Histopathologic and Molecular Characterization of IDH-Mutant Prostatic Adenocarcinoma.

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 TMPRSS2ERG 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.