PRECISION ONCOLOGY: GENOMICS, NEXT GENERATION SEQUENCING, AND EMERGING THERAPIES.

Prof. Hannah Omunakwe

MBBCh, DOccMed, FMCPath

Reader and Consultant Haematologist

RSU/RSUTH

DEFINITION OF TERMS

Precision Oncology, Genomics, NGS, Targeted Therapy

ONCOLOGY

• Oncology is a branch of medicine that deals with the study, treatment, diagnosis and prevention of cancer.
• The practice of Oncology therefore is done by a multidisciplinary team – Oncologists, nurses, radiologist, laboratorians, psychologists, clergy, physiotherapist etc.

Precision Oncology, Genomics, NGS, Targeted Therapy

PRECISION MEDICINE

• A form of medicine that uses information about a person’s own genes or proteins to prevent, diagnose, or treat disease.
• The future of precision medicine will enable health care providers to tailor treatment and prevention strategies to people’s unique characteristics, including their genome sequence, microbiome composition, health history, lifestyle, and diet.

Precision Oncology, Genomics, NGS, Targeted Therapy

• To get there, we need to incorporate many different types of data, from metabolomics (the chemicals in the body at a certain point in time), the microbiome (the collection of microorganisms in or on the body), and data about the patient collected by health care providers and the patients themselves.

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• Success will require that health data is portable, that it can be easily shared between providers, researchers, and most importantly, patients and research participants.

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Precision Oncology, Genomics, NGS, Targeted Therapy

PRECISION ONCOLOGY

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• In cancer, precision medicine uses specific information about a person’s tumor to help make a diagnosis, plan treatment, find out how well treatment is working, or make a prognosis.

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• Examples of precision oncology include using targeted therapies to treat specific types of cancer cells, such as HER2-positive breast cancer cells, or using tumor marker testing to help diagnose cancer. Also called personalized medicine.

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Precision Oncology, Genomics, NGS, Targeted Therapy

GENES

• The gene is considered the basic unit of inheritance. Genes are passed from parents to offspring and contain the information needed to specify physical and biological traits.
• Most genes code for specific proteins, or segments of proteins, which have differing functions within the body.
• Humans have approximately 20,000 protein-coding genes.  

Precision Oncology, Genomics, NGS, Targeted Therapy

CHARACTERISTICS OF GENES

• Genes are the units of heredity
• They are arranged in a linear fashion along chromosomes.
• A gene is composed of a series of mutable sites that are also sites for recombination (now recognized as nucleotides).
• One gene encodes one polypeptide.
• Single amino acids are specified by a set of three adjacent mutable sites; this set is called a codon.

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Precision Oncology, Genomics, NGS, Targeted Therapy

Precision Oncology, Genomics, NGS, Targeted Therapy

GENETICS

• Genetics is the study of genes and their roles in inheritance – in other words, the way that certain traits or conditions are passed down in the genes from one generation to the next.
• In healthcare, genetics has typically focused on variations in a single gene when determining the cause of a health condition.

Precision Oncology, Genomics, NGS, Targeted Therapy

GENOMICS

• Genomics is an area within genetics that concerns the sequencing and analysis of an organism’s genome.
• It involves the study of all genes at the DNA, mRNA and the Proteome level as well as the cellular or tissue level.
• It is a discipline in Genetics that applies recombinant DNA, DNA sequencing methods and bioinformatics to sequence, assemble and analyze the structure and function of the genome.

Precision Oncology, Genomics, NGS, Targeted Therapy

Precision Oncology, Genomics, NGS, Targeted Therapy

• One of the most exciting developments in genomics has been the development of next-generation sequencing technology.
• This technology allows us to ‘read’ a person’s or organism's whole genome relatively quickly and cheaply.
• Sequencing the first human genome took more than 10 years and millions of pounds. Today, it can be done in around 24 hours for under £1000.

Precision Oncology, Genomics, NGS, Targeted Therapy

DNA SEQUENCING

• Sequencing simply means determining the exact order of the bases in a strand of DNA.
• Because bases exist as pairs, and the identity of one of the bases in the pair determines the other member of the pair, researchers do not have to report both bases of the pair..

Precision Oncology, Genomics, NGS, Targeted Therapy

BACK TO PRECISON ONCOLOGY

• Cancers are a growing enance in our communities today because of changing lifestyle, exposure to more infectious agents, immunosuppression, environmental pollution and other risk factors that can cause damage to the DNA.
• More people are being diagnosed of cancers in developing countries and more die of cancers because of delayed diagnosis, mis-diagnosis and not diagnosing.

