Innovative genomics and bioinformatics research at the Greehey Institute

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Dr Siyuan Zheng discusses how the Greehey Institute is continuing to advance the care of children affected by cancer through innovative and translational research.

The past decade has witnessed a revolution in cancer research, largely driven by advances in high-throughput sequencing, functional genomics, and computational technologies. The affordability and technological maturity of high-throughput data generation enable individual labs to test and validate their hypotheses using unbiased approaches and facilitate consortium efforts such as The Cancer Genome Atlas (TCGA), Therapeutically Application Research to Generate Effective Treatments (TARGET), and Clinical Proteomic Tumor Analysis Consortium (CPTAC) to profile tens of thousands of tumours on multiple molecular levels. In parallel, faster and smarter computational tools run both locally and on the cloud are continuously developed to analyse cancer genomic and epigenomic data. These advances help make precision oncology a reality for some cancer patients.

However, many challenges remain. For instance, we still do not have a complete understanding of resistance mechanisms to various treatments in some cancers, and for genomically quiet tumours we often fail to detect targetable alterations that would allow molecularly targeted therapies. To our advantage, genomic data are being generated and shared at an unprecedented scale thus equip us with adequate statistical power to address these questions.

Recognising the necessity of utilising the accumulated considerable genomic information in the public domain and from our internal paediatric research efforts, the Greehey Children’s Cancer Research Institute – UT Health San Antonio (Greehey Institute) embraces this shift of research paradigm and is dedicated to tackling the challenges. Central to its mission is the establishment of a next-generation sequencing facility headed by Dr Zhao Lai and a cancer bioinformatics shared facility led by Dr Yidong Chen. The sequencing facility currently has HiSeq, NextSeq and MiSeq platforms open to researchers inside and outside of the Greehey Institute and is fully integrated with the cancer-focusing computational genomics division.

All the data generated is deposited to university-backed storage and are processed by pipelines consisting of established tools. Advanced analysis can be tailored to individual requests on a collaboration basis. To further boost this effort, the Greehey Institute recently hired two new faculty members, Drs Siyuan Zheng and Xiaojing Wang, who specialise in cancer genomic and proteomic data analysis. Zheng was extensively involved in TCGA and has made significant contributions to TCGA brain and adrenal cancer projects. Wang helped define the emerging proteogenomics field through pioneering the integration of RNA sequencing into the analysis of shotgun proteomics data and has played a crucial role in the CPTAC phase I and II projects.

Furthering understanding

The focus of the bioinformatics and cancer genomics program at the Greehey Institute is to further the understanding of molecular oncology and pharmacogenomics of pediatric cancer. This emphasis is lined with our core mission to develop effective and less toxic treatments for children with cancer. Towards this goal, faculty members on this programme work closely with bench scientists to address their data analysis needs and meanwhile conduct independent studies using public and in-house datasets.

To develop informed as well as artificial intelligence-based approaches to predicting
drug responses. At the Greehey Institute, we have a preclinical drug screening platform led by Drs Peter Houghton and Raushan Kurmasheva to use cell lines and xenograft models to find effective preclinical compounds and approved drugs on childhood cancer. In conjunction with this effort, Chen’s group trains deep learning models using multimodal genomic data of cancer cell lines and tumours and their associated drug testing data from the public domain and apply these models to patient tumours. Wang is developing an informed machine learning model that can predict pathway activities in a cancer sample from their expression or genetic data. This model promises decent prediction power but meanwhile provides insights into the underlying biology.

Cancer proteogenomics and RNA methylation

A critical difference between paediatric and adult cancers is the mutational burden: cancers in children have roughly ten times lower mutations than their adult counterparts. This difference connotes that transcriptome and the downstream proteome are essential complements to genomics for understanding paediatric cancer.

We are developing projects, in conjunction with genomics, to examine the proteome and post-transcriptional modification that are not visible to direct DNA sequencing, first in cell lines and then xenograft models and patient samples. This unique proteogenomic scrutiny in cancers has the potential to reveal genetics- dependent or independent changes in paediatric cancer. Specifically, we are working closely with the Greehey Institute investigators Drs Manjeet Rao and Yogesh Gupta on Ewing sarcoma and osteosarcoma, investigating the functions of RNA N6-adenosine methylation status in these tumors, with the novel computational methods we developed within the programme.

Understand tumour heterogeneity using single-cell sequencing

The Computational Biology group works closely with several labs in the Greehey Institute on studying tumour heterogeneity and stromal cell biology in children or childhood cancer survivors using single-cell RNA sequencing. The goal is to discover the clonal structure of the tumours and delineate how this structure may enable tumors to survive targeted agents or sweeping evolutionary pressure exerted by cytotoxic treatments.

Telomeres and chromosomal instability

Telomere maintenance is essential for cancer cell immortality. Excessive telomere shortening before any maintenance mechanisms are activated is intricately linked to chromosomal instability in cancer. Zheng’s lab is interested in dissecting that link, and whether it can be exploited therapeutically.

Determining significant chemotherapy drivers of late effects in cardiac stromal cells

Late cardiac dysfunction is a typical morbidity closely associated with the successful treatment of childhood cancers. When compared to community age-matched controls, childhood cancer survivors (CCS) have a 4-40 fold increase in the risk of developing heart failure in the setting of uncontrolled hypertension. Sensitivity to hypertension highlights a loss of cardiac stress resilience that is critical to understand to prevent cardiac disability in long-term CCS.

To this end, Dr Gregory Aune’s lab investigates the cardiac mesenchymal-immune stroma, or fibroblasts and myeloid cells, which modulate the cardiac injury response. Using a combination of in vivo and in vitro models, the Aune lab is developing novel approaches with single-cell technologies, such as RNA sequencing and mass cytometry, to identify significant drivers of stromal cell dysfunction following early-life chemotherapy treatment.

Europeans and American Indians are the major genetic ancestry of Hispanics in the USA

There are marked disparities in incidence rates and outcomes in many types of cancers, including paediatric cancers, between non-Hispanic whites and Hispanics. It is thus essential to determine the population admixture of patients, including children, before conducting genetic studies in South Texas. Chen and his team have carefully designed a series of Ancestry Informative Marker (AIM) panels with up to a few hundred ancestry-informative SNPs to infer ancestry admixture within conventional whole exome sequencing protocols using carefully selected continental populations of non-Hispanic whites, Africans and Asians. This allows investigators at the Greehey Institute to evaluate all existing pediatric samples for their genetic studies.

Building resources for the community

Because of the rarity of paediatric cancer, data sharing can benefit the research community and ultimately the patients. The Greehey Institute strongly advocates for data sharing. In addition to contributing samples to various large-scale consortium efforts, the bioinformatics groups are developing data portals to share our internally generated data, particularly those from our xenograft models. The goal is to blend our resources and integrate them with external datasets, both from paediatric and adult cancers, and make them easily accessible to both bench and dry lab researchers.

Though this short list outlines the current focus of the cancer genomics programme at the Greehey Institute, as a group we need to keep abreast of the latest research and technology development and frequently adjust our aims and approaches. Nevertheless, we are committed to our role as a genomics infrastructure and lead in big data, and we will continue to work diligently with our institution and the community to advance the care of children affected by cancer through innovative and translational research.

Dr Yidong Chen
Professor
Dr Siyuan Zheng
Assistant Professor
Epidemiology & Biostatistics
Greehey Children’s Cancer Research Institute
+1 210 562 9000
Cheny8@uthscsa.edu
Zhengs3@uthscsa.edu
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