Disparities in genomic application:
As genomic data guide subsequent therapy, differential access to genomic testing can widen disparities in clinical trial participation. To date, AAM have been underrepresented in germline and somatic genetic studies of prostate cancer64. The lack of racial diversity in current genetic studies has a potential to exacerbate current disparities in health care.
As the result of the deficiency in racial representation in the genetic studies, the genetic variants that increase cancer risk in AAM and other minority groups are likely to be overlooked. Understanding genetic variant among different racial groups might explain the underlying biological cause for a higher prevalence and worsened prognosis in AAM with PCa. European American men were associated with increased ERG and ETS expression, and decreased SPINK1 expression. The AAM group was associated with higher expression of CRYBB2, GSTM3, with increased expression of SPINK148. Compared to EAM, mutations in ZFHX3 as well as focal deletions in ETV3 were more frequent in tumors from AAM and also MYC amplifications were more frequent in tumors from AAM men with metastatic PCa65. TMPRSS2 and FOXA1 alterations continued to be more frequent in EAM in the metastatic setting66. Recent data suggest that AAM with PCa exhibit genetic alterations in highly penetrant germline genes as well as low-penetrant single nucleotide polymorphisms (SNP). Higher rates of germline variants of uncertain significance (VUS) have been reported in the AAM population than European ancestry patients with PCa, the meaning of which remains to be elucidated. More studies are needed to facilitate the possible reclassification of VUS32. In addition, it has been found that in AAM, the mutational frequency within 8q24 confers a higher incidence of PCa, an earlier age of onset, and a more clinically aggressive disease. The diagnosis of PCa has also been associated with several additional loci at 8q2432. Risk SNPs have a relatively small effect size and the underlying etiology of the non-coding changes remains under study.
However, these studies that evaluate germline and somatic alterations in African American men have shown that there is no significant difference in mutation rate of actionable genes between AAM and EAM with PCa64 65 6667.
In the metastatic setting, germline and somatic genetic testing is an important part of clinical management68. This review will focus on comparing the mutation rate of actionable genes between AAM and EAM with metastatic PCa (the stage of disease has higher mutational burden), as seen in Table 1 and 2. In order to achieve this, we conducted a bibliographic search in PubMed to search for multi-racial prostate cancer studies with result on genes with clinical actionability and report on race/ethnicity. We used the keywords: Racial disparity in germline testing of prostate cancer, tumor mutation across racial group, prevalence of germline mutation in prostate cancer, African American men, germline, prostate cancer, racial disparity in somatic testing of prostate cancer, and racial disparity in genetic alteration of prostate cancer. We found 4 studies analyzing PCa somatic mutations and 6 studies analyzing PCa germline mutations in the metastatic or lethal PCA setting. We then removed studies that did not have data for metastatic or lethal prostate cancer, which includes the Sartor et al. study, Kwon et al. study, and Nicolosi et al. study. Finally, we removed the Schumacher et al. and Mahal et al. study, because they used previous versions of GENIE compared to the Kamran et al. study. In the end, we included studies of somatic mutations total: the Koga et al67 study which includes data from the MC3 (Multi-Center Mutation Calling in Multiple Cancers) call set from the Pan-Cancer Atlas Project of The Cancer Genome Atlas (TCGA), from the Foundation cohort and also from prostate cancers profiled with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT); and the Kamran et al69studio that uses data extracted from the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange (GENIE), version 8.1. In summary, we were left with a total of 5 studies (2 somatic and 4 germline). We identified the most frequent actionable mutations in PCa in these studies and analyzed the rates of somatic and germline mutations expressed in the different ethnic groups.