Transcript Case Studies in Human Cytogenetics

Diving Into the Gene Pool:
Genetics, Genomics and
Primary Care Medical Practice
H. Eugene Hoyme, MD
Chief Academic Officer, Sanford Health
President, Sanford Research USD
Professor of Pediatrics
(Medical Genetics)
Sanford School of Medicine
University of South Dakota
Learning Objectives
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Define: genetics, genomics and genomic medicine.
Understand the importance of the role of primary care
physicians in the provision of genetic/genomic
information to their patients.
List four applications of genomic medicine currently
in use in clinical practice.
Apply principles of genetics and genomics in
provision of health maintenance for some of the
common disorders of adult life.
Discuss the need to exercise caution in provision of
genetic and genomic information to patients in light
of its potential ethical, legal and social implications.
Definitions
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Genetics: The study of specific, individual genes
and their role in inheritance. (In medicine,
genetics has historically applied to the study of
rare single gene disorders).
Genomics: The study of an organism's entire
genetic makeup (genome)and its interaction with
environmental or non-genetic factors, including
lifestyle.
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Applied to the study of complex diseases such as
cancer, diabetes, heart disease, hypertension and
asthma.
Definitions
•Genomic Medicine:
The medical discipline
that involves using genomic information about
an individual as part of his/her comprehensive
health care supervision (e.g., for diagnostic or
therapeutic decision-making).
−Genomic medicine is becoming an integral part of
primary care for adults.
Why Must Primary Care Physicians
Understand Genetics and Genomics?
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To answer requests for information
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Practitioners need to be able to respond to
patients' questions about the possibility of a
genetic disease in the family.
A survey conducted by the American Medical
Association in March 1998 found that 71% of
patients who questioned whether there was a
genetic disease in their family would contact
their primary care physician first.
American Medical Association. Genetic testing: a study of consumer attitudes.
March 1998: AMA survey results. www.amaassn.org/ama/pub/article/2304-2937.html
Accessed September 23, 2007.
Why Must Primary Care Physicians
Understand Genetics and Genomics?
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To assist in case recognition
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By increasing their awareness of the
manifestations of common genetic diseases,
practitioners can expand the differential
diagnoses of some patients' symptoms to
include common genetic diseases.
Whereas all diseases have both a genetic and an
environmental component, in some, the genetic
effect predominates, and these are commonly
referred to as “genetic diseases.”
Why Must Primary Care Physicians
Understand Genetics and Genomics?
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To provide effective health supervision
for patients with genetic disorders
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Practitioners need to know how patients'
primary genetic diseases may affect their
health, what secondary diseases they are
likely to develop, and the unusual ways that
common diseases may present in these
patients.
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Children and adolescents with genetic disorders
must transition to knowledgeable adult medicine
primary care physicians who can provide
comprehensive health supervision.
Why Must Primary Care Physicians
Understand Genetics and Genomics?
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To decrease over-utilization of limited
genetics resources
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Primary care physicians play a crucial role in
the integration of genetics into clinical
practice, since there are currently few MD
clinical geneticists and genetic counsleors.
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In a study of referrals for genetics services in the
United Kingdom, most referrals were found to be
low-risk persons who could have received
reassurance from their primary care physicians.
Harris R, Harris HJ. Primary care for patients at genetic risk [editorial].
BMJ 1995;311: 579-580.
Why Must Primary Care Physicians
Understand Genetics and Genomics?
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To screen for potential genetic disorders
in patients in their practices
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Genetic screening measures historically have
focused on reproductive issues, such as
preconception screening for those at risk of being
carriers of autosomal recessive diseases (TaySachs disease, CF) or prenatal diagnosis (Down
syndrome).
Newborn screening is generally mandated by state
or federal government health policies and occurs
outside the physician's purview (newborn
screening).
Why Must Primary Care Physicians
Understand Genetics and Genomics?
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The role of genetics and genomics in routine
health care maintenance for adults as a means
to assess the genetic risk of disease is
becoming increasingly important.
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An understanding of the genomic components of
the common chronic diseases of adult life will lead
to a personalized approach to health supervision,
i.e, personalized or genomic medicine.
