The prevalence and clinical implication of rare germline deleterious alterations in Chinese patients with prostate cancer: A real‐world multicenter study

Dear Editor, Germline deleterious alterations interrupting the function of DNA damage repair (DDR) have proven to be related to a high risk of prostate cancer (PCa), which are recommended for testing in general practice.1 Moreover, the genetic background has recently emerged as a potential factor in racial diversity, especially in the epidemiology of PCa.2 Since our understanding of the genomics wasmostly derived from the Caucasian population, we conducted a real-world multicenter retrospective study of 490 patients with PCa across distinct clinical states in order to better elucidate the prevalence and clinical implication of rare germline deleterious alterations in Chinese men. A total of 490 patients with PCa, including 181 patients with localized PCa, 156 patients with metastatic hormonesensitive PCa, 147 patients with metastatic castrationresistant PCa, and 6 patients with neuroendocrinedifferentiated PCa,were included in the present study (Figure 1A and Table 1). To explore the landscape of germline deleterious alterations, targeted gene sequencing of 50 genes covering DDR pathway genes and HOXB13 was performed. In addition, concurrent HSD3B1 genotypes were detected in 348 patients. Detailed sequencing and bioinformatics are summarized in Supplementary Methods. Although the distinctiveness in genetic background might play an essential role in the ethnic disparity in the same disease, the similar prevalence of germline deleterious alterations in DDR pathway genes between the Chinese and American populations has been reported a prior single-center study.3 However, due to its relatively small sample size and limited detected genes, the ethnic differences in the germline genomes still remain to be further elucidated. To better determine the interracial heterogeneity in the genomics, we compared the incidence of germline DDR pathway gene alterations in our cohort with the unselected cohort by Nicolosi et al. study.4 In addition, the hereditary susceptibility

Dear Editor, Germline deleterious alterations interrupting the function of DNA damage repair (DDR) have proven to be related to a high risk of prostate cancer (PCa), which are recommended for testing in general practice. 1 Moreover, the genetic background has recently emerged as a potential factor in racial diversity, especially in the epidemiology of PCa. 2 Since our understanding of the genomics was mostly derived from the Caucasian population, we conducted a real-world multicenter retrospective study of 490 patients with PCa across distinct clinical states in order to better elucidate the prevalence and clinical implication of rare germline deleterious alterations in Chinese men.
A total of 490 patients with PCa, including 181 patients with localized PCa, 156 patients with metastatic hormonesensitive PCa, 147 patients with metastatic castrationresistant PCa, and 6 patients with neuroendocrinedifferentiated PCa, were included in the present study (Figure 1A and Table 1). To explore the landscape of germline deleterious alterations, targeted gene sequencing of 50 genes covering DDR pathway genes and HOXB13 was performed. In addition, concurrent HSD3B1 genotypes were detected in 348 patients. Detailed sequencing and bioinformatics are summarized in Supplementary Methods.
Although the distinctiveness in genetic background might play an essential role in the ethnic disparity in the same disease, the similar prevalence of germline deleterious alterations in DDR pathway genes between the Chinese and American populations has been reported a prior single-center study. 3 However, due to its relatively small sample size and limited detected genes, the ethnic differences in the germline genomes still remain to be further elucidated. To better determine the interracial heterogeneity in the genomics, we compared the incidence of germline DDR pathway gene alterations in our cohort with the unselected cohort by Nicolosi et al. study. 4 In addition, the hereditary susceptibility  Figure 1B). Interestingly, we found a relatively higher prevalence of germline deleterious alterations in PALB2 (2.4% vs. 0.5%, p < 0.0001) and lower germline deleterious alteration rates in CHEK2 (0.2% vs. 2.9%, p < 0.001) in our cohort in comparison with the cohort by Nicolosi et al. study ( Figure 1C). Germline deleterious alterations in PALB2, interrupting the recombinational repair and the tumor suppression function, were associated with increased risk of various malignancies. 5 However, the molecular pattern of germline PALB2 alteration and its prognostic value need to be further elucidated. Similar to PALB2, CHEK2 plays an important role in DDR and germline deleterious alterations in CHEK2 may lead to the carcinogenesis of normal prostate cell. 6 Further studies need to be conducted in a larger Chinese population to characterize possible alteration-specific risks of CHEK2 due to its low incidence.
