Year 4 intro to cancer genomics and pgx JK March 25
Page 1: Introduction
Title: Cancer Genomics
Presenter: Jessica Keen – Pharmacy Lead, NHS NW Genomic Medicine Service Alliance
Date: February 2025
Page 2: Intended Learning Outcomes
Apply principles of clinical therapeutics, pharmacology, and genomics to:
Make effective use of medicines for people.
Understand the implications for prescribing practice (GPhC 29).
Page 3: What We Will Cover
Topics:
Genomics refresher.
Genomics and Precision Medicine.
Inherited/familial risk variants.
Principles of Pharmacogenomics.
Equality, Diversity, and Inclusion (EDI) in genomics.
Clinical implementation of Pharmacogenomics in cancer care.
Page 4: Genomics and Personalized Medicine
To personalise treatment you use genomic information.
Page 5: Genetics vs. Genomics
Genetics: Study of genes and inheritance.
Genomics: Study of individuals' and organisms' genomic content (coding and non-coding regions).
Pharmacogenetics: Impact of a single gene on medicine interactions.
Pharmacogenomics (PGx): Study of how a patient’s genome influences medicine response.
Page 6: Fundamentals of Genomic Variation
Germline (Inherited) Variants:
Present at birth.
Passed to future generations.
Somatic (Acquired) Variants:
changes in dna that have Developed over a lifetime.
Not inherited, so not necessarily passed on.
Page 7: Genomic Variation Examples
Germline Variants:
Drug metabolizing enzymes (P450).
Target proteins and immune-mediated ADRs (e.g., CFTR in cystic fibrosis).
Cancer risk variants (e.g., BRCA). can increase risk of certiain cancers and can be passed down through generations
proteins involved in the absorption/ metabolism of drugs so are important to look at with DNA.
Page 8: Genomics in Oncology Practice
Screening: Lynch Syndrome, BRCA.
Diagnosis: Somatic testing (e.g., lung cancer).
Treatment: Targeted treatments based on somatic variation and pharmacogenomics.
inherited risk - different screening programmes as they have increased risk.
Page 9: Pharmacogenomics in Cancer
Cancer Pharmacogenomics:
how dna is used in the interaction between the body and drugs.
Tumor/Somatic Variants: Variants often relate to drug targets (e.g., EGFR, KRAS).
Inherited Variants: Involve whole-body variations typically affecting pharmacokinetics. is someone more/less likely to get side effects etc because of their specific pharmacokinetic factors
Page 10: Genomics and Precision Medicine
Focus on:
Diagnosis and treatment variation.
Different types of genomic testing and their applications.
Page 11: Hallmarks of Cancer
Key hallmarks include:
Sustaining proliferative signaling.
Evading growth suppressors.
Deregulating cellular metabolism.
Resisting cell death.
Inducing angiogenesis and avoiding immune destruction.
Enabling replicative immortality.
Activating invasion and metastasis.
Nonmutational epigenetic reprogramming.
Page 12: Somatic Variants
Acquired during a lifetime, important for:
Cancer diagnosis.
Treatment selection by oncologists analyzing both somatic and germline variants.
Page 13: Genomic Tumor Testing
microscope- see chromosomes and irregularities in appearance. amongst other methods.
Page 14: Tumor Evolution
Circulating Tumor DNA (ctDNA) observations related to tumor evolution and metastasis.
different pockets of variants within clumps of cancer cells. metastasis and fast division leads to different DNA changes.
Page 15: Clinical Value of Liquid Biopsies
Circulating tumour DNA (ctDNA)
Advantages:
Useful when tissue samples are limited.
Offers insight into tumor heterogeneity.
can be less invasive for patients.
Limitations:
Requires sensitive technologies for low ctDNA detection.
Handling issues and false-negative risks.
some sample handling issues.
Page 16: Tumor Genomic Profile Monitoring
Emphasizes Comprehensive Genomic Profiling (CGP).
Detects residual disease and monitors therapy response.
sometimes this can be used to catch cancer very early, but ctdna might not be high enough to treat in some cases.
Page 17: Inherited Variants and Cancer Risk
Impact on:
Cancer risk determination.