Genomic Medicine Future State
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In addition to the usual tools physicians use in
health assessment, the tools of genomics will
allow for personalizing:
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Screening protocols for heart disease, cancer and other
chronic disorders
Informed dietary and lifestyle choices
Individualized presymptomatic medical therapies, e.g.,
antihypertensive agents before hypertension develops,
anti-schizophrenia agents before schizophrenia
develops
Prescribing medications based on
pharmacogenetics/pharmacogenomics
A Fun Fact: How Many Human Genes Do All
Current Drugs Target?
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~500 (5% of the genome)
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~1,000 (10%)
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~5,000 (25%)
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~10,000 (50%)
5)
~ 15,000 (75%)
6)
~20,000 (100%)
A Fun Fact: How Many Human Genes Do All
Current Drugs Target?
1)
~500 (5% of the genome)
2)
~1,000 (10%)
3)
~5,000 (25%)
4)
~10,000 (50%)
5)
~ 15,000 (75%)
6)
~20,000 (100%)
The Benefits of Genomic Medicine
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Detect disease at an
earlier stage, when it is
easier to treat effectively;
Enable the selection of
optimal therapy and
reduce trial-and-error
prescribing;
Reduce adverse drug
reactions;
Increase patient
compliance with therapy;
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Improve the selection of
targets for drug
discovery and reduce
the time, cost, and
failure rate of clinical
trials;
Shift the emphasis in
medicine from reaction
to prevention;
Reduce the overall cost
of healthcare.
Personalized Medicine: A Shift
from Reactive to Preventive
Health Care Savings
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Personalized medicine may help control
costs by decreasing the number of
unnecessary screening and diagnostic
tests ordered.
Personalized medicine may identify
individuals genetically at high risk for the
common diseases of adulthood
(hypertension, heart disease, cancer and
diabetes), allowing for extensive
environmental intervention.
Health Care Savings
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Personalized medicine may lead to more
rapid recovery since the correct
medication and dosing for the individual
patient will lead to the end of “trial and
error” prescribing.
Drugs may become less expensive since
pharmaceutical companies will use
genetic and molecular data to develop
more effective “targeted” therapies.
Current Applications of Genomic
Medicine in the Clinic
Tumor-based Screening
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Current oncology practice has moved
toward tumor genotyping of cancers such
as melanoma, breast, colon and lung for
targeting of therapy.
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Sanford’s SSKT trial
Genetic screening of patients with a
family history of breast or colon cancer
may be indicated based on the nature of
the tumor(s) and the number and degree
of relatedness of affected relatives.
BRCA1/BRCA2 and Breast Cancer
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The likelihood of a harmful mutation in
BRCA1 or BRCA2 is increased with
certain familial patterns of cancer. These
patterns include the following:
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Multiple breast and/or ovarian cancers within
a family (often diagnosed at an early age)
Two or more primary cancers in a single
family member (more than one breast cancer,
or breast and ovarian cancer)
Cases of male breast cancer
Genetics and Colon Cancer
Family History Directed Decision Support
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Electronic family history data collection tools
allowing patients to input their family history
have been validated, allowing for individual
genetic risk assessment.
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Surgeon General’s My Family Health Portrait
Integrating this information into the EHR has proven
to be formidable.
Duke University has designed a web-based tool that
collects family history and provides decision support
information on four conditions (breast, ovarian
and colon cancer and venous thrombosis).
https://familyhistory.hhs.gov/
eMERGE
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The eMERGE (Electronic Medical Records
and Genomics) Network is a national
consortium formed to develop,
disseminate, and apply approaches to
research that combine DNA
biorepositories with electronic medical
record (EMR) systems for large-scale,
high-throughput genetic research.
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Goal is to provide user-friendly decision
support algorithms for health care providers
Pharmacogenomics
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Nearly every pathway of drug metabolism,
transport and action is influenced by
genetic variation.
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The FDA lists 131 prescription medications
with genomic biomarkers that affect: clinical
response variability, risk for adverse events,
genotype specific dosing, mechanisms of
drug action and polymorphic drug target and
disposition genes.
http://www.fda.gov/drugs/scienceresearchareas/pharmacogenetics/
Pharmacogenomics
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20-90% of individual variability of response to
prescribed medications is genetically based.
