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Importance: The incidence and biochemical consequences of rare tumor subtypes are often hard to study. Fibrolamellar liver cancer (FLC) is one such rare malignancy affecting adolescents and young adults. To better characterize the incidence and biochemical consequences of this disease, we combined a comprehensive analysis of electronic medical record and national payee data and find that FLC incidence is likely 6–8 times higher than previous estimates. By deploying unsupervised learning modes on clinical laboratory data on patients with hyperammonemia, we find that FLC-associated hyperammonemia mirrors metabolic dysregulation in Urea Cycle Disorders. We demonstrate that advanced computational analysis of rich clinical datasets can provide key clinical and biochemical insights into rare cancers.

Organ donors are systematically screened for infection, whereas screening for malignancy is less rigorous. The true incidence of donor-transmitted malignancies is unknown due to a lack of universal tumor testing in the posttransplant setting. Donor-transmitted malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. We describe the detection of a gastrointestinal adenocarcinoma transmitted from a young donor to 4 transplant recipients. Multidimensional histopathologic and genomic profiling showed aCDH1mutation andMETamplification, consistent with gastric origin. At the time of writing, one patient in this series remains alive and without evidence of cancer after prompt organ explant after cancer was reported in other recipients. Because identification of a donor-derived malignancy changes management, our recommendation is to routinely perform short tandem repeat testing (or a comparable assay) immediately upon diagnosis of cancer in any organ transplant recipient. Routine testing for a donor-origin cancer and centralized reporting of outcomes are necessary to establish a robust evidence base for the future development of clinical practice guidelines.

e16169 Background: Rare cancers including FLC make up 25% of adult tumors, but are difficult to study due to low incidence and incomplete case identification. FLC occurs in adolescents and young adults without liver dysfunction. Hyperammonemia has been frequently reported in FLC patients, but is poorly understood. Methods: Data from three clinical trials allowed us to establish the incidence of hyperammonemia (serum ammonia value > 75 µmol/L) in FLC. In these studies, FLC patients received everolimus, estrogen deprivation therapy (EDT) with leuprolide + letrozole or everolimus + EDT (Oncologist. 2020 25(11):925-e1603), ENMD-2076 (Oncologist. 2020 25(12):e1837-e1845), or neratinib (J Clin Oncol 39, 2021 (suppl 3; abstr 310); ammonia was tested prospectively in the latter two studies. To assess impacts of cancer therapy or liver dysfunction, we studied hyperammonemia in FLC and non-FLC patients at UCSF in parallel. Using Natural Language Processing (NLP) of pathology reports and oncology notes from > 2300 liver cancer patients from the last 12 years of UCSF records, we identified a cohort of patients with FLC, contrasting their laboratory data to all UCSF patients with ammonia testing for the last 10 years. We used leiden clustering and umap dimensionality reduction to contrast FLC and other patients to assess the clinical context of hyperammonemia. Results: Data from the 3 trials showed hyperammonemia in 10 of 32 (31.3%) FLC patients during study participation, independent of the therapy received. These patients exhibited hyperammonemia with varying levels, and at different points in their treatment. NLP identified 37 patients with FLC ( < 0.1% of liver cancer patients), with 33% showing hyperammonemia. Across all UCSF patients, we found 24,000 independent visits where ammonia was tested, with > 2400 demonstrating hyperammonemia. Using leidan clustering on all encounters with ammonia > 75 µmol/L, we found distinct subsets of hyperammonemia corresponding to known metabolic and physiologic processes (e.g., fulminant liver failure, tumor lysis syndrome, etc). FLC patients clustered separately from hepatocellular carcinoma patients with hyperammonemic encephalopathy due to cirrhosis. Conclusions: NLP of large EMRs is a valuable tool to study FLC, a rare cancer. Herein, we have defined hyperammonemia as a frequent event in FLC, not directly linked to hepatic dysfunction or individual therapies. Further investigation may determine whether hyperammonemia is related to FLC tumor biology.

