Germline DNA was sequenced using a multigene panel, and pathogenic/likely pathogenic (P/LP) mutation frequencies in patients with PCa were compared with populations from the gnomAD (Genome Aggregation Database) and ChinaMAP (China Metabolic Analytics Project) databases. Clinical characteristics and progression-free survival were assessed by mutation status. Results: Of 1,160 patients from hospitals, 89.7% had Gleason scores ≥8, and 65.6% had metastases. P/LP mutations were identified in 8.49% of Chinese patients with PCa. Association with PCa risk was significant for mutations in ATM (odds ratio [OR], 5.9; 95% CI, 3.1–11.1), BRCA2 (OR, 15.3; 95% CI, 10.0–23.2), MSH2 (OR, 15.8; 95% CI, 4.2–59.6), and PALB2 (OR, 5.9; 95% CI, 2.7–13.2). Compared with those without mutations, patients with mutations in ATM, BRCA2, MSH2, or PALB2 showed a poor outcome with treatment using androgen deprivation therapy and abiraterone (hazard ratio, 2.19 [95% CI, 1.34–3.58] and 2.47 [95% CI, 1.23–4.96], respectively) but similar benefit from docetaxel. Conclusions: The present multicenter study confirmed that a significant proportion of Chinese patients with PCa had inherited mutations and identified predisposition genes in this underreported ethnicity. These data provide empirical evidence for precision prevention and prognostic estimation in Chinese patients with PCa.

Background

Prostate cancer (PCa) is the second most common male cancer worldwide and has the highest incidence rate in Western nations.1 In recent years, significant advances have been made in understanding the contribution of inherited susceptibility to PCa risk.24 Genome-wide association studies (GWAS) have identified approximately 180 common variants, which can account for approximately 30% of familial PCa risk.5,6 Some rare or low-frequency variants in DNA repair genes (DRGs; ATM, BRCA1, BRCA2, CHEK2, MLH1, MSH2, MSH6, NBN, PALB2, and PMS2) and HOXB13 (G84E) have also been identified to be associated with increased PCa risk in men of European ancestry.7,8 In addition, germline mutations in DRGs were associated with aggressive disease and could inform targeted treatment and the enrollment of clinical trials.9,10

However, there are limited genetic data from Chinese patients with PCa, who have a lower incidence of PCa (age-standardized rate, 9.1 vs 65.9 per 100,000) but a 3 times higher ratio of mortality to incidence (0.52 vs 0.17).1 The seminal study by Pritchard et al,2 which comprised 693 patients from 7 institutes, only included 15 patients (2.2%) of Asian ancestry. Besides, GWAS results suggested that among 147 susceptibility loci in PCa in European populations, only 11 of these common loci were reproducible in the Asian population,1113 indicating the difference of inherited background between patients with PCa of Asian ancestry and European ancestry. The data for breast and ovarian cancer also support the idea that germline variants in DRGs are ethnicity specific.14 This raised the question whether the association between germline mutations and the risk or prognosis of PCa remained stable in Chinese patients with PCa. We previously reported the frequency of these mutations in a small set of unselected patients with PCa (31/316; 9.8%).15 However, it is unknown whether this small cohort is representative and whether these mutations confer an elevated risk of PCa and indicate a poor clinical outcome in Chinese populations. Thus, we conducted this multicenter study to determine the contribution of germline mutations in 19 known or suspected PCa susceptibility genes to the risk of PCa, and its implications in a large group of Chinese patients with PCa.

Patients and Methods

Study Population

Patients with PCa (n=1,836) were identified from 5 sources: (1) 755 consecutive patients who consented for germline sequencing at the Fudan University Shanghai Cancer Center (FU-SCC), (2) 100 patients undergoing primary treatment at the Chinese University of Hong Kong Prince of Wales Hospital (CUHK-PWH), (3) 157 consecutive patients who were enrolled at the Sichuan University West China Hospital (SU-WCH), (4) 148 consecutive patients recruited at the Sun Yat-sen University Cancer Center (SYSU-CC), and (5) 676 patients derived from a commercial clinical laboratory. All of the patients had a diagnosis of prostate adenocarcinoma and were not selected based on age at diagnosis, family history, or genetic background knowledge. A subset of patients from FU-SCC has been described previously.15 Clinical data were collected by medical records and test requisition forms (when available), but detailed clinical characteristics were not available for patients from the commercial laboratory. Patients from the laboratory were offered germline sequencing, according to the genetic testing recommendations in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer Early Detection.16 Most of these patients had metastatic PCa (mPCa). Protocols for all participants were approved by local Institutional Review Boards, and written informed consent was obtained from all patients at the local sites before enrollment.

