Biology subjects

Hyman, D. M.

Publications and source records attributed to Hyman, D. M..

2 recordsLinked to original sources

bioRxiv2019

Oncologic Therapy Shapes the Fitness Landscape of ClonalHematopoiesis

Clonal hematopoiesis (CH) is frequent in cancer patients and associated with increased risk of therapy related myeloid neoplasms (tMN). To define the relationship between CH, oncologic therapy, and tMN progression, we studied 24,439 cancer patients. We show that previously treated patients have increased rates of CH, with enrichment of mutations in DNA Damage Response (DDR) genes (TP53, PPM1D, CHEK2). Exposure to radiation, platinum and topoisomerase II inhibitors have the strongest association with CH with evidence of dose-dependence and gene-treatment interactions. We validate these associations in serial sampling from 525 patients and show that exposure to cytotoxic and radiation therapy imparts a selective advantage specifically in hematopoietic cells with DDR mutations. In patients who progressed to tMN, the clone at CH demarcated the dominant clone at tMN diagnosis. CH mutational features predict risk of therapy-related myeloid neoplasm in solid tumor patients with clinical implications for early detection and treatment decisions.

genetics↗

bioRxiv2018

Isoform switching as a mechanism of acquired resistance to isocitrate dehydrogenase inhibition

Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors.\n\nSignificanceIDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by \"isoform switching\" from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2-hydroxyglutarate (2HG) production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.

cancer biology↗