Eligibility for screening programs and alternative treatments.
Page 18: Overview of Cancer Genomics
Cancer is a heterogeneous disease characterized by:
Uncontrolled cell growth and spread.
It is driven by both germline and somatic genetic changes.
imbalance between proliferation and cell death
Page 19: Familial/Inherited Cancers
Genetic predisposition can lead to:
Early onset of cancer.
Multiple primary tumors.
Example: BRCA mutations and associated cancer risks. - significantly higher risk of breast cancer in these individuals.
Page 20: Knudson's "Two-Hit" Hypothesis
Cancer development involves:
Two mutations in tumor suppressor genes.
Hereditary cases require one inherited and one acquired mutation.
Useful for guiding genetic testing and targeted therapies.
Page 21: Screening for Genetic Variants
Germline testing offered to those with family history.
Management strategies include regular screenings and risk-reducing therapies.
eg imaging- MRI, mammogram, blood tests, risk reducing surgeries
Page 22: Treatment Choices in Inherited Conditions
Example: Lynch Syndrome and its implications for treatment, requiring tailored assignments for surgical care.
chemo vs immunotherapy.
Page 23: Pharmacogenomics in Practice
Shift from a standard approach to a pharmacogenomic approach for individualized medicine based on genetic testing results.- can give insignt into the likelihood of pt experiencing certain side effects, individual differences in drug metabolism etc- can help to select the most appropriate and effective treatment options for each patient.
Page 24: Genetic Variation Impact on Medicine
Common genetic variants linked to:
Medicine effectiveness and adverse drug reactions (ADRs).
Significant healthcare costs associated with ADRs in UK hospitals.
Page 25: PGx Nomenclature
Star allele system for identifying genetic variants:
Alleles are categorized by function (normal, increased, decreased, or no function).
star 1 is reference- normal functional copy.
Page 26: CYP2C19 Star Alleles Example
Differentiates metabolic phenotypes based on star allele variations affecting drug metabolism.
normal metaboliser, intermediate, rapid , ultra rapid.
Page 27: Duplications & Copy Number Variants
codeine is an inactive prodrug- if someone doesnt hae a specific enzyme, cannot be converted to actuve metabolite, so will not work.
Page 28: Personalized Dosing
Critical for chemotherapy agents affected by hepatic impairment and pharmacogenomic testing to avoid toxicity.
Page 29: Toxicity Avoidance through PGx
Highlighting the DPYD gene and its link to severe toxicity risks in certain cancer treatments. (likelihood of side effects)
Page 30: DPYD Hotspot Testing
routine testing in clinical practice. This practice allows for the identification of patients at risk for adverse reactions, enabling personalized treatment plans that minimize toxicity. testlign on the NHS looks at the 4 most common variants.
Page 31: Genetic Variation Diversity in Genomic Studies
Emphasizes the importance of understanding genetic diversity beyond social constructs of race in pharmacogenomics.
Dna stuff that we know about may not be what is the same globally etc- variation in different parts of the world.
Page 32: Continued Emphasis on Genetic Variation Diversity
eg Carbamazepine can cause steven johnson syndrome in some patients with a partucylar variation (typically asian populations).
Page 33: Clinical Implementation of Pharmacogenomics
Best practices pathways for pharmacists in oncology.
Education roles among interdisciplinary teams and overcoming accessibility challenges.
Page 34: Pharmacist Involvement in Pharmacogenomics
Page 35: Promotion of Genomics Education
Engage in conversations surrounding pharmacy and personalized medicine.
Page 36: Personalizing Healthcare with Pharmacogenetics
Illustrates importance of pharmacogenetic testing results at various ages for medication optimization.
Page 37: Drugs with PGx Guidelines
Overview of recommended drug-gene pairs from Clinical Pharmacogenetics Implementation Consortium (CPIC).
Page 38: Summary of Key Topics
Recaps main areas covered:
Genomics refresher, Pharmacogenomics principles, Precision Medicine, Inherited/Familial Risk Variants, EDI in Genomics, Clinical Implementation of Pharmacogenomics in Cancer Care.