59% of the 27 most frequently cited
medications in adverse drug reactions have
gene variants that code for reduced
functioning or non-functioning proteins.
NEJM 348; 529-538, 2003 / JAMA 286; 2270, 2001)
Pharmacogenomics
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Pharmacogenetic testing has the potential to
minimize side effects and decrease the
frequency of adverse drug events by allowing for
individualized rather than “one size fits all”
prescribing.
Among drugs for which pharmacogenetic testing
is currently available are:
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SSRI and TCA antidepressants
Opioid pain medications
Beta blockers
Type I antiarrhythmics
Anticoagulants (coumadin and plavix)
Pharmacogenomics
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Example of pharmacogenetic testing: Plavix
(clopidogrel)
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One cytochrome gene variant (CYP2C19) appears
to account for most of the variability in
bioactivation and efficacy among patients.
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2% of whites, 4% of African Americans and 14% of Asians
are slow metabolizers and at higher risk of cardiovascular
events and stroke. This group may benefit from an
alternative medication or a larger dose of the medication.
The number of medications for which
pharmacogenetic testing is indicated is
expected to grow at a rapid pace.
“Pre-emptive” Genotyping in
Pharmacogenomics
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Pharmacogenomic testing for multiple
drugs becomes clinically practical if
appropriate decision support tools present
relevant data to physicians only when
needed.
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Reactive genotyping is slow and the uptake by
physicians has been low.
“Pre-emptive” Genotyping in
Pharmacogenomics
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However, programs for “pre-emptive”
genotyping are being developed whereby
patients have extensive array based
pharmacogenomic genotyping as part of their
health supervision, the data being presented
to the physician only when a related drug is
being prescribed.
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At St. Jude’s, array based testing for 225 genes is
performed, and results for those genes with the
strongest clinical evidence are placed in the EHR.
Diagnostic Genome Sequencing
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Whole exome (the protein coding exons)
and whole genome sequencing are now
clinically available through CLIA certified
laboratories.
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Whole exome sequencing has revealed the
etiology of many rare single gene disorders
Whole genome and RNA (transcriptome)
sequencing are necessary in oncology, since
genetic material other than exomes (e.g.,
regulatory genes) often drive cancer.
Next Generation sequencing Technology:
the Engine of “Genomic Medicine”
The Cost of Genome Sequencing
is Decreasing Rapidly
Evolution of Genomic Sequencing
in Clinical Laboratory Testing
Bioinformatics and Next
Generation Sequencing
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Bioinformatics is the science of collecting
and analyzing complex biological data.
In 2013, the sequencing of the genome has
become relatively routine.
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The difficult part of its clinical application is
sorting out normal genetic variation from the
DNA changes that are clinically actionable.
Any CLIA certified whole exome or genome
sequencing laboratory must have access to
such bioinformatics skill.
The 1000 Genomes Project
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The goal of the 1000 Genomes Project is to provide
a comprehensive resource on human genetic
variation to aid with genomics research and clinical
interpretation of sequencing data for genomic
medicine.
The first phase is complete, with 1092 individual
genomes sequenced with low coverage.
Subsequent work will provide deep coverage and
more clinically applicable data.
The 1000 Genomes Project
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The project catalogs human DNA variants present
at >1% frequency, or within genes, at >0.5%
frequency.
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Include not only SNPs, but also rearrangements, deletions,
and duplications.
In its initial production phase, produced about 8.2 billion
bases/day (> two genomes/day).
Samples from: Europeans: British, Finnish, Italian,
Spanish, European Americans (Utah); Asians: Japanese,
Chinese (Beijing and Denver); Africans: Yoruba, Maasai,
African American (Los Angeles); Gujarata Indian; Mexican
American (Los Angeles).
Integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491:56-65
The Multiplex Initiative
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Investigates the interest of 1,000 healthy, young
adults in genetic testing for eight common
conditions: type 2 diabetes, coronary disease,
hypercholesterolemia, hypertension, lung cancer,
osteoporosis, colorectal cancer, and malignant
melanoma.
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Evaluates responses to offer of free genetic testing to
learn about influences on deciding whether to be tested
and how individuals who are tested interact with the health
care system.
