diving into the gene pool: genetics, genomics and primary care medical practice

Diving Into the Gene Pool:Diving Into the Gene Pool:Genetics, Genomics and Genetics, Genomics and Primary Care Medical Practice Primary Care Medical Practice

H. Eugene Hoyme, MDH. Eugene Hoyme, MDChief Academic Officer, Sanford HealthChief Academic Officer, Sanford HealthPresident, Sanford Research USDPresident, Sanford Research USDProfessor of Pediatrics Professor of Pediatrics (Medical Genetics)(Medical Genetics)Sanford School of MedicineSanford School of MedicineUniversity of South DakotaUniversity of South Dakota

Learning ObjectivesLearning Objectives

DefineDefine:: genetics, genomics and genomic medicine.genetics, genomics and genomic medicine. Understand the importance of the role of primary care Understand the importance of the role of primary care

physicians in the provision of genetic/genomic physicians in the provision of genetic/genomic information to their patients.information to their patients.

List four applications of genomic medicine currently List four applications of genomic medicine currently in use in clinical practice. in use in clinical practice.

Apply principles of genetics and genomics in Apply principles of genetics and genomics in provision of health maintenance for some of the provision of health maintenance for some of the common disorders of adult life.common disorders of adult life.

Discuss the need to exercise caution in provision of Discuss the need to exercise caution in provision of genetic and genomic information to patients in light genetic and genomic information to patients in light of its potential ethical, legal and social implications.of its potential ethical, legal and social implications.

DefinitionsDefinitions

Genetics:Genetics: The study of specific, The study of specific, individualindividual genes and genes and their role in inheritance. (In medicine, genetics has their role in inheritance. (In medicine, genetics has historically applied to the study of rare single gene historically applied to the study of rare single gene disorders).disorders).

Genomics:Genomics: The study of an organism's The study of an organism's entire entire genetic genetic makeup (genome)and its interaction with makeup (genome)and its interaction with environmental or non-genetic factors, including environmental or non-genetic factors, including lifestyle.lifestyle.– Applied to the study of complex diseases such as cancer, Applied to the study of complex diseases such as cancer,

diabetes, heart disease, hypertension and asthma.diabetes, heart disease, hypertension and asthma.

DefinitionsDefinitions

•Genomic Medicine:Genomic Medicine: The medical discipline The medical discipline that involves using genomic information about that involves using genomic information about an individual as part of his/her comprehensive an individual as part of his/her comprehensive health care supervision (e.g., for diagnostic or health care supervision (e.g., for diagnostic or therapeutic decision-making).therapeutic decision-making).

−Genomic medicine is becoming an integral part of Genomic medicine is becoming an integral part of primary care for adults.primary care for adults.

Why Must Primary Care Physicians Why Must Primary Care Physicians Understand Genetics and Genomics? Understand Genetics and Genomics?

To answer requests for informationTo answer requests for information– Practitioners need to be able to respond to Practitioners need to be able to respond to

patients' questions about the possibility of a patients' questions about the possibility of a genetic disease in the family. genetic disease in the family.

– A survey conducted by the American Medical A survey conducted by the American Medical Association in March 1998 found that 71% of Association in March 1998 found that 71% of patients who questioned whether there was a patients who questioned whether there was a genetic disease in their family would contact genetic disease in their family would contact their primary care physician first.their primary care physician first.

American Medical Association. Genetic testing: a study of consumer attitudes. American Medical Association. Genetic testing: a study of consumer attitudes. March 1998: AMA survey results. March 1998: AMA survey results. www.amaassn.org/ama/pub/article/2304-2937.html

Accessed September 23, 2007.Accessed September 23, 2007.


To assist in case recognitionTo assist in case recognition– By increasing their awareness of the By increasing their awareness of the

manifestations of common genetic diseases, manifestations of common genetic diseases, practitioners can expand the differential practitioners can expand the differential diagnoses of some patients' symptoms to diagnoses of some patients' symptoms to include common genetic diseases. include common genetic diseases.