Sequencing and Variant Interpretation

Germline DNA extracted from the patients’ peripheral blood mononuclear cells was sequenced on a next-generation sequencing platform using a multigene panel ranging from 2 to 618 genes or whole-exome sequencing at the discretion of the ordering clinician. Variants, including single-nucleotide variants and insertions/deletions (indels), were detected as described previously.15 The mean sequencing depth of coverage was >200× coverage for all participants, and sequencing reads were aligned to the human reference genome (hg19).

For this study, we constructed a 19-gene panel (ATM, ATR, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, FANCA, HOXB13, MLH1, MRE11, MSH2, MSH6, NBN, PALB2, PMS2, RAD51C, RAD51D, and TP53) for further variant interpretation after a literature review.8,1719 The 19 genes were requisitioned in 1,563 (85.1%) of 1,836 patients. The flowchart of the variant interpretation process is described in supplemental eAppendix 1 (available with this article at JNCCN.org). Notably, given that the HOXB13 G135E variant was associated with the risk of PCa in the Chinese population,20 we defined G135E in HOXB13 as a pathogenic variant in this study. Only pathogenic/likely pathogenic (P/LP) variants were considered to be deleterious and further analyzed in this study. The general population data were obtained from the gnomAD (Genome Aggregation Database) and mBiobank databases and are summarized in supplemental eAppendix 1.

Statistical Analysis

To investigate the association between mutations and clinical factors, we used the chi-square or Fisher exact test for categorical variables and the Kolmogorov-Smirnov test for continuous variables. Multivariate logistic analysis was used to identify the predictive factors for germline mutations. Case–control association was assessed by logistic regression. The significance of associations was adjusted for multiple testing by using the Bonferroni correction.

Survival analysis was restricted to patients with mPCa receiving germline sequencing covering 18 DRGs who had available treatment histories. The association between mutations and survival was evaluated using the Kaplan-Meier method and Cox regression models. All reported P values were 2-tailed, and an adjusted P<.05 was considered statistically significant. All analyses were performed with R version 3.5.2 (R Foundation for Statistical Computing).

Results

Characteristics of Study Population

The phenotypic characteristics of 1,836 patients with PCa from all sources are listed in Table 1 and supplemental eTable 1. There was an increased fraction of patients with mPCa in FU-SCC, SYSU-CC, and SU-WCH compared with CUHK-PWH (∼70% vs 34%) (supplemental eTable 3). Among patients with available clinical data, 89.7% had International Society of Urologic Pathologists (ISUP) grade ≥3 at diagnosis, and 65.6% of patients had mPCa, representing a clinically aggressive disease cohort.

Table 1.

Clinicopathologic Characteristics Between Mutation Carriers and Noncarriers

Table 1.