Protein Kinase A (PKA) is a major effector of cyclic-AMP (cAMP) signaling and has recently been appreciated to play a role in multiple malignancies. Mutations of its catalytic subunit (PRKACA) have been identified in a substantial proportion of adrenocortical tumors, and are also detected in a wide spectrum of tumor types in the TCGA dataset, although at a low frequency. A unique fusion protein of PRKACA and DNAJB1 is seen in the majority of fibrolamellar liver cancers (FLC), a rare malignancy of young adults, where it is suspected to be the primary oncogenic driver. However, the key effectors of oncogenic signaling in FLC and other PRKACA driven cancers remain unknown. To understand PKA's downstream targets, we generated genetic cell models with doxycycline-inducible PRKACA or its dominant negative counterpart, a mutant form of the PRKAR1A regulatory subunit. These cell models were then subjected to mass spectrometry for kinome profiling in order to detect kinases with significant altered activity following PKA modulation. This was integrated with small molecule inhibition and siRNA knockdown to identify PKA-regulated kinases that impact cell proliferation. Our analysis revealed activation of the aurora-family kinase AURKA, with preferential sensitivity to the confirmation-disrupting AURKA inhibitor (CD-AURKAi) CD532 compared to other AURKA inhibitors. CD-AURKAi not only selectively inhibit AURKA's kinase activity, but also disrupt its interaction with MYC-family transcription factors. These key oncogenic mediators are necessary to drive the proliferation of multiple tumor types, although they have not yet been connected with oncogenic PKA signaling. Our follow up quantitative PCR experiments confirm that CD-532 treatment results in reduced expression of MYC family members and their transcriptional targets. We next confirmed that MYC family members support the proliferation of PKA-driven cell models with live cell imaging. Finally, we have begun to investigate other kinases identified in our siRNA screen for potential effects on MYC, and have identified several potential combination partners to augment the activity of CD-532 and other CD-AURKAi. These data suggest that CD-AURKAi, either alone or in combination, have the potential to serve as therapeutic agents for PKA-driven cancers. Citation Format: Gary Kwan Leung Chan, Samantha M. Maisel, Y. Christina Hwang, Rebecca Wolber, Danielle L. Swaney, Nabeel Bardeesy, John D. Gordan. Mapping oncogenic signal transduction in PKA-driven cancers [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 309.

414 Background: Donor-derived malignancy may occur even when not suspected based on donor or recipient factors, including age and time to cancer diagnosis. Early recognition of donor-derived malignancy has treatment implications. We describe the molecular characterization of a gastric cancer transmitted from an organ donor to heart, liver (LR), left kidney (LKR), and right kidney-pancreas (KPR) recipients. Methods: IRB approval for chart review was obtained; LR, LKR, and KPR also provided research consent for molecular profiling. Short Tandem Repeat (STR) genotyping was performed by polymerase chain reaction and gel electrophoresis. Tumor and germline DNA from patients and the organ donor were subjected to next generation sequencing (NGS) of 479 genes. Fluorescence in situ hybridization (FISH) was used to confirm MET amplification. Results: Donor origin was established by STR analysis, with the tumors showing high levels of donor alleles. Pathology revealed a poorly differentiated adenocarcinoma with signet ring features. Immunohistochemical staining and CA-19-9 elevation were most consistent with gastric or pancreas origin. Tumor sequencing was notable for somatic mutation of CDH1, MET amplification and wild-type KRAS genes. Tumors from LR and KPR were nearly identical based on pathogenic variants, allele frequency, and copy number variation. Insufficient tumor cellularity in all LKR specimens precluded NGS profiling, but clinical testing found that the cancer was mismatch repair proficient; ERBB2 equivocal; and PDL-1 positive. A circulating tumor DNA test did not uncover any genomic alterations; however, MET amplification was confirmed in this tumor using FISH probes. Conclusions: STR analysis and reporting should be standard immediately following diagnosis of cancer in an organ transplant recipient to ascertain donor derivation. Further molecular characterization, including NGS, may aid in defining primary tumor origin. Here, diagnosis with PDL1-positive gastric cancer enabled use of pembrolizumab. One patient remains alive and without evidence of cancer following prompt organ explant after cancer was reported in other recipients.