Epco-22. Longitudinal Molecular Characterization Identifies Treatment Driven Evolution of Oligodendroglioma
Year: 2023
Type: conference-abstract
Abstract: Oligodendroglioma is characterized by oligodendrocyte-like histology, mutation in the IDH genes, along with codeletion of chromosome arms 1p and 19q. Treatment for oligodendrogliomas combines surgery, followed by observation, and chemotherapy and/or radiotherapy when tumors progress. Most oligodendrogliomas eventually recur with a more aggressive phenotype, leading to patient mortality but molecular mechanisms remain poorly understood. To investigate the molecular trajectory of oligodendroglioma, we collected more than 270 longitudinal samples from over 130 oligodendroglioma patients, to perform whole genome or whole exome sequencing, bulk RNA, and single-nucleus RNA sequencing (n = 30 samples). Common mutations in IDH1/2, TERT promoter, CIC, and FUBP1 were observed. About half of the CIC and FUBP1 mutations occurred in the initial sample and persisted stably throughout recurrence. The majority of PIK3CA and PIK3R1 mutations were either shared or present in recurrences only implicating the PI3K pathway in oligodendroglioma recurrence. Mutational signature analysis revealed 34.5% of tumors treated with alkylating agents acquired SBS11/SBS31 associated hypermutation. By integrating signatures with clonality estimates, we approximated the timing of mutational processes and found that clonal timings of treatment related mutations correlate with the treatment administration date. We found that aging signature-related mutations were mostly clonal, and treatment signature-related mutations were more likely to be sub-clonal, supporting the late emergence of these mutations following treatment. We observed increased somatic copy number alterations in oligodendroglioma recurrences, reflected in notable chromosome 4 losses. Associating treatment with snRNAseq derived cellular states, we observed a significant increase in the fraction of proliferating stem-like cells in the hypermutator versus non-hypermutator recurrent samples. These findings shed light on the molecular changes occurring in oligodendrogliomas following treatment and provide insights that may aid in targeting treatment resistance.
Source: Neuro-Oncology
Authors: Tamrin Chowdhury, Kevin Johnson, Emre Kocakavuk, Chaewon Heo, Gordon Y Ye, Padmaja Ghospurkar, Taylor Wade, Jill Barnholtz-Sloan, Joseph Costello, Carol Elliott, Pim French, Anna Golebiewska, Beth Hermes, Chibo Hong, Craig Horbinski, Mustafa Khasraw, Peter LaViolette, Kay Ka-Wai Li, Eric Lipp, Allison Lowman, Katy McCortney, Hyo-Eun Moon, Ho-Keung Ng, Marta Padovan, Sun Ha Paek, Wies Vallentgoed, Rachael Vaubel, Pieter Wesseling, Kerryn Westcott, Frederick Varn, Roel Verhaak
Institutions: Yale University, Jackson Laboratory, National Cancer Institute, University of California, San Francisco, St. Joseph's Hospital and Medical Center, Erasmus MC, Luxembourg Institute of Health, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Duke University, Medical College of Wisconsin, Chinese University of Hong Kong, Northwestern University, Seoul National University, Mayo Clinic, Amsterdam University Medical Centers, Olivia Newton-John Cancer Research Institute
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4388588775