Frequency of Mutations and Comparison With the General Population

Sequencing of 19 PCa-related genes identified 919 variants with uncertain significance and 152 P/LP variants. Among the 152 P/LP variants, 39 (25.7%) were novel and not reported in the ClinVar or dbSNP database (supplemental eTable 2).21,22 The combined mutation frequency in genes from all germline sequencing panels was 8.49% for all patients with PCa (supplemental eTables 2 and 4). Among 152 P/LP variants, 136 patients (7.4%) carried mutations in homologous recombination repair genes, whereas 12 (0.78%) harbored mutations in mismatch repair genes and 3 (0.23%) had G135E mutations in HOXB13 (supplemental eTable 4). One patient had deleterious mutations in both ATR and MSH6. The 149 germline mutations in DRGs included 143 truncating mutations and 6 known deleterious missense mutations (supplemental eFigure 1). Although BRCA2 had the highest prevalence of mutations (n=79; 4.3%), mutations were also frequently observed in ATM (n=19; 1.04%), PALB2 (n=12; 0.67%), MSH2 (n=8; 0.45%), BRCA1 (n=7; 0.38%), FANCA (n=5; 0.3%), and ATR (n=5; 0.29%) (supplemental eTable 4 and Figure 1A). A smaller number of mutations was observed in other PCa-related genes, including RAD51D (n=4; 0.25%), HOXB13 (n=3; 0.23%), CHEK2 (n=3; 0.17%), MSH6 (n=3; 0.17%), NBN (n=1; 0.06%), RAD51C (n=1; 0.06%), PMS2 (n=1; 0.06%), and BRIP1 (n=1; 0.06%) (supplemental eTable 4 and Figure 1A). There were no deleterious alterations in 4 genes: FAM175A, MLH1, MRE11, and TP53.

Figure 1.
Figure 1.

Germline cancer susceptibility gene mutations identified in patients with prostate cancer. (A) Distribution of the 152 mutations among 15 genes identified in 151 patients. (B) Proportions of patients with a germline mutation, by specific clinical characteristics.

Abbreviations: CUHK-PWH, Chinese University of Hong Kong Prince of Wales Hospital; FU-SCC, Fudan University Shanghai Cancer Center; gDDRm, germline DNA damage repair gene mutation; ISUP, International Society of Urologic Pathologists; SU-WCH, Sichuan University West China Hospital; SYSU-CC, Sun Yat-sen University Cancer Center.

Citation: Journal of the National Comprehensive Cancer Network 2021; 10.6004/jnccn.2021.7010

We further compared the DRG mutation frequency in our cohort versus the general population. We observed that 4 genes were significantly associated with PCa compared with gnomAD control subjects. These included BRCA2, with mutations in 4.3% of cases and 0.27% of control subjects (odds ratio [OR], 16.6; 95% CI, 10.7–25.7); MSH2, with mutations in 0.45% of cases and 0.03% of control subjects (OR, 14.9; 95% CI, 3.9–56.3); PALB2, with mutations in 0.67% of cases and 0.12% of control subjects (OR, 5.6; 95% CI, 2.5–12.5); and ATM, with mutations in 1.04% of cases and 0.37% of control subjects (OR, 2.8; 95% CI, 1.6–4.9) (Table 2). Association analysis using the ChinaMAP (China Metabolic Analytics Project) reference control subjects confirmed all significant associations for BRCA2, MSH2, and PALB2, whereas ATM exhibited an increased risk association (OR, 5.3; 95% CI, 2.9–9.9). Thus, 4 genes significantly associated with PCa were designated as PCa predisposition genes for the Chinese populations. The specific mutation locations in these 4 genes are presented in supplemental eFigure 2.

Table 2.

Comparisons of Mutation Carriers by DRG Between Patients With PCa and Controls From gnomAD and ChinaMAP Databases

Table 2.

Clinical Characteristics and DRG Mutation Status

We categorized the PCa-related mutations into 4 categories based on the association analysis above: (1) mutations in ATM/BRCA/MSH2/PALB2, (2) mutations in other germline DRGs (ATR, BRCA1, BRIP1, CHEK2, FANCA, MSH6, NBN, RAD51C, RAD51D, and PMS2), (3) mutations in any DRGs, and (4) no mutations. Patients with mutations in ATM/BRCA/MSH2/PALB2 were more likely to have a younger age at diagnosis (P=.014) (Table 1) and higher ISUP grade (P=.009) (Table 1) than noncarriers. Moreover, patients with mutations in ATM/BRCA/MSH2/PALB2 more often had a history of cancers in a first-degree relative (36.2% vs 19.5%; P<.001) (Table 1). There was no difference between patients with mutations in ATM/BRCA/MSH2/PALB2 and noncarriers in prostate-specific antigen at diagnosis (P=.2), TNM classification, and NCCN risk group (P=.124). Results from univariate logistic regression analysis also confirmed these findings (supplemental eTables 5 and 6). In a multivariate model, the most informative predictors of presence of germline mutations in ATM/BRCA/MSH2/PALB2 were age of onset (OR, 0.96; 95% CI, 0.93–0.99; P<.016), ISUP grade (OR, 2.25; 95% CI, 0.94–5.37; P=.068), family history of BRCA2-associated cancers (OR, 3.04; 95% CI, 1.26–7.35; P=.013), and family history of cancers associated with Lynch syndrome (OR, 2.1; 95% CI, 0.91–4.89; P=.08). However, only family history of cancers was significantly associated with positive mutations in other DRGs (P=.002).