– Whereas all diseases have both a genetic and an Whereas all diseases have both a genetic and an environmental component, in some, the genetic environmental component, in some, the genetic effect predominates, and these are commonly effect predominates, and these are commonly referred to as referred to as ““genetic diseases.genetic diseases.””


To provide effective health supervision for To provide effective health supervision for patients with genetic disorderspatients with genetic disorders– Practitioners need to know how patients' primary Practitioners need to know how patients' primary

genetic diseases may affect their health, what genetic diseases may affect their health, what secondary diseases they are likely to develop, and secondary diseases they are likely to develop, and the unusual ways that common diseases may the unusual ways that common diseases may present in these patients. present in these patients.

Children and adolescents with genetic disorders must Children and adolescents with genetic disorders must transition to knowledgeable adult medicine primary care transition to knowledgeable adult medicine primary care physicians who can provide comprehensive health physicians who can provide comprehensive health supervision. supervision.


To decrease over-utilization of limited To decrease over-utilization of limited genetics resourcesgenetics resources– Primary care physicians play a crucial role in Primary care physicians play a crucial role in

the integration of genetics into clinical the integration of genetics into clinical practice, since there are currently few MD practice, since there are currently few MD clinical geneticists and genetic counsleors. clinical geneticists and genetic counsleors.

In a study of referrals for genetics services in the In a study of referrals for genetics services in the United Kingdom, most referrals were found to be United Kingdom, most referrals were found to be low-risk persons who could have received low-risk persons who could have received reassurance from their primary care physicians. reassurance from their primary care physicians.

Harris R, Harris HJ. Primary care for patients at genetic risk [editorial]. Harris R, Harris HJ. Primary care for patients at genetic risk [editorial].

BMJ 1995;311: 579-580.BMJ 1995;311: 579-580.


To screen for potential genetic disorders To screen for potential genetic disorders in patients in their practicesin patients in their practices– Genetic screening measures historically have Genetic screening measures historically have

focused on reproductive issues, such as focused on reproductive issues, such as preconception screening for those at risk of being preconception screening for those at risk of being carriers of autosomal recessive diseases (Tay-carriers of autosomal recessive diseases (Tay-Sachs disease, CF) or prenatal diagnosis (Down Sachs disease, CF) or prenatal diagnosis (Down syndrome). syndrome).

– Newborn screening is generally mandated by state Newborn screening is generally mandated by state or federal government health policies and occurs or federal government health policies and occurs outside the physician's purview (newborn outside the physician's purview (newborn screening).screening).


– The role of genetics and genomics in routine The role of genetics and genomics in routine health care maintenance for adults as a means health care maintenance for adults as a means to assess the genetic risk of disease is to assess the genetic risk of disease is becoming increasingly important.becoming increasingly important.

An understanding of the genomic components of An understanding of the genomic components of the common chronic diseases of adult life will lead the common chronic diseases of adult life will lead to a personalized approach to health supervision, to a personalized approach to health supervision, i.e, i.e, personalized or genomic medicinepersonalized or genomic medicine..

Genomic Medicine Future StateGenomic Medicine Future State

In addition to the usual tools physicians use in In addition to the usual tools physicians use in health assessment, the tools of genomics will allow health assessment, the tools of genomics will allow for personalizing:for personalizing:– Screening protocols for heart disease, cancer and other Screening protocols for heart disease, cancer and other

chronic disorderschronic disorders– Informed dietary and lifestyle choicesInformed dietary and lifestyle choices– Individualized presymptomatic medical therapies, e.g., Individualized presymptomatic medical therapies, e.g.,

antihypertensive agents before hypertension develops, antihypertensive agents before hypertension develops, anti-schizophrenia agents before schizophrenia developsanti-schizophrenia agents before schizophrenia develops

– Prescribing medications based on Prescribing medications based on pharmacogenetics/pharmacogenomicspharmacogenetics/pharmacogenomics

A Fun Fact: How Many Human Genes Do A Fun Fact: How Many Human Genes Do AllAll Current Drugs Target?Current Drugs Target?