Research team combines scientists in NHGRI’s intramural
program and at Henry Ford Health System in Detroit
and the Group Health Cooperative in Seattle.
Two Case Illustrative Case
Studies
Case #1: Sara’s Story in 2020
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Sara completes the Surgeon General’s
family history tool at age 14, learns of uncles
with early heart disease
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She consults her health care provider who
suggests complete genome sequencing at
age 18 for $500
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She inquires about the risk of genetic
discrimination, but her pediatrician tells her
that federal legislation has outlawed this
Case #1: Sara’s Story in 2020
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At 18, she is found to have four genetic
variants that well validated studies have
conclusively shown increase risk of early
heart attack five-fold
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She and her health care team design a
program of prevention based on diet,
exercise, and medication, at age 35, precisely
targeted to her genetic makeup
Case #1: Sara’s Story in 2020
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Sara does well until age 75
She develops left arm pain that she assumes
is due to gardening, but her primary care
provider knows her higher risk and
diagnoses an acute MI
Referring to her genome sequence, the drugs
that will work best to treat her are chosen
She survives and is alive and well in the 22nd
century
Case #1: Sara’s Story…An
Alternative Reality
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The Surgeon General’s Family History
Initiative never really takes off and her
pediatrician is too busy filling out insurance
forms to ask about family history, so Sara
never learns about her family history
Sara is offered genome sequencing, but after
seeing her brother lose his disability
insurance from this information, she declines
Case #1: Sara’s Story…An
Alternative Reality
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Sara eats an unhealthy diet, gains weight,
and develops hypertension
While tests to predict which drug would be
most effective for Sara have been proposed,
they have never been validated, and are not
reimbursed
Sara’s hypertension is treated with a drug
that causes a hypersensitivity reaction, so
she stops treatment
Case #1: Sara’s Story…An
Alternative Reality
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After 10 years of uncontrolled hypertension,
Sara develops left arm pain at age 45
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Since she has no primary care physician, she
presents to urgent care, where the physician,
unaware of her high risk, assumes her pain
to be musculoskeletal and prescribes rest
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Sara returns to the ER the next day in
cardiogenic shock
Case #1: Sara’s Story…An
Alternative Reality
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The absence of her genome sequence
information prevents optimal choice of
therapy
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Sara dies in the ER
Case #2: Genomic Medicine
in Oncology
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A true case study from a few years ago:
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A young leukemia researcher is diagnosed with
the cancer he had devoted his life to studying.
With no other treatment available, his colleagues
decide to sequence his entire genome and his
RNA, to see if they can find the gene(s) that are
driving his cancer, adult acute lymphoblastic
leukemia (ALL).
The sequencing takes a month to complete and
reveals multiple pathologic changes in several
genes, none of which are in pathways responsive
to existing medications.
Case #2: Genomic Medicine
in Oncology
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However, RNA analysis points to a single gene
which is driving overproduction of a protein that
spurs growth of cancer cells.
A new drug, Sutent, blocks the effects of the gene.
However, the cost ($330 per day) is prohibitive. His
insurance company will not pay for it, and despite
two appeals, the manufacturer, will not grant him a
supply through its compassionate use program.
After scraping up some money to buy a week’s
worth, he begins taking Sutent. His colleagues also
pitch in to buy a month’s supply for him.
Two weeks later, bone marrow biopsy reveals a full
remission.
Conclusions
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Primary care physicians must be familiar
with the principles of genetics in order to:
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Recognize genetic disease in their patients.
Provide effective health supervision for their
patients with genetic disorders.
Answer patients’ questions about genetic vs.
environmental factors in common diseases.
Appropriately refer cases to clinical geneticists
and genetic counselors for additional
diagnostic evaluation.
Conclusions
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The fruits of the Human Genome Project and the
vast array of genetic testing available to
clinicians have greatly enhanced primary care
physicians’ ability to diagnose genetic disorders
and those disorders with a major genetic
predisposition.
Genomic medicine is already being applied in
tumor-based screening, family history-oriented
decision support, pharmacogenomics and
diagnostic genome sequencing.
BUT…this is only the beginning!