Mutation frequency by clinical and demographic characteristics is summarized in Figure 1B and supplemental eFigure 3. Overall, patients from CUHK-PWH had a lower mutation frequency than those from other centers, although this finding was not statistically significant (P=.28). The mutation frequency of patients with PCa tends to decrease with advancing age at diagnosis (P=.04). Notably, among patients aged ≥80 years, the proportion of P/LP variants was up to 5.8%. Moreover, even among 47 patients with ISUP grade 1, 4.26% (n=2) harbored positive variants. The mutation frequency was similar between patients with mPCa and those without metastasis (8.4% vs 7.6%; P=.6).

Distribution of P/LP Variants Across Mainland China

Considering the heterogeneity in genetic background across different geographic areas in China,23 we further described the birthplace distribution of 148 patients with deleterious mutations in DRGs. We identified the birthplace of patients from their identification card numbers. The number of tested patients was very few in some provinces, such as Qinghai, Tibet, Jilin, Ningxia, Guangxi, Hainan, Guizhou, Inner Mongolia, Xinjiang, and Gansu, which would lead to an unreliable analysis. The highest rates of germline mutations in DRGs were observed in Hubei, Shandong, and Jiangxi (16.7%, 15.8%, and 15.6%, respectively) (Figure 2A), whereas the lowest rates of germline mutations in DRGs were found in Yunnan, Shanghai, and Hong Kong (4.2%, 4.4%, and 5%, respectively) (Figure 2A). When we restricted patients to localized high risk to mPCa, the highest rates of germline mutations in DRGs were observed in Shandong, Jiangxi, and Sichuan (19.4%, 16%, and 12.3%, respectively) (Figure 2B), whereas the lowest rates of germline mutations were found in Shanghai, Zhejiang, and Hong Kong (4.7%, 5.1%, and 5.8%, respectively) (Figure 2B).

Figure 2.
Figure 2.

Distribution of cases of (A) 148 men with prostate cancer with inherited mutations in DRGs and (B) 91 men carrying mutations in DRGs with localized high risk to metastatic prostate cancer in mainland China. Values given inside and outside parentheses indicate the number of tested patients and mutation rate (%) in each region, respectively.

Abbreviations: DRG, DNA repair gene; gDDRm, germline DNA damage repair gene mutation.

Citation: Journal of the National Comprehensive Cancer Network 2021; 10.6004/jnccn.2021.7010

Associations Between Germline DRG Mutations and Survival

For patients with metastatic castration-resistant PCa (mCRPC) receiving androgen deprivation therapy (ADT), the median follow-up was 31.1 months. The median progression-free survival (PFS) for patients with mutations in ATM/BRCA2/MSH2/PALB2 was 12.3 months, and the median PFS for patients without mutations was 22.2 months (P=.0107) (Figure 3A). Relative to noncarriers, the HR for ATM/BRCA2/MSH2/PALB2 mutations was 2.19 (95% CI, 1.34–3.58; P=.002) (supplemental eTable 7) after adjusting for age at diagnosis, metastasis status, family history, and ISUP grade. However, there was no significant association between germline mutations in other DRGs and a higher risk of progression.

Figure 3.
Figure 3.

Kaplan-Meier curves for PFS by mutation category in patients with mCRPC receiving (A) ADT, (B) abiraterone, and (C) docetaxel.

Abbreviations: ADT, androgen deprivation therapy; gDDRm, germline DNA damage repair gene mutation; mCRPC, metastatic castration-resistant prostate cancer; mPFS, median progression-free survival; PFS, progression-free survival; WT, wild-type.

