The AACR Project GENIE is an international data-sharing consortium focused on generating an evidence base for precision cancer medicine by integrating clinical-grade cancer genomic data with clinical outcome data for tens of thousands of cancer patients treated at multiple institutions worldwide. In conjunction with the first public data release from approximately 19,000 samples, we describe the goals, structure, and data standards of the consortium and report conclusions from high-level analysis of the initial phase of genomic data. We also provide examples of the clinical utility of GENIE data, such as an estimate of clinical actionability across multiple cancer types (>30%) and prediction of accrual rates to the NCI-MATCH trial that accurately reflect recently reported actual match rates. The GENIE database is expected to grow to >100,000 samples within 5 years and should serve as a powerful tool for precision cancer medicine. Significance The AACR Project GENIE aims to catalyze sharing of integrated genomic and clinical datasets across multiple institutions worldwide, and thereby enable precision cancer medicine research, including the identification of novel therapeutic targets, design of biomarker-driven clinical trials, and identification of genomic determinants of response to therapy.

Protein phosphatase 2A (PP2A) is regulated through a variety of mechanisms, including post-translational modifications and association with regulatory proteins. Alpha4 is one such regulatory protein that binds the PP2A catalytic subunit (PP2Ac) and protects it from polyubiquitination and degradation. Alpha4 is a multidomain protein with a C-terminal domain that binds Mid1, a putative E3 ubiquitin ligase, and an N-terminal domain containing the PP2Ac-binding site. In this work, we present the structure of the N-terminal domain of mammalian Alpha4 determined by x-ray crystallography and use double electronelectron resonance spectroscopy to show that it is a flexible tetratricopeptide repeat-like protein. PP2A3 is a ubiquitous serine/threonine phosphatase involved in the regulation of numerous cell signaling pathways and cellular functions, including proliferation, cytoskeletal rearrangement, apoptosis, and cell migration (1-3). Several pathologies have been linked to dysregulation of PP2Ac, including Alzheimer disease, cancer, and diabetes (4 -8). The activity of PP2Ac is tightly controlled in vivo via association with regulatory subunits, interactions with other cellular proteins, and various post-translational modifications (9 -12). PP2A regulatory subunits play a critical role in determining phosphatase activity and substrate selectivity, as well as directing the subcellular localization of the PP2A holoenzyme (3). PP2A exists primarily as a heterotrimeric holoenzyme consisting of a structural A-subunit, a variable regulatory B-subunit, and PP2Ac. However, an atypical pool of PP2Ac exists in complex with the regulatory subunit Alpha4 that binds directly to PP2Ac in the absence of the A-and B-subunits (13-16). Recent studies have shown that Alpha4 plays a crucial role in the control of PP2A ubiquitination and stability (12,17,18).Alpha4, a multidomain protein with similarity to Tap42 from yeast, was initially discovered as a 52-kDa phosphoprotein in B-cell receptor complexes (16,19). Both Alpha4 and Tap42 consist of an N-terminal domain that contains the residues important for PP2Ac binding (20) and a C-terminal domain that is protease-sensitive and intrinsically disordered (21). The C-terminal domain of Alpha4 binds Mid1, a putative E3 ligase (12,22). Alpha4 regulates all three type 2A protein phosphatases (PP2Ac, PP4, and PP6), modulating both catalytic activity and expression levels (13,14,17,23). In addition to its association with PP2A family members, Alpha4 associates and co-localizes with Mid1, a putative E3 ubiquitin ligase thought to facilitate PP2Ac polyubiquitination (12,22). The C terminus of Alpha4 and the B-box1 domain of the Mid1 protein mediate the association between Mid1 and Alpha4 (12,22). Mutations in Mid1 have been linked to Opitz syndrome, a developmental disorder (24,25). At the cellular level, mutations in Mid1 lead to decreases in ubiquitination and degradation of PP2Ac, especially microtubule-associated PP2Ac (12, 26).Alpha4 serves as a scaffold for PP2Ac and Mid1 and protects PP2Ac fr...

AKT inhibitors have promising activity in AKT1 E17K-mutant estrogen receptor (ER)positive metastatic breast cancer, but the natural history of this rare genomic subtype remains unknown. Utilizing AACR Project GENIE, an international clinicogenomic data-sharing consortium, we conducted a comparative analysis of clinical outcomes of patients with matched AKT1 E17K-mutant (n = 153) and AKT1-wild-type (n = 302) metastatic breast cancer. AKT1-mutant cases had similar adjusted overall survival (OS) compared with AKT1-wild-type controls (median OS, 24.1 vs. 29.9, respectively; P = 0.98). AKT1-mutant cases enjoyed longer durations on mTOR inhibitor therapy, an observation previously unrecognized in pivotal clinical trials due to the rarity of this alteration. Other baseline clinicopathologic features, as well as durations on other classes of therapy, were broadly similar. In summary, we demonstrate the feasibility of using a novel and publicly accessible clincogenomic registry to defi ne outcomes in a rare genomically defi ned cancer subtype, an approach with broad applicability to precision oncology. SIGNIFICANCE: We delineate the natural history of a rare genomically distinct cancer, AKT1 E17Kmutant ER-positive breast cancer, using a publicly accessible registry of real-world patient data, thereby illustrating the potential to inform drug registration through synthetic control data.

The American Association for Cancer Research (AACR) Project GENIE is an international pan-cancer registry with the goal to inform cancer research and clinical care worldwide. Founded in late 2015, the milestone GENIE 9.1-public release contains data from >110,000 tumors from >100,000 people treated at 19 cancer centers from USA, Canada, the United Kingdom, France, Netherlands, and Spain. Here, we demonstrate use of these real-world data, harmonized through a centralized data resource to accurately predict enrollment on genome-guided trials, discover driver alterations in rare tumors, and identify cancer types without actionable mutations that could benefit from comprehensive genomic analysis. The extensible data infrastructure and governance framework support additional deep patient phenotyping through biopharma collaborations, and expansion to include new data types such as cell-free DNA sequencing. AACR Project GENIE continues to serve a global precision medicine knowledgebase of increasing impact to inform clinical decision making and bring together cancer researchers internationally.