#0130

Comprehensive Genomic and Proteomic Profiling of Adrenocortical Carcinoma in Chinese Patients Identifies an IDH1-Mutant Subtype with Therapeutic Implications

S. Fu¹, H. Wang¹, X. Chen², J. Wang¹, M. Ding¹, H. Shi¹, C. Guo³

¹The Second Affiliated Hospital of Kunming Medical University, Urology, Kunming, China
²Sun Yat-Sen Memorial Hospital, Urology, Guangzhou, China
³Yunnan University, School for Life Science, Kunming, China

Introduction:

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited genomic and proteomic profiles, particularly in Asian populations. This study provides a comprehensive characterization of Chinese ACC patients, identifying unique genomic features, exploring the pathogenesis of isocitrate dehydrogenase 1 (IDH1)-mutated ACC, and uncovering potential therapeutic targets.

Material and methods:

Sixty-five ACC cases from three centers underwent Integrated genomic and proteomic analyses, including exome sequencing (45 tumors), SNP array (45 tumors), proteomics (45 tumors), spatial transcriptomics, and proteomics (4 tumors). Gene Set Variation Analysis (GSVA) was applied using gene sets from MSigDB (e.g., HALLMARK_HYPOXIA and HALLMARK_GLYCOSIS). GSVA scores were mapped onto slides using the scanpy function sc.pl.spatial, allowing the delineation of four metabolic regions based on glycolysis and hypoxia levels: GlycosishighHypoxiahigh, GlycosishighHypoxialow, GlycosislowHypoxiahigh, GlycosislowHypoxialow. These regions were isolated by laser-capture microdissection followed by high-sensitivity mass spectrometry to spatially define the proteomic profiles. Patient-derived xenografts (PDXs) were established by grafting IDH1-mutated tumors under the renal capsules of NSG mice. Mice were administered either vehicle, ivosidenib (75 mg/kg orally), or a combination of ivosidenib and ganitumab (3 mg/mL, i.p.) twice a week.

Results:

Frequent mutations were detected in known driver genes (CTNNB1, TP53, MEN1) and previously unreported genes in ACC, such as IDH1 and IDH2. Mutations in IDH1 (28.9%) and IDH2 (40%) were significantly more prevalent in our cohort than in the TCGA (0%) and COSMIC (0%) datasets, which primarily include Caucasian patients. We have enrolled one case with metastatic ACC harboring an IDH1 mutation who achieved a partial response and exhibited 13 months of progression-free survival and 32 months of overall survival after treatment with ivosidenib, an IDH1 inhibitor. Ethical Committee approval was obtained from the Second Affiliated Hospital of Kunming Medical University. Spatial transcriptomics revealed that IDH1-mutated tumors were characterized by activation of glycolysis and hypoxia pathways. Spatial proteomic analysis across the four defined regions identified IGF-1R as the most upregulated protein in the GlycosishighHypoxiahigh region. In PDX models, combined therapy with IDH1 inhibitor (ivosidenib) and IGF-1R inhibitor (ganitumab) showed superior efficacy over monotherapy.