Citation: Journal of the National Comprehensive Cancer Network 2021; 10.6004/jnccn.2021.7010

Regarding patients with mCRPC receiving abiraterone, compared with those without mutations, patients with mutations in ATM/BRCA2/MSH2/PALB2 exhibited shorter PFS (6.05 vs 10.0 months; P=.001) (Figure 3B). A multivariate Cox model revealed that mutations in ATM/BRCA2/MSH2/PALB2 remained an independent prognostic factor after adjusting for age at diagnosis, metastasis status, family history, ISUP grade, and prior chemotherapy (supplemental eTable 8). However, the median PFS was similar between patients with mutations in other DRGs and those without mutations. Moreover, we found that PFS in patients with mCRPC receiving docetaxel chemotherapy was not significantly different in patients with or without mutations (6.1 vs 4.3 months; P=.8) (Figure 3C, supplemental eTable 9).

We further separately explored the prognostic role of germline mutations in BRCA2 in patients with PCa, and observed results similar to those for the role of germline ATM/BRCA2/MSH2/PALB2 variants. Kaplan-Meier analysis showed a shorter median PFS for ADT or abiraterone in BRCA2 mutation carriers compared with noncarriers (ADT, 12.3 vs 22.2 months; P=.003; abiraterone, 5.1 vs 10 months; P=.001; docetaxel, 4.3 vs 6.1 months; P=.5) (supplemental eFigure 4).

Discussion

To our knowledge, this is the first large study evaluating inherited predisposition of PCa in a Chinese population. P/LP mutations in 19 genes with established or emerging evidence of increased PCa risk in European populations3 were found in 8.49% of Chinese patients with PCa, and 25.7% P/LP variants were newly identified in our study, confirming the importance of population-specific data for genetic testing. Rare P/LP variants in ATM, BRCA2, MSH2, and PALB2 were significantly associated with a higher risk of PCa in our Chinese population. Patients with P/LP variants in ATM/BRCA2/MSH2/PALB2 have specific clinical characteristics and showed a poor outcome for treatment with ADT or abiraterone. Our study strongly showed the value of genetic testing in Chinese patients with PCa.

Validation of the contribution of P/LP germline variants in ATM, BRCA2, MSH2, and PALB2 to PCa risk is of great importance in Chinese populations. Despite consensus about the value of genetic testing in men with PCa,3 it remained unknown which genes should be prioritized for testing, especially in patients with Chinese ethnicity. Our study makes it more credible that germline mutations in ATM, BRCA2, MSH2, and PALB2 could increase the risk of PCa in Chinese populations. Notably, CHEK2 mutation events were significantly lower in Chinese patients with PCa than in an American population2 when metastatic PCa was examined (1.87% vs 0.13%; P<.001). Recently, emerging germline data from non-White patients have been reported and indicated ethnicity specificity in inherited PCa predisposition.24,25 Momozawa et al25 performed the largest case–control sequencing study, which included 7,636 unselected Japanese patients with PCa and 12,366 control subjects. They found that HOXB13, BRCA2, and ATM were significant causative genes in a Japanese population, but variants in BRCA1, CHEK2, PALB2, BRIP1, and NBN were not associated with PCa risk. Matejcic et al24 analyzed the germline mutations in 2,098 men with PCa of African ancestry and 1,481 control subjects and identified variants in ATM, BRCA2, PALB2, and NBN as the major risk factors for aggressive PCa in men of African ancestry. These studies, together with sequencing studies in men of European ancestry with PCa,2,4 provided solid support regarding the contribution to PCa of P/LP variants in some DRGs in genetically diverse populations, and highlighted the necessity of developing population-specific multiple gene panels for patients with PCa. Differences in the distribution of germline variants may result in disparate tumor biology and differential response to the same treatment between patients with PCa in different populations. Therefore, more efforts should be made to elucidate the functional implications of single-gene mutations rather than regarding all of these related genes as a whole. Such efforts could help to promote the optimal use of precision treatment approaches.