1)1) ~500 (5% of the genome)~500 (5% of the genome)

2)2) ~1,000 (10%)~1,000 (10%)

3)3) ~5,000 (25%)~5,000 (25%)

4)4) ~10,000 (50%)~10,000 (50%)

5)5) ~ 15,000 (75%)~ 15,000 (75%)

6)6) ~20,000 (100%)~20,000 (100%)

A Fun Fact: How Many Human Genes Do A Fun Fact: How Many Human Genes Do AllAll Current Drugs Target?Current Drugs Target?

1)1) ~500 (5% of the genome)~500 (5% of the genome)2)2) ~1,000 (10%)~1,000 (10%)

3)3) ~5,000 (25%)~5,000 (25%)

4)4) ~10,000 (50%)~10,000 (50%)

5)5) ~ 15,000 (75%)~ 15,000 (75%)

6)6) ~20,000 (100%) ~20,000 (100%)

The Benefits of Genomic MedicineThe Benefits of Genomic Medicine

Detect disease at an earlier Detect disease at an earlier stage, when it is easier to stage, when it is easier to treat effectively;treat effectively;

Enable the selection of Enable the selection of optimal therapy and reduce optimal therapy and reduce trial-and-error prescribing;trial-and-error prescribing;

Reduce adverse drug Reduce adverse drug reactions;reactions;

Increase patient Increase patient compliance with therapy;compliance with therapy;

Improve the selection of Improve the selection of targets for drug targets for drug discovery and reduce discovery and reduce the time, cost, and the time, cost, and failure rate of clinical failure rate of clinical trials;trials;

Shift the emphasis in Shift the emphasis in medicine from reaction medicine from reaction to prevention;to prevention;

Reduce the overall cost Reduce the overall cost of healthcare.of healthcare.

Personalized Medicine: A Shift Personalized Medicine: A Shift from Reactive to Preventivefrom Reactive to Preventive

Health Care SavingsHealth Care Savings

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 SavingsHealth Care Savings

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 Current Applications of Genomic Medicine in the ClinicMedicine in the Clinic

Tumor-based ScreeningTumor-based Screening

Current oncology practice has moved toward Current oncology practice has moved toward tumor genotyping of cancers such as melanoma, tumor genotyping of cancers such as melanoma, breast, colon and lung for targeting of therapy.breast, colon and lung for targeting of therapy. Sanford’s SSKT trialSanford’s SSKT trial

Genetic screening of patients with a family Genetic screening of patients with a family history of breast or colon cancer may be history of breast or colon cancer may be indicated based on the nature of the tumor(s) indicated based on the nature of the tumor(s) and the number and degree of relatedness of and the number and degree of relatedness of affected relatives.affected relatives.

BRCA1/BRCA2 and Breast CancerBRCA1/BRCA2 and Breast Cancer

The likelihood of a harmful mutation in The likelihood of a harmful mutation in BRCA1BRCA1 or or BRCA2BRCA2 is increased with certain is increased with certain familial patterns of cancer. These patterns include the patterns of cancer. These patterns include the following:following:– Multiple breast and/or ovarian cancers within a Multiple breast and/or ovarian cancers within a

family (often diagnosed at an early age)family (often diagnosed at an early age)– Two or more primary cancers in a single family Two or more primary cancers in a single family

member (more than one breast cancer, or breast member (more than one breast cancer, or breast and ovarian cancer)and ovarian cancer)

– Cases of male breast cancerCases of male breast cancer

Genetics and Colon CancerGenetics and Colon Cancer

Family History Directed Decision SupportFamily History Directed Decision Support

Electronic family history data collection tools Electronic family history data collection tools allowing patients to input their family history have allowing patients to input their family history have been validated, allowing for individual genetic risk been validated, allowing for individual genetic risk assessment.assessment. Surgeon General’s My Family Health PortraitSurgeon General’s My Family Health Portrait Integrating this information into the EHR has proven to be Integrating this information into the EHR has proven to be

formidable.formidable. Duke University has designed a web-based tool that collects Duke University has designed a web-based tool that collects

family history and provides decision support information on family history and provides decision support information on four conditions (breast, ovarian and colon cancer and four conditions (breast, ovarian and colon cancer and venous thrombosis).venous thrombosis).

