David M. Higgins

International cancer registries make real-world genomic and clinical data available, but their joint analysis remains a challenge. AACR Project GENIE, an international cancer registry collecting data from 19 cancer centers, makes data from >130,000 patients publicly available through the cBioPortal for Cancer Genomics (https://genie.cbioportal.org). For 25,000 patients, additional real-world longitudinal clinical data, including treatment and outcome data, are being collected by the AACR Project GENIE Biopharma Collaborative using the PRISSMM data curation model. Several thousand of these cases are now also available in cBioPortal. We have significantly enhanced the functionalities of cBioPortal to support the visualization and analysis of this rich clinico-genomic linked dataset, as well as datasets generated by other centers and consortia. Examples of these enhancements include (i) visualization of the longitudinal clinical and genomic data at the patient level, including timelines for diagnoses, treatments, and outcomes; (ii) the ability to select samples based on treatment status, facilitating a comparison of molecular and clinical attributes between samples before and after a specific treatment; and (iii) survival analysis estimates based on individual treatment regimens received. Together, these features provide cBioPortal users with a toolkit to interactively investigate complex clinico-genomic data to generate hypotheses and make discoveries about the impact of specific genomic variants on prognosis and therapeutic sensitivities in cancer. Significance: Enhanced cBioPortal features allow clinicians and researchers to effectively investigate longitudinal clinico-genomic data from patients with cancer, which will improve exploration of data from the AACR Project GENIE Biopharma Collaborative and similar datasets.

The Gabriella Miller Kids First Pediatric Research Program (Kids First) aims at facilitating researchers to uncover new insights into the biology of childhood cancer (CC) and structural birth defects (SBD), including the discovery of shared genetic pathways between these disorders. Kids First has two initiatives, which are whole genome sequencing (WGS) of biospecimens from families with CC/SBD, and establishing Kids First Data Resource. Kids First Data Resource Center (KFDRC) developed Kids First Data Resource Portal (KFDRP; https://portal.kidsfirstdrc.org/), which is a centralized platform to search, view, analyze, and identify currently accessible data from both Kids First and collaborative cohorts, incorporating omics and phenotypic information of 30 studies and 26,300 participants. Recently KFDRC released two new KFDRP components named Variant DataBase (VDB) and Variant WorkBench (VWB), enabling users to query, mangle, analyze and visualize germline genomic variants. The current release includes ~309 million unique variants in a matrix of more than 61.3 billion individual-chromosomal position occurrences from over 11,500 participants in 17 studies. While VDB provides a quick variant summary, VWB supports scripting languages such as Python, Spark, SQL, R, and MarkDown as in-depth analysis tools enabled by Apache Zeppelin notebooks. In addition to variant calls and phenotypic information such as Human Phenotype Ontology (HPO) terms and Mondo IDs, VWB hosts rich external variant annotations in the public domain, such as Cancer Hotspots, ClinVar, COSMIC, dbNSFP, gnomAD, TOPMed, as well as gene-phenotype links provided by OMIM, HPO, Orphanet, and the Deciphering Developmental Disorders Project. Users can also load additional databases within a notebook (such as the subscription-based Human Gene Mutation Database [HGMD]), import custom datasets as temporary query tables, export analysis outputs to local drives, visualize analysis results in multiple chart styles, display local figures, and save notebooks for sharing, further use and Cavatica projects. In an effort to screen tier 1 genes (n=578) from the most recent Cancer Gene Census provided by COSMIC for rare deleterious variants in all six currently available CC cohorts in KFDRP, we identified over 1.2 million germline variants that are with minor allele frequency no more than 0.00001 among gnomAD/TOPMed datasets and with ratio of number of “damaging” predictions over number of all predictions in dbNSFP between 0.5 and 1, or that are already cataloged in the most recent version of ClinVar/HGMD. The whole process took less than two hours which is much faster than conventional methods. These variant tools in KFDRP enable efficient genomic variant analysis in cancer research with advanced big data technology. Citation Format: Yiran Guo, Jeremy Costanza, Christophe Botek, Miguel Brown, David Higgins, Yuankun Zhu, Bailey Farrow, Allison Heath, Adam Resnick, Vincent Ferretti, Kids First Data Resource Center. Making discoveries with Kids First Variant DataBase and WorkBench [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB501.

CBioPortal for Cancer Genomics is an open-source platform for interactive, exploratory analysis of large-scale cancer genomics data sets. cBioPortal provides a user-friendly interface that integrates genomic and clinical data, and provides a suite of visualizations and analyses, including OncoPrints, mutation “lollipop” plots, variant interpretation, group comparison, survival analysis, expression correlation analysis, alteration enrichment analysis, cohort and patient-level visualization. cBioPortal also integrates external tools including CIViC, Cancer Digital Slide Archive, Next-Generation Clustered Heat Map, IGV and Bioconductor to facilitate interpretation. The public site (https://www.cbioportal.org) is accessed by ~35,000 unique visitors each month and hosts data from >325 studies spanning individual labs and large consortia. In addition, >67 instances of cBioPortal are installed at academic institutions and pharmaceutical/biotechnology companies worldwide. In 2021 we added data from 32 studies, totaling >24,000 samples, to the public site. All data is also available in the cBioPortal Datahub: https://github.com/cBioPortal/datahub/. We also host a dedicated instance for AACR Project GENIE, enabling access to the GENIE cohort of >135,000 clinically sequenced samples from 19 institutions (https://genie.cbioportal.org). In addition, the GENIE Biopharma Collaborative (BPC) enables the collection of comprehensive clinical annotations, including response, outcome, and treatment histories. The first BPC release contains data from >1,800 non-small cell lung cancer samples and will be released in early 2022. The growing GENIE cohort and the BPC clinical data have driven a number of recent developments, including performance improvements (the load time for the GENIE cohort was reduced from minutes to seconds). To leverage the BPC clinical data, we enabled sample selection based on treatment status, extended support for outcome analysis, and enhanced the patient timeline representation to incorporate response data. Additional development work has focused on improvements to variant interpretation, enhancements to the Mutations tab, and support for novel molecular assays via the ‘generic assay’ data type. Documentation on these new features and many others is available at https://www.cbioportal.org/news. cBioPortal is fully open source (https://github.com/cBioPortal/) under a GNU Affero GPL license. Development is a collaborative effort among groups at Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, Children’s Hospital of Philadelphia, Princess Margaret Cancer Centre, Bilkent University and The Hyve. We welcome open source contributions from others in the cancer research community. Citation Format: Jianjiong Gao, Tali Mazor, Ino de Bruijn, Adam Abeshouse, Diana Baiceanu, Ziya Erkoc, Elena Garcia Lara, Benjamin Gross, David M. Higgins, Prasanna K. Jagannathan, Priti Kumari, Ritika Kundra, Xiang Li, James Lindsay, Aaron Lisman, Divya Madala, Ramyasree Madupuri, Angelica Ochoa, Oleguer Plantalech, Sander Rodenburg, Baby A. Satravada, Robert Sheridan, Lucas Sikina, Jessica Singh, S. Onur Sumer, Yichao Sun, Pim van Nierop, Avery Wang, Manda Wilson, Hongxin Zhang, Gaofei Zhao, Sjoerd van Hagen, Kees van Bochove, Ugur Dogrusoz, Allison Heath, Adam Resnick, Trevor J. Pugh, Chris Sander, Ethan Cerami, Nikolaus Schultz. cBioPortal for cancer genomics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1155.