Abstract 2439: Transcriptome-wide polysome profiling of glioblastomas identifies molecular subgroups with impact in survival and treatment

Abstract

Abstract Glioblastoma (GBM) is the most common primary brain malignancy in adults and one of the most aggressive cancers. While the genetic landscape of glioblastomas has been characterized, the identified molecular subgroups have so far had limited impact on prognosis and clinical practice. Translation of mRNA into proteins is a key mechanism governing gene expression and a node for convergence of signaling pathways frequently dysregulated in cancer. For example, in vitro, mTORC1 activity has been linked to selective translation of a subset of mRNAs including those encoding pro-proliferative and pro-survival proteins, commonly referred to mTORC1 sensitive translation. Thus, cancer may be associated with altered mRNA translation, leading to differences between the transcriptome and the proteome, which could underlie tumor-associated properties. Transcriptome-wide quantification of efficiently translated mRNAs, or the translatome can, in addition to increasing the knowledge on post-transcriptional dysregulation of gene expression, provide a better approximation of the tumor proteome, as compared to studies of transcriptomes, and identify patient subsets defined by altered mRNA translation. Herein, we used a recently developed transcriptome-wide polysome profiling for small samples approach to quantify efficiently translated mRNA from 37 human GBM samples. The resulting translatomes allowed classification into three molecular subgroups differing in survival. Group 1, which had a median survival of 5 months, was characterized by increased translation of mRNAs encoding components of the mTORC2 pathway, mitochondria and cilia. Group 2, with a median survival of 6.3 months, was characterized by augmented mTORC1 dependent translation despite low translation of mRNAs encoding mitochondria associated proteins together with increased translation of mRNAs encoding angiogenesis related proteins. In contrast, group 3 showed a relatively longer median survival of 21.1 months and was characterized by high translation of mRNAs encoding mitochondria associated proteins despite low mTORC1 dependent translation, as well as low translation of mRNAs encoding cilia and mTORC2 pathway associated proteins. Strikingly, these groups could not be defined using corresponding data originating from total RNA and thus do not match previous molecular classifications. These translation profiles suggest that distinct treatment regimens employing e.g. mitochondria inhibitors, mTOR inhibitors or anti-angiogenic agents may be effective in patient subsets defined by translation. In conclusion, although this study is limited in terms of the number of studied patients, our data support that that translatomes may define molecular subgroups of GBMs amendable to distinct therapeutic approaches. Funding support: FAPESP 2018/17796-6 Citation Format: Glaucia N. Hajj, Fernanda C. Lupinacci, Martin Roffe, Hermano M. Bellaro, Tiago G. Santos, Victor P. Andrade, Paulo Sanematsu, Rui M. Reis, Christian Oertlin, Laia M. Sanz, Vilma R. Martins, Ola Larsson. Transcriptome-wide polysome profiling of glioblastomas identifies molecular subgroups with impact in survival and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2439.