Abstract 445: Integrated proteogenomic characterization across seven histological types of pediatric brain tumors
Authors: Petralia Francesca , Tignor Nicole , Reva Boris , Raman Pichai , Chowdhury Shrabanti , Rykunov Dmitry , Krek Azra , Ma Weiping , Ji Jiayi , Song Xiaoyu , Zhu Yuankun , Rokita Jo Lynne , Colaprico Antonio , Calinawan Anna , Whiteaker Jeffrey R. , Ivey Richard G. , Gumus Zeynep , Kalayci Selim , Garcia Gonzalo L. , Yoo Seungyeul , Katsnelson Lizabeth , Wang Ying , Kennedy Jacob J. , Voytovich Uliana J. , Zhao Lei , Leprevost Felipe , Chang Hui-Yin , Gaonkar Krutika S. , Appert Elizabeth M. , Cuellar Ximena , Lilly Jena , Zhu Jun , Schadt Eric E. , Mesri Medhi , Boja Emily , Hiltka Tara , Rodriguez Henry , Ding Li , Iavarone Antonio , Wiznerowicz Maciej , Nesvizhskii Alexey I. , Fenyo David , Gygi Steven , Paulovich Amanda , Resnick Adam C. , Storm Phillip B. , Rood Brian , Wang Pei ,   Children's Brain Tumor Tissue Consortium and Clinical Proteomic Tumor Analysis Consortium
Published: September 2020

We performed a comprehensive proteogenomic analysis across seven major types of childhood brain tumors for a deeper understanding of their functional biology. Whole genome seq, RNAseq, quantitative proteomic and phosphoproteomic profiling were performed on 219 fresh frozen tumor samples representing the histologic diagnoses of: low grade astrocytoma (93), ependymoma (32), high grade astrocytoma (26), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16) and atypical teratoid rhabdoid tumor (12). Characterization of the tumor microenvironment through multi-omics based deconvolution analyses revealed 5 distinct tumor clusters associated with different populations of infiltrating immune cells: Cold-medullo, Cold-mixed, Epithelial, Neuronal and Hot. The two cold-tumor clusters have the lowest immune cell infiltration, one characterized by the enrichment of medulloblastoma tumors; while the other is a mixture of ependymoma, ATRT, HGG and medulloblastoma. The Epithelial group, on the other hand, was enriched in craniopharyngioma samples, an epithelium derived tumor. Interestingly, the RNA levels of PD-1 and CTLA4 were significantly upregulated in this Epithelial group, confirming that craniopharingioma could potentially benefit from anti PD-1 and/or CTLA-4 therapies as previously reported. LLG and ganglioglioma were allocated into two groups of Neuronal and Hot, the former characterized by the presence of neuronal cells, and the latter by the presence of macrophages, microglia, and dendritic cells. Adenosine producers (e.g., ENTPD1 and NT5E), which act as inhibitory immune checkpoint molecular, showed up-regulation in the Hot cluster based on both RNAseq and proteome data, suggesting patients in this group might benefit from adenosine reducing treatments. Among LGG tumors, there is a significant difference between microglial and macrophage polarization across BRAF statuses: BRAF-fusion promoted more pro-regenerative (immune suppressive) microglia than pro-inflammatory microglia, while BRAF-V600E promoted more pro-regenerative macrophages than pro-inflammatory macrophages, implying different immunosuppressive mechanisms in the BRAF-V600E and fusion tumors. This study reports the first large-scale deep comprehensive proteogenomic analysis crossing traditional histologic boundaries to uncover foundational pediatric brain tumor biology relating to tumor microenvironment. The incorporation of the proteomic and phosphoproteomic dimension into this large-scale multi-omic study adds functional insight that helps drive translational efforts.

Citation Format: Francesca Petralia, Nicole Tignor, Boris Reva, Pichai Raman, Shrabanti Chowdhury, Dmitry Rykunov, Azra Krek, Weiping Ma, Jiayi Ji, Xiaoyu Song, Yuankun Zhu, Jo Lynne Rokita, Antonio Colaprico, Anna Calinawan, Jeffrey R. Whiteaker, Richard G. Ivey, Zeynep Gumus, Selim Kalayci, Gonzalo L. Garcia, Seungyeul Yoo, Lizabeth Katsnelson, Ying Wang, Jacob J. Kennedy, Uliana J. Voytovich, Lei Zhao, Felipe Leprevost, Hui-Yin Chang, Krutika S. Gaonkar, Elizabeth M. Appert, Ximena Cuellar, Jena Lilly, Jun Zhu, Eric E. Schadt, Medhi Mesri, Emily Boja, Tara Hiltka, Henry Rodriguez, Li Ding, Antonio Iavarone, Maciej Wiznerowicz, Alexey I. Nesvizhskii, David Fenyo, Steven Gygi, Amanda Paulovich, Adam C. Resnick, Phillip B. Storm, Brian Rood, Pei Wang, Children's Brain Tumor Tissue Consortium and Clinical Proteomic Tumor Analysis Consortium. Integrated proteogenomic characterization across seven histological types of pediatric brain tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 445.