GenomeWebinars: Recent

Non-small cell lung cancer (NSCLC) accounts for nearly 80 percent of lung cancer cases and exhibits a median survival of less than one year following diagnosis. A relatively unexplored avenue of immunotherapy for specific cancers may lie in chimeric RNAs that differentiate cancerous cells from their non-cancerous neighbors. Additionally, novel peptide junctions may form neoantigens, which may be targeted by the immune system de novo or by vaccines.

In this webinar, Micah Castillo, lead scientist at the University of Houston Sequencing and Gene Editing Core, will discuss work undertaken to develop a vaccine targeting the fusion junction of KIF5B-RET in lung cancer and to establish a robust pipeline for the generation of vaccines directed against chimeric RNAs in other types of cancers. Castillo will discuss assessing the affinity of neopeptides formed by the translated junction of the patient-derived chimeric RNA to major histocompatibility class I molecules, testing their in vitro affinity in peripheral blood mononuclear cells by enzyme-linked immune absorbent spot assay, and designing an mRNA vaccine to express the KIF5B-RET fusion.

Interest in combinations of systemic and targeted therapies as well as the administration of multiple modalities — such as small-molecule kinase inhibitors, monoclonal antibodies, and immunotherapy — continues to increase.  The success of specific therapeutic combinations is being attributed to a variety of factors: tumor-specific biology, such as gene mutations and the tumor microenvironment, as well as patient-specific attributes, such as their immune repertoire. Thus, gathering expanded tumor- and patient-specific genotypic information becomes critical to successfully identify which patients may benefit from specific combinations. 

In this webinar, our speakers will discuss how genotypic biomarkers are being used to better understand cancer biology, develop prognostic markers, and predict therapeutic success. 

Attendees will learn about:

• The changing landscape of combination cancer therapies and mutations of interest in colorectal cancer.
• Implementing fragment analysis-based MSI testing and sequencing-based targeted genotyping of key genetic biomarkers such as KRAS in formalin-fixed paraffin-embedded tissues.
• Retrospective annotation of a large biorepository with the latest clinically relevant biomarkers to generate highly targeted cohorts to better understand the mechanism of action and underlying biology of new therapies.
• Multi-omic evaluation of high microsatellite instability (MSI-H) tumors to correlate MSI status with immunomodulatory receptor expression in matched human biospecimens.

Environmental monitoring requires scalable sequencing capabilities to enable communities to make important decisions surrounding public health. Data generated from these localized population studies also helps build phylogenetic trees that further our understanding of infectious disease transmission.

In this webinar, Krystal Sheridan, from the Translational Genomics Research Institute, will discuss the institute’s path in automating sequencing workflows using the Firefly and Watchmaker DNA Library Prep Kit with Fragmentation to meet the needs of Arizona’s first statewide invasive group A strep surveillance project. Her talk will review the reason behind their decision to automate, the practical considerations and insights learned from their process optimizations, and their approach to kit selection in ultimately building out their WGS workflow.

In this webinar, Anne Minnich, biomarker consultant at Bristol Myers Squibb, will present the use of the new SomaSignal NASH bundle test in a recently completed clinical trial. This trial, FALCON 1, was a Phase IIb multicenter double-blind study of three pegbelfermin doses in patients with stage III nonalcoholic steatohepatitis (NASH). The primary endpoint of this and currently all NASH late-stage clinical trials consisted of liver biopsy histological staging, but, due to the issues inherent in the procedure and method, the ultimate ambition in the field is to replace biopsy with more noninvasive tests (NITs). Minnich will describe the use of several NITs, including SomaSignal, their performance, and their relationship to the primary endpoint in the study. Minnich will cover:

• Pharmacodynamics of drug response as measured by NIT’s.
• Correlations of biomarkers covering all mechanistic features of NASH with each other and with biopsy-related endpoints.
• Within-patient concordance of response and nonresponse to drug as measured by NIT’s and biopsy parameters.

Bladder cancer is the seventh most common cancer in the UK, with over 100,000 people being referred to hospital clinics annually for bladder cancer investigation, usually after passing blood in their urine. The first stage of investigation is usually flexible cystoscopy, which is invasive and painful.  

Galeas Bladder is a molecular biomarker test, developed by liquid biopsy company Nonacus and validated by Richard Bryan and Douglas Ward from the University of Birmingham, that leverages targeted next-generation sequencing to interrogate the key somatic mutations found across all bladder cancers. Galeas Bladder enables highly sensitive and accurate detection of tumor-derived DNA from a urine sample, offering a viable non-invasive alternative to flexible cystoscopy.

