Abstract 3302: The molecular landscape of oncogenic signaling pathways in The Cancer Genome Atlas

Abstract

Over the past decade, The Cancer Genome Atlas (TCGA) has profiled more than 11,000 tumors spanning 33 distinct cancer types. The TCGA PanCanAtlas is a collaborative project by the TCGA Research Network that aims to address relevant overarching questions in oncology based on a cross-cancer analysis of the full, uniformly reprocessed TCGA data set. Here, we present results from our analysis of genetic alterations in mitogenic signaling pathways across cancer. Genetic alterations in signaling pathways that control cell cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations and copy-number changes in 9,125 tumor samples profiled by TCGA, we analyzed the mechanisms and patterns of alterations in 10 canonical pathways: cell cycle, Hippo, Myc, Notch, beta-catenin / WNT, PI-3-Kinase / Akt, receptor-tyrosine kinase / RAS / MAP-kinase signaling, TP53, and TGF-beta signaling, as well as oxidative stress response. For each of these pathways, we propose an expert-curated description (or “template”) that includes the relevant (altered) genes and the connections between them, as well as a detailed catalogue of the driver mutations and copy number changes with known oncogenic relevance. We provide a high-level map of pathway alteration frequencies across tissues and relevant cancer subtypes as well as detailed frequencies of alteration at the gene level for each individual pathway. We also investigate relationships of co-occurrence and mutual exclusivity across pathways and evaluate therapeutic implications, including drug combinations. Forty-nine percent of tumors had at least one potentially targetable alteration in the evaluated pathways, and 31% of tumors had multiple targetable alterations, making them candidates for combination therapy. Our work delineates the full landscape of oncogenic alterations in mitogenic signaling pathways across cancer, and the pathway templates as well as the richly annotated data set that we provide will constitute an invaluable public resource for future use by the cancer genomics and precision oncology communities. Citation Format: Francisco Sanchez-Vega, Marco Mina, Joshua Armenia, Walid K. Chatila, Augustin Luna, Konnor La, Sofia Dimitriadoy, David L. Liu, Havish S. Kantheti, Zachary Heins, Angelica Ochoa, Benjamin Gross, Jianjiong Gao, Hongxin Zhang, Ritika Kundra, Cyriac Kandoth, Istemi Bahceci, Leonard Dervishi, Ugur Dogrusoz, Wanding Zhou, Hui Shen, Peter W. Laird, Alice H. Berger, Trever G. Bivona, Alexander J. Lazar, Gary Hammer, Thomas Giordano, Lawrence Kwong, Grant McArthur, Chenfei Huang, Mitchell J. Frederick, Frank McCormick, Matthew Meyerson, The Cancer Genome Atlas Research Network, Eliezer Van Allen, Andrew D. Cherniack, Giovanni Ciriello, Chris Sander, Nikolaus Schultz. The molecular landscape of oncogenic signaling pathways in The Cancer Genome Atlas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3302.

Gain Fat—Lose Metastasis: Converting Invasive Breast Cancer Cells into Adipocytes Inhibits Cancer Metastasis

“…The observations regarding cell-cycle arrest in cancer-derived adipocytes motivated a detailed analysis of oncogenic pathway activation during cancer adipogenesis (Sanchez-Vega et al, 2018). Oncogenic pathways involved in the regulation of cell cycle, Myc transcriptional activity, and receptor tyrosine kinase/ RAS signaling showed decreased expression of oncogenic and increased expression of tumor-suppressive genes in cancer-derived adipocytes ( Figure 3E).…”

Oncogenic Signaling Pathways in Cancer: An Overview

“…Several pieces of evidence indicate that association therapeutic approaches combining Wnt inhibitors and chemotherapy might enhance tumor shrinkage in several solid neoplasias, holding promise aimed at immune microenvironment targeting too [21-23]. Oncogenic mutations may affect downstream nuclear targets of signaling pathways, such as chromatin remodelers (e.g., EZH2), cell cycle effectors (e.g., cyclins), and transcription factors (e.g., NF-κB and Myc) [1]. Additionally, mutations and deletions may inactivate negative regulators that generally function as suppressors of tumors.…”

“…In the RTK pathway, KRAS is the most frequently modified gene, followed by B-Raf proto-oncogene (BRAF) and finally, the epidermal growth factor receptor [32]. Cancers affected by this pathway include (in descending frequency): melanoma, the gnomically-stable subtype of colorectal cancer, HER2-enriched breast cancer, pancreatic cancer, IDH1-wild-type glioma, lung adenocarcinoma and thyroid carcinoma [1]. Despite great promise in the clinical practice [33-35], overcoming target therapy resistance remains an unmet clinical need in the tailored therapy era, due to the underlying acquired mutation [36,37].…”

“…Another important pathway that is significantly altered in colorectal cancer is the Wnt signaling pathway. In some pathways, the alterations are distributed over many genes (e.g., cell cycle, PI3K), whereas in others, the modifications involve only limited genes (Wnt, Myc, and NRF2) [1]. Aberrations in the PI3K pathway [38] have been primarily noted to be activating events in PI3K catalytic subunit alpha (PIK3CA), less commonly in PI3K catalytic subunit beta (PIK3CB) and inactivating events in PIK3R1 or PTEN, with the most common PIK3CA and palterations occurring in breast cancer, head and neck cancer, gynecological and gastrointestinal tumors [2].…”

“…Cancer is the 2 nd leading cause of death worldwide. It has been theorized that genetic and/or epigenetic modifications are the potential drivers of malignancy [1,2] The process of carcinogenesis is the result of increasing cell proliferation, resistance to apoptosis, genetic instability, induction of angiogenesis, metabolic modifications, and augmented migratory capability [3,4]. The trigger for most of these changes is the dysregulation of cellular signal transduction pathways [5].…”