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.