In the era of personalized medicine, identifying molecular differences in cancer between different ethnicities is increasingly important. It is known that African American men (AAM) have a higher incidence of prostate cancer and higher mortality from the disease from that observed in Caucasian men (CaM). While socioeconomic factors have been shown to contribute to this disparity, underlying molecular differences in these tumors may play a role as well. In light of new and evolving molecular diagnostic modalities and targeted treatments for prostate cancer, identification of ethnic differences in the molecular classification of this disease is an essential step in the process.
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Over the past decade, there have been several new discoveries of specific molecular aberrations occurring in prostate cancer, including recurrent gene fusions involving androgen-regulated genes (i.e., TMPRSS2) and ETS family genes (ERG), PTEN genomic deletion, overexpression of the protein SPINK1 (a low molecular weight trypsin inhibitor), and, more recently, nonsynonymous somatic mutations of SPOP. Prior studies have consistently shown that ERG rearrangement and ERG overexpression are less prevalent in prostate cancer from AAM compared to CaM, but studies investigating the differences in incidence of other molecular aberrations between AAM and CaM are lacking.
In order to assess the differences in frequency of ERG rearrangement, PTEN deletion, SPINK1 overexpression, and SPOP mutations between AAM and CaM, we examined radical prostatectomy (RP) specimens from 105 AAM and 113 CaM, all of whom were treated at a single academic medical center. The pre- and post-operative clinicopathologic characteristics of the two groups were similar. In the dominant tumor nodules from the RP specimens, we evaluated SPINK1 overexpression by immunohistochemistry, ERG rearrangement and PTEN deletion by FISH, and SPOP mutations by Sanger sequencing.
ERG rearrangement was present in 48 of 113 tumors (42.5%) in CaM compared with 29 of 105 tumors (27.5%) of AAM (p=0.024). Heterozygous PTEN deletion was observed in 19 of 96 tumors (19.8%) in CaM and 7 of 101 tumors (6.9%) in AAM (p=0.011). SPINK1 overexpression was identified in 9 of 110 tumors (8.2%) in CaM and 25 of 105 tumors (23.4%) in AAM (p=0.002). SPOP mutations were identified in 8 of 78 (10.3%) of tumors in CaM, compared with 4 of 88 (4.5%) tumors in AAM (p=0.230). The difference in prevalence of ERG rearrangement and SPINK1 overexpression remained statistically significant (p=0.018 and p=0.008, respectively) when adjusted for age, body mass index, Gleason score, and pathologic stage, while differences in PTEN deletion and SPOP mutations approached significance (p=0.061 and p=0.087).
Our study is the first to compare all four of these recurrent molecular aberrations in prostate cancer between AAM and CaM. We found that significant differences exist, with SPINK1 overexpression occurring more frequently and ERG rearrangements and PTEN deletions occurring less frequently in AAM. Although in the current study, we did not thoroughly assess the long-term clinical outcomes of these patients, these molecular aberrations have been found in other studies to have prognostic significance and/or diagnostic implications. Further investigation is warranted to ascertain whether any of these molecular differences explain some of the disparity in incidence and mortality in prostate cancer between these two ethnic groups. Ultimately, a better understanding of the ethnic differences in this disease will allow for optimizing screening methods and selecting appropriate treatment plans.
Francesca Khani, MD and Brian Robinson, MD
Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University and New York-Presbyterian Hospital, New York, New York; Department of Urology, Weill Medical College of Cornell University and New York-Presbyterian Hospital, New York, New York.