The germline data from these studies also revealed a difference in the prevalence of P/LP variants in DRGs in different ethnicities. Our data suggested that 8.4% of Chinese patients with metastatic PCa harbored P/LP variants in 18 DRGs, whereas 5.7% of men of African ancestry and 11.8% of men of European ancestry with metastatic PCa were carriers of P/LP variants when we focused on similar DRGs.24,25 This tendency was in agreement with a prior study including the largest series of patients with PCa (n=3,607), which reported the highest germline DRG mutation frequency in patients of Ashkenazi Jewish descent (22.2%), followed by White men (17.8%), Asian men (15.1%), and African American men (10.1%).4 Notably, Chinese men with the lowest incidence of PCa had a mutation prevalence similar to that in men of European ancestry, whereas African American men with the highest PCa incidence had the lowest mutation frequencies in DRGs, indicating that there were other important risk factors contributing to the carcinogenesis of PCa.1

A landmark study recently described the centralized analysis of deep whole-genome sequencing data in 10,588 individuals from the ChinaMAP database and divided the Chinese Han population into 7 population clusters based on inherited background.22 Our study also identified substantial geographic variability in germline DRG mutation prevalence among men with PCa across mainland China. Patients in Hubei, Shandong, and Jiangxi had the highest rate of DRGs mutations, whereas those in Yunnan, Shanghai, and Hong Kong had the lowest mutation rate. With an increasing number of clinical trials testing targeted treatment in China, these distribution data had great value in recruiting patients for clinical trials. Moreover, our findings could guide the development of prevention strategies of DRG-related PCa in each province. Universal genetic screening was proposed for patients in areas with high mutation frequency. The small number of patients in some provinces limited our ability to draw conclusions; thus, larger-sample studies are warranted to confirm our findings.

Germline mutation in DRGs was associated with aggressive disease, indicating a poor response to standard-of-care systemic therapies.9 Our previous study revealed that patients with mutations in DRGs tend to have a shorter time to castration resistance than those without mutations.26 This conclusion was validated in this study with a larger sample size, but variants in genes other than ATM, BRCA2, MSH2, and PALB2 lost their prognostic role in patients receiving ADT treatment. As a more effective androgen receptor–targeted agent, we also found abiraterone could not overcome the poor outcome of patients with metastatic castration-resistant PCa with mutations in ATM, BRCA2, MSH2, and PALB2. Novel therapeutic strategies such as olaparib combined with abiraterone may be promising for these mutation carriers, despite needing more evidence from phase III clinical trials.27,28

Our data are consistent with those of another recent study suggesting that patients with germline DNA repair deficiency exhibited attenuated response to abiraterone/enzalutamide (3.3 vs 6.2 months).29 Moreover, our findings were also concordant with the results of PROREPAIR-B trial suggesting that germline mutations in BRCA2 rather than any other genes would result in poor outcome for patients with mCRPC,30 although in our study poor outcome was also observed in patients with germline mutations in ATM/MSH2/PALB2. Limited patient numbers in studies make it obscure for the prognostic role of rare variants. Additional prospective data with a larger sample are warranted to shed further light on this issue.

Our study also has a few limitations. First, the detailed clinical data of patients in the laboratory were not available, which may have led to misestimation of the proportion of patients with aggressive disease, although most of these patients had mPCa according to discussions with ordering clinicians. Second, we analyzed only variants including single-nucleotide polymorphisms and indels, but we did not investigate copy number variants, which also could result in loss of function of genes. Future studies should aim to explore the comprehensive genetic variants, including large indel and noncoding variants. Third, although this is the largest study of genetic predisposition for PCa in Chinese men, the sample size for studying rare mutations remains relatively small. This limitation prevents certainty about the association of specific genes with PCa and stable estimation of mutation frequency. We did not find evidence supporting the association of the remaining 15 genes with PCa risk in our study, although these genes have been reported to contribute to PCa susceptibility. Therefore, future larger-sample studies are warranted to confirm our results.

Conclusions

This multicenter study confirmed that a significant proportion of Chinese patients with PCa had inherited mutations and identified predisposition genes in this underreported ethnicity. These data provide empirical evidence for precision prevention and prognostic estimation in Chinese patients with PCa.