Furthermore, a notable distinction of our cohort was the absence of HOXB13 p.G84E mutation compared to 0.9% in the cohort by Nicolosi et al. study (p = 0.02) ( Figure 1C). HOXB13 plays essential roles in prostate-lineage differentiation and tumorigenesis, which is recommended for family counseling. 1 Specially, the missense mutation G84E in the Caucasian populations has been identified to be strongly associated with increased PCa susceptibility, early onset, and aggressive disease. 7 However, we failed to detect G84E in any of the 490 studied patients, instead, we found other four mutational sites, including G135E. The locations of germline deleterious alterations in the five most frequently altered genes are shown in Figure 2A. Since the recurrent mutation G135E was a founder mutation in a Chinese cohort, 8   Fisher's exact test was used to compare the differences to the fact that HOXB13 p.G135E may be a prominent signature in the Chinese population. Although few PCa riskassociated rare mutations in HOXB13 have been identified to date, it is expected that additional mutations, such as G135E, will be found in ongoing studies in order to better understand the genetic mechanism underlying PCa.
Additionally, concurrent HSD3B1 genotype was detected in 348 (71.0%) of the 490 studied patients. To our knowledge, it was the first time to report the genotype of HSD3B1 in the Chinese population. We compared the alteration frequencies of HSD3B1 with the cohort by Hearn et al. study, 9 surprisingly finding a relatively lower incidence of HSD3B1 c.1245C > A alteration, especially homozygous HSD3B1 (1245CC) alteration (0.8% in our cohort vs. 7.4% in the cohort by Hearn et al. study, p < 0.001) ( Figure 1D). HSD3B1 is responsible for the transformation of steroidal precursors into potent androgens. In addition, HSD3B1 c.1245A > C was associated with rapid resistance to androgen deprivation therapy but was sensitive to abiraterone. 9 The rare homozygous alteration of HSD3B1 in our cohort was also of interest, which might partly interpret the distinct efficacy of conventional hormonal therapy in the Asian population. 2 Next, we examined the predictive value of germline deleterious alterations in DDR pathway genes. Our results suggested that the germline status of DDR pathway genes was associated with severe disease phenotype and shorter time to castration resistance (18.0 months in the gDDR altered group vs. 23.0 months in the gDDR wild-type group, p < 0.001) ( Figure 2B). Specifically, patients harboring deleterious germline BRCA2 mutation has emerged as a distinct subset with inferior outcomes (15.5 months in the gBRCA2 altered group vs. 22.0 months in the gBRCA2 wild-type group, p = 0.0059) ( Figure 2C). Nevertheless, recent evidence suggested that those patients harboring germline DDR defect could experience superior clinical outcomes from poly (ADP-ribose) polymerase inhibitors or platinum-combined chemotherapy. 1,10 Thus, we inferred that the patients with metastatic PCa harboring germline deleterious alterations in DDR pathway genes might benefit more from intensive combination therapy, instead of androgen deprivation therapy alone.
In conclusion, we investigated the genomic landscape of rare germline alterations in the Chinese population and highlighted the prognostic value of germline DDR status in general practice. Comparative analysis of the genomic data from our cohort and Caucasian cohorts revealed the interracial diversity in genetic background, suggesting that PALB2 might be an underlying genomic signature in Chinese population. Especially, the frequency and unique pattern of HOXB13 p.G135E and HSD3B1 c.1245A > C were unique in the Chinese population. In brief, further investigations by incorporating the genetic background might be helpful to understand the racial diversity and establish therapeutic interventions.