https://familyhistory.hhs.gov/

eMERGEeMERGE

The eMERGE (Electronic Medical Records The eMERGE (Electronic Medical Records and Genomics) Network is a national and Genomics) Network is a national consortium formed to develop, disseminate, consortium formed to develop, disseminate, and apply approaches to research that and apply approaches to research that combine DNA biorepositories with electronic combine DNA biorepositories with electronic medical record (EMR) systems for large-medical record (EMR) systems for large-scale, high-throughput genetic research.scale, high-throughput genetic research.– Goal is to provide user-friendly decision support Goal is to provide user-friendly decision support

algorithms for health care providersalgorithms for health care providers

PharmacogenomicsPharmacogenomics

Nearly every pathway of drug metabolism, Nearly every pathway of drug metabolism, transport and action is influenced by transport and action is influenced by genetic variation.genetic variation.– The FDA lists 131 prescription medications The FDA lists 131 prescription medications

with genomic biomarkers that affect: clinical with genomic biomarkers that affect: clinical response variability, risk for adverse events, response variability, risk for adverse events, genotype specific dosing, mechanisms of genotype specific dosing, mechanisms of drug action and polymorphic drug target and drug action and polymorphic drug target and disposition genes.disposition genes.

http://www.fda.gov/drugs/scienceresearchareas/pharmacogenetics/http://www.fda.gov/drugs/scienceresearchareas/pharmacogenetics/


– 20-90% of individual variability of response to 20-90% of individual variability of response to prescribed medications is genetically based.prescribed medications is genetically based.

– 59% of the 27 most frequently cited 59% of the 27 most frequently cited medications in adverse drug reactions have medications in adverse drug reactions have gene variants that code for reduced gene variants that code for reduced functioning or non-functioning proteins.functioning or non-functioning proteins.

NEJMNEJM 348; 529-538, 2003 / 348; 529-538, 2003 / JAMAJAMA 286; 2270, 2001) 286; 2270, 2001)


Pharmacogenetic testing has the potential to minimize Pharmacogenetic testing has the potential to minimize side effects and decrease the frequency of adverse side effects and decrease the frequency of adverse drug events by allowing for individualized rather than drug events by allowing for individualized rather than “one size fits all” prescribing.“one size fits all” prescribing.

Among drugs for which pharmacogenetic testing is Among drugs for which pharmacogenetic testing is currently available are:currently available are:– SSRI and TCA antidepressantsSSRI and TCA antidepressants– Opioid pain medicationsOpioid pain medications– Beta blockersBeta blockers– Type I antiarrhythmicsType I antiarrhythmics– Anticoagulants (coumadin and plavix)Anticoagulants (coumadin and plavix)


Example of pharmacogenetic testing: Plavix Example of pharmacogenetic testing: Plavix (clopidogrel)(clopidogrel)– One cytochrome gene variant (CYP2C19) appears to One cytochrome gene variant (CYP2C19) appears to

account for most of the variability in bioactivation and account for most of the variability in bioactivation and efficacy among patients.efficacy among patients.

2% of whites, 4% of African Americans and 14% of Asians are slow 2% of whites, 4% of African Americans and 14% of Asians are slow metabolizers and at higher risk of cardiovascular events and stroke. metabolizers and at higher risk of cardiovascular events and stroke. This group may benefit from an alternative medication or a larger This group may benefit from an alternative medication or a larger dose of the medication.dose of the medication.

The number of medications for which The number of medications for which pharmacogenetic testing is indicated is expected to pharmacogenetic testing is indicated is expected to grow at a rapid pace.grow at a rapid pace.

““Pre-emptive” Genotyping in Pre-emptive” Genotyping in PharmacogenomicsPharmacogenomics

Pharmacogenomic testing for multiple Pharmacogenomic testing for multiple drugs becomes clinically practical if drugs becomes clinically practical if appropriate decision support tools present appropriate decision support tools present relevant data to physicians relevant data to physicians only when only when needed.needed.– Reactive genotyping is slow and the uptake by Reactