Histopathologic and Molecular Characterization of IDH-Mutant Prostatic Adenocarcinoma.

in Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc by Benzion Samueli, Hikmat Al-Ahmadie, Ying-Bei Chen, Anuradha Gopalan, Judy Sarungbam, Satish K Tickoo, Victor E Reuter, Samson W Fine, Jie-Fu Chen

TLDR

  • The study looked at prostate cancer (PCa) and found that some cases of PCa have a genetic change called a gain-of-function isocitrate dehydrogenase (IDH) mutation. The study found that these mutations can be oncogenic (cancer-causing) and can be found in different parts of the PCa genome. The study also found that these mutations can be associated with certain clinical characteristics, such as the grade of the cancer and the presence of certain proteins. The study also found that these mutations can be associated with other genetic changes in the PCa genome. The study suggests that further research is needed to understand the role of these mutations in PCa and to develop new treatments for this rare yet distinct molecular subset of PCa.

Abstract

Gain-of-function isocitrate dehydrogenase (IDH) mutations are pathogenically significant in many tumor types and are actionable in cholangiocarcinoma, low-grade glioma, and acute myeloid leukemia. Rare IDH mutations have been described in prostatic adenocarcinoma (PCa). Recent publications suggested that psammomatous calcifications in PCa are associated with IDH1 mutation. In this retrospective study, we queried our institutional clinical sequencing database (Cohort 1), and previously published PCa datasets in cBioPortal (Cohort 2). Samples were stratified by oncogenic hotspot IDH mutations at IDH1 R132 and IDH2 R140/R172, and other non-hotspot IDH mutations. Seventeen (0.4%) cases were identified from 4033 PCa in Cohort 1 harboring mutually exclusive oncogenic hotspot IDH1 (N=15, one of which was subclonal) or IDH2 (N=2) mutations, and 20 (0.5%) cases had non-hotspot IDH1/2 mutations. Histologic review of 13 cases with IDH1 hotspot mutation and available material showed Grade Group 3 or higher disease. Immunohistochemistry was performed on cases with IDH1 hotspot mutation when possible, and showed AR, PSA, PSMA and NKX3.1 positive in all four cases stained. In Cohort 2, nine cases (0.3%) harboring IDH1 hotspot mutations were identified from 2749 patients, and nine cases carried non-hotspot IDH1/2 mutations. The combined cohorts of 23 PCa with clonal IDH1 hotspot mutations had no ETS fusions, SPOP hotspot mutations, somatic or germline alterations in BRCA1/2, ATM, RB1 or AR; 19 cases with successful microsatellite instability (MSI) testing were all microsatellite stable. Conversely, among 29 cases with non-hotspot IDH mutations, there were four with TMPRSS2::ERG fusion, six with SPOP hotspot mutations, and 10 with AR amplifications/hotspot mutations; eight were MSI-high. Notably, only two cases with IDH1 hotspot mutation had psammomatous calcifications. Our findings provide evidence that IDH1 hotspot mutations serve as driver alterations in this rare yet distinct molecular subset of PCa. Further studies are warranted to correlate response to androgen deprivation and IDH inhibitors.

Overview

  • The study investigates the prevalence and clinical characteristics of prostate cancer (PCa) with gain-of-function isocitrate dehydrogenase (IDH) mutations. The study uses a retrospective approach, querying the institutional clinical sequencing database (Cohort 1) and previously published PCa datasets in cBioPortal (Cohort 2). The study focuses on oncogenic hotspot IDH1 and IDH2 mutations and other non-hotspot IDH1/2 mutations. The primary objective of the study is to determine if IDH1 hotspot mutations serve as driver alterations in PCa and to identify any clinical characteristics associated with these mutations.

Comparative Analysis & Findings

  • The study found that 0.4% of PCa cases harbor oncogenic hotspot IDH1 mutations, and 0.5% of cases have non-hotspot IDH1/2 mutations. The study also found that 0.3% of PCa cases harbor IDH1 hotspot mutations, and 0.3% of cases have non-hotspot IDH1/2 mutations. The study found that PCa cases with IDH1 hotspot mutations had Grade Group 3 or higher disease and were positive for AR, PSA, PSMA, and NKX3.1. The study also found that PCa cases with non-hotspot IDH mutations had TMPRSS2::ERG fusion, SPOP hotspot mutations, and AR amplifications/hotspot mutations. The study found that only two cases with IDH1 hotspot mutation had psammomatous calcifications.

Implications and Future Directions

  • The study provides evidence that IDH1 hotspot mutations serve as driver alterations in a rare yet distinct molecular subset of PCa. The study also highlights the importance of identifying clinical characteristics associated with these mutations. Future studies are warranted to correlate response to androgen deprivation and IDH inhibitors in PCa with IDH1 hotspot mutations. The study also suggests that further research is needed to identify other clinical characteristics associated with non-hotspot IDH1/2 mutations in PCa.
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