Acknowledgments

We sincerely thank all of the study participants for their involvement in this research. We thank the Burning Rock Biotech (Guangdong, China) Medical Department, 3D Medicines Inc (Shanghai, China), and Hangzhou Life Healthcare Clinical Laboratories (Hangzhou, China) for their help in analyzing and interpreting the genetic data.

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    Wei Y, Wu J, Gu W, et al. Prognostic value of germline DNA repair gene mutations in de novo metastatic and castration-sensitive prostate cancer. Oncologist 2020;25:e10421050.

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    Clarke N, Wiechno P, Alekseev B, et al. Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2018;19:975986.

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    Annala M, Struss WJ, Warner EW, et al. Treatment outcomes and tumor loss of heterozygosity in germline DNA repair–deficient prostate cancer. Eur Urol 2017;72:3442.

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  • 30.

    Castro E, Romero-Laorden N, Del Pozo A, et al. PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2019;37:490503.

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Submitted October 8, 2020; final revision received January 15, 2021; accepted for publication January 15, 2021.

Published online October 15, 2021.

Author contributions: Study concept: Zhu. Data curation: Wei, Sun, Ni, Qin, Wu. Formal analysis: Zhou, He, Chiu, Teoh, Wang, Pan, Wan, Dai, Lin, Gan. Funding acquisition: Zhu. Investigation: Zeng, Li, Ng. Methodology: Zhu, Zhou, He, Chiu, Teoh, Wan, Dai, Gan. Resources: Zhu, Zeng, Li, Ng. Supervision: Zhu, Wu, Ye. Validation: Wang, Pan, Lin. Visualization: Wei, Zeng, Li, Ng, Wu. Writing – original draft: Wei, Zeng, Li, Ng, Wu. Writing – review and editing: Zhu, Ye.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This work was supported by the National Natural Science Foundation of China (grants 81972375 [Y. Zhu], 81902568 [J. Wu]), Shanghai Rising Star Program (grant 16QA1401100 [Y. Zhu]), Shanghai “Rising Stars of Medical Talent” Youth Development Program, the General Program of Beijing Xisike Clinical Oncology Research Foundation (grant Y-2019AZMS-0012 [Y. Zhu]), and Shanghai Anti-Cancer Association Eyas Project (grant SACA-CY19A01 [Y. Wei]). The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.

Data availability: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Correspondence: Yao Zhu, MD, Department of Urology, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China. Email: yaozhu09@fudan.edu.cn; Junlong Wu, MD, Department of Urology, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China. Email: wujunlong920601@163.com; and Dingwei Ye, MD, Department of Urology, Fudan University Shanghai Cancer Center, 270 Dong’an Road, Shanghai 200032, China. Email: dwye.shca@gmail.com

Supplementary Materials

  • View in gallery

    Germline cancer susceptibility gene mutations identified in patients with prostate cancer. (A) Distribution of the 152 mutations among 15 genes identified in 151 patients. (B) Proportions of patients with a germline mutation, by specific clinical characteristics.

    Abbreviations: CUHK-PWH, Chinese University of Hong Kong Prince of Wales Hospital; FU-SCC, Fudan University Shanghai Cancer Center; gDDRm, germline DNA damage repair gene mutation; ISUP, International Society of Urologic Pathologists; SU-WCH, Sichuan University West China Hospital; SYSU-CC, Sun Yat-sen University Cancer Center.

  • View in gallery

    Distribution of cases of (A) 148 men with prostate cancer with inherited mutations in DRGs and (B) 91 men carrying mutations in DRGs with localized high risk to metastatic prostate cancer in mainland China. Values given inside and outside parentheses indicate the number of tested patients and mutation rate (%) in each region, respectively.

    Abbreviations: DRG, DNA repair gene; gDDRm, germline DNA damage repair gene mutation.

  • View in gallery

    Kaplan-Meier curves for PFS by mutation category in patients with mCRPC receiving (A) ADT, (B) abiraterone, and (C) docetaxel.

    Abbreviations: ADT, androgen deprivation therapy; gDDRm, germline DNA damage repair gene mutation; mCRPC, metastatic castration-resistant prostate cancer; mPFS, median progression-free survival; PFS, progression-free survival; WT, wild-type.

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    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
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