In this webinar, Richard Bryan and Douglas Ward will provide an overview of the novel Galeas Bladder test and outline how it has been validated using urine samples from three UK clinical cohorts.

This webinar is part four of the four-part Precision Oncology News Virtual Molecular Tumor Board series.

In this tumor-specific session, our expert panelists will review patient cases in which the clinical utility of genomics has presented various therapy considerations for patients diagnosed with gastrointestinal and genitourinary cancers.

Discussions will address homologous recombination deficiency (HRD), the evaluation of fusion-positive malignancies, as well as resistance mechanisms following targeted therapy and thoughts on re-challenging a patient.

Our panel will address these challenges and opportunities within the context of specific clinical cases. The session will wrap up with a live Q&A in which attendees can discuss the cases with the Virtual Molecular Tumor Board panelists.

Triple-negative breast cancer (TNBC) is a molecularly heterogeneous subtype of breast cancer, and responses to standard neoadjuvant chemoimmunotherapy are variable. While multiple prognostic biomarkers have been identified in TNBC, we currently lack predictive biomarkers for response to specific therapies. The development of robust validated biomarkers could enable biology-adapted administration of specific cytotoxic agents and potentially selective administration of immunotherapy, thereby enabling personalized systemic therapy.

In this webinar, Shane Stecklein of the Kansas University Medical Center will discuss how, using Almac ClaraT, he identified the DNA damage immune response (DDIR) gene expression signature as prognostic in a cohort of TNBC patients enrolled on the SWOG S9313 adjuvant chemotherapy trial. He also showed that DDIR, in combination with homologous recombination deficiency, can identify immune-enriched and immune-depleted prognostic groups that have unique immune microenvironmental features that may reflect variable vulnerabilities to chemoimmunotherapy.

Despite significant research efforts, there are thousands of both rare and more common complex diseases without a line of sight toward a viable therapeutic intervention. Genetics and precision medicine offer great promise to address unmet needs for these patients, and selecting genetically supported targets may increase success rates in clinical development. However, to be successful, scientists need access to genetic and clinical data across sizable populations of affected patients.

This session will highlight an approach between scientists at Deerfield Management Company, a healthcare investment firm, and Invitae, a leading medical genetic testing company, to advance drug discovery and development, using genomic and clinical data from millions of patients with rare disease. 

In this webinar, Matt Nelson and Alix Lacoste will share perspectives on combining genomic and clinical data in a large disease cohort to:

• Identify opportunities to treat genetically defined diseases with a high unmet need.
• Study incidence and prevalence rates of both rare and complex disorders.
• Uncover novel genotype-phenotype associations underlying more common complex diseases.

The use of next-generation sequencing (NGS) approaches in the clinical setting has continued to advance precision oncology, aiding in biomarker-informed therapy selection for cancer patients. Moreover, the use of this technology has also enabled the rapid pace at which biomarkers are being identified, presenting a challenge for diagnostic labs in providing comprehensive testing of all relevant biomarkers, while maintaining operational efficiency and viable cost per test.

Comprehensive genomic profiling (CGP) is an approach that allows laboratories to implement broad-based testing that addresses multiple tumor types while also allowing for streamlined workflows, minimizing the need for serial testing and reducing the frequency of content updates of panel-based tests. Though this approach presents significant benefits, facilitating a path to appropriate reimbursement rates with this approach remains a challenge.

In this webinar, Sandra Pearson, president of Pearson Healthcare Consulting, will walk through a snapshot of the current oncology testing and reimbursement landscape and discuss opportunities that may present viable options for laboratories interested in adopting comprehensive genomic profiling.

Whole-exome sequencing is a powerful tool for analyzing the approximately 22,000 genes in the human genome and understanding the different types of mutations that cause diseases. In this webinar, Madhuri Hegde of PerkinElmer Genomics will discuss her experience in creating an augmented exome that aims to maximize the utility of whole-exome sequencing through thoughtful curation of the panel content. This is achieved by translating learnings from whole-genome sequencing and bringing these insights back into the exome. The augmented exome for clinical research provides a comprehensive survey of the protein-coding sequences, clinically relevant targets in the non-exonic regions of the genome, enhanced detection of common CNVs, PGx and ancestry SNPs, and full sequence coverage (genome in an exome) of targeted genes. Hegde will also discuss how the clinical research exome is validated and implemented in her laboratory to decipher the cause of rare diseases.