Precision Oncology, Genomics, NGS, Targeted Therapy

DNA CAN BE DAMAGED

• DNA is prone to damage from environmental insults and during DNA replication
• Protective mechanisms are in place to remove detrimental abnormalities
• DNA repair through various pathways
• Proof Reading by DNA Polymerase
• If these paths fail
• The cells final “line of defence” is APOPTOSIS
• Survival advantage is bestowed on cells that undergo some types of mutation
• Genes that regulate cell growth and differentiation are altered
• Eg a gene that is part of the protective process (Tumor Supressor genes)
• Cells may be open to more abnormalities as a result of its ability to evade protection becoming increasingly unstable – genetic instability

Causes of Mutations

• Mutagens are agents that cause mutations
• Spontaneous: no known cause; wrong nucleotide
• Occurs 1/100,000 base pairs
• Remains unfixed less than one in one billion

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Causes of Mutations

• Chemicals like asbestos, benzene, formaldehyde, multiple agents in cigarette smoke, Hydrocarbons, Pesticides and many others
• Affect DNA by changing chemical nature of the bases
• May resemble nucleotides and bond in place of the DNA nucleotides preventing DNA replication

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Causes of Mutations

• Radiation: high energy rays like X rays and gamma rays; form free radicals (charged escaped electrons) that damages DNA
• UV radiation can cause adjacent thymines to bind with each other instead of complementary nucleotides causing a “kink” in the DNA molecule which prevents replication

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HOW DO WE IDENTIFY THESE DNA DAMAGE?

• This goes beyond our regular biopsy, H&E stain in Histopathology to a lot more science in a rapidly growing field of technology.
• Molecular characterization strategies
• NGS sequencing, such as genomics, transcriptomics, proteomics
• Immunophenotyping,
• Epigenetic profiling,
• Single-cell analyses

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Precision Oncology, Genomics, NGS, Targeted Therapy

APPLICATIONS OF NGS IN CLINICAL PRACTICE

• NGS is utilized to novel diagnostic and rare cancer mutations, detection of translocations, inversions, insertions and deletions, detection of copy number variants, detect familial cancer mutation carriers, provide the molecular rationale for appropriate targeted, therapeutic and prognostic.

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Precision Oncology, Genomics, NGS, Targeted Therapy

Applications of Genomic Testing in Medicine

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Applications of Genomic Testing in Medicine

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A New Taxonomy of Cancer�From organs to molecules

• For more than a century, cancers have been classified by the organ or tissue �– with therapies geared to those specific areas
• As more is learned about the basic biological processes in cancers, a new perspective has emerged
• The shift from an organ-focused to a gene-focused approach to cancer is already having a profound effect on the way cancer is treated

Interview with Edward J. Benz, Jr., MD

www.standup2cancer.org/innovations_in_science/view/genomics_and_the_future_of_cancer_treatment

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Genomic Alterations in Cancer�Major classes

�TS, tumor suppressor

CML, chronic myelogenous leukemia

Macconaill LE, Garraway LA. Clinical implications of the cancer genome. Journal of Clinical Oncology, 28(35), 5219-5228 (2010).

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Genomic Alterations in Cancer�Major classes

�TS, tumor suppressor

CML, chronic myelogenous leukemia

Macconaill LE, Garraway LA. Clinical implications of the cancer genome. Journal of Clinical Oncology, 28(35), 5219-5228 (2010).

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Genomic Alterations in Cancer�Major classes

�TS, tumor suppressor

CML, chronic myelogenous leukemia

Macconaill LE, Garraway LA. Clinical implications of the cancer genome. Journal of Clinical Oncology, 28(35), 5219-5228 (2010).

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Breast Cancer�Genomic analysis

Hampton OA, Den Hollander P, Miller CA et al. A sequence-level map of chromosomal breakpoints in the MCF-7 breast cancer cell line yields insights into the evolution of a cancer genome. Genome Research, 19(2), 167-177 (2009).

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NGS Application Examples-�Neoplastic Conditions

Precision Oncology, Genomics, NGS, Targeted Therapy

Precision Oncology, Genomics, NGS, Targeted Therapy

Precision Oncology, Genomics, NGS, Targeted Therapy

HER2, CK7, EGFR Positive Breast CA

Precision Oncology, Genomics, NGS, Targeted Therapy

CD20 positive DLBCL

Precision Oncology, Genomics, NGS, Targeted Therapy

TARGETED THERAPY

Precision Oncology, Genomics, NGS, Targeted Therapy

What can we target precisely?

Precision Oncology, Genomics, NGS, Targeted Therapy

THERE ARE MANY TARGETS

Precision Oncology, Genomics, NGS, Targeted Therapy

WHAT DO WE DO WITH SO MUCH INFORMATION?

Precision Oncology, Genomics, NGS, Targeted Therapy

Clinical Utility-Challenges

Informed Consent and Ethical Considerations

• Create patient awareness of benefits and harms
• No specific guidance exists- institutional policies vary
• Potential for anxiety and uncertainty exist especially for variants of unknown significance
• Discovery of incidental findings unrelated to the disease in question

SUMMARY

• The human gene carries all the information about the individual.
• Utilization of genomics in patient care provides physicians with a powerful tool to aid the diagnosis and management of disease, particularly in precision oncology.

REFERENCES

• https://www.genome.gov/about-genomics/fact-sheets/A-Brief-Guide-to-Genomics
• https://www.researchgate.net/publication/234040504_Disease_progression_after_R-CHOP_treatment_associated_with_the_loss_of_CD20_antigen_expression/figures?lo=1
• https://www.researchgate.net/publication/268232500_Cross-reactivity_of_EGFR_Mutation-specific_Immunohistochemistry_Assay_in_HER2-positive_Tumors/figures?lo=1
• Sabour l et al doi: 10.1007/s12253-016-0124-z. Epub 2016 Oct 8. PMID: 27722982.

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Precision Oncology, Genomics, NGS, Targeted Therapy