Molecular multiplex panels can simultaneously detect more than one infectious pathogen associated with various clinical syndromes such as gastroenteritis, pneumonia, meningoencephalitis, and others more quickly than traditional microbiology laboratory test methods.

In this webinar, Matthew Sims, of Corewell Health East, and Joseph Yao, of the Mayo Clinic, will discuss the benefits and limitations of commercially available infectious disease syndromic panels and how diagnostic laboratory stewardship can help to optimize test utilization and improve patient care while keeping costs under control. In addition, the speakers will discuss the implications of the latest Medicare administrative contractors (MAC) reimbursement criteria and rules finalized in October 2022 on such syndromic panel testing and their implications for clinicians.

Wastewater-based epidemiology continues to gain traction as a viable complement to traditional, clinical-based epidemiology. Wastewater provides an aggregate sample of an entire community and circumvents biases in clinical surveillance approaches resulting from patients avoiding medical care and socioeconomic or religious factors. Wastewater data can lead to actionable outcomes such as directed vaccine campaigns, early warning signs for hospital staff, and anticipated therapeutic efficacy based on identifying the circulating virus(es).

During this webinar, Sarah Kane, director of research and development at GT Molecular, will describe the ability to co-monitor influenza A, influenza B, RSV, and SARS-CoV-2 using RNA obtained from a single wastewater sample. GT Molecular devised a wastewater processing workflow and extraction process, as well as validated droplet digital PCR assays capable of quantifying these RNA viruses from a single RNA eluate. Kane will showcase longitudinal monitoring datasets from de-identified US locations that reveal drastic surges of RSV overlayed with static influenza A and SARS-CoV-2 loads during the sampling period.

Immune development in early life is critical for establishing a trajectory towards long-term health; however, little is understood about how early-life inflammation may impact immune development.

In this webinar, Jessica Lasky-Su, associate professor in medicine at Harvard Medical School and Brigham and Women’s Hospital, will discuss a study in which she and colleagues measured 203 inflammatory protein targets across 180 samples from healthy children at ages 1 and 6 using Alamar Biosciences’ NULISAseq Inflammation panel. The team identified the inflammatory proteins at age 1 that were associated with proneness to infection and the development of asthma by age 6. They also characterized critical changes in the inflammatory profile that developed among those with infection proneness and asthma by age 6. Finally, they assessed the impact of sex on these findings. 

Conventionally, human immune responses have been extensively characterized using blood. Immune cells, though abundant in blood, are also found in various tissues in varying numbers and with locally relevant functional specification. Assessing immune responses in the airways over the course of infection and convalescence is critical to comprehensively mapping immunity to respiratory viral infections including influenza and SARS-CoV-2.

In a study recently published in eLife, Sindhu Vangeti and colleagues at the Icahn School of Medicine at Mount Sinai demonstrated that innate immune cells like monocytes and dendritic cells possess unique dynamics defined by location and pathogen. In addition to characterizing immune cells in blood, the team also investigated immune cell distribution and function in the human nasopharynx.

In this webinar, Vangeti will discuss:

• Monocytes and dendritic cells in human respiratory viral infections.
• Studying immune responses in the human airways. 
• Integrating state-of-the-art platforms into conventional study design.

BRCA mutations represented the first biomarker for precision oncology in ovarian cancer, as BRCA-mutated ovarian cancer samples were found to be sensitive to PARP inhibitors. Mutations in the BRCA1 or BRCA2 genes lead to a deficiency of the homologous recombination (HR) DNA damage repair pathway. However, a similar deficit can be caused by epigenetic or genetic alterations in various genes involved in the HR pathway. In fact, homologous recombination deficiency (HRD) has been found in about 50 percent of ovarian cancer cases, while somatic or germline BRCA mutations are detected in about 20 percent of cases. Clinical studies have shown that PARP inhibitors are effective in non-BRCA-mutant HRD-positive samples, so it is essential to identify this biomarker in clinical practice.

In this webinar, Philip Jermann will first present a short overview of when it is important to consider comprehensive genomic profiling (CGP) and its role in clinical research of solid tumors. Nicola Normanno will then present a research study of the analytical validation for in-house HRD assessment performed in his lab with the Oncomine Comprehensive Assay Plus on a cohort of ovarian cancer samples. He will also present a retrospective analysis how these data correlate with the clinical outcome of the same cohort.

Learning Objectives:

• How and why HRD is being measured currently by leading labs.
• The importance of BRCA to HRD testing in ovarian cancer.
• How the Genomic Instability Metric (GIM) compares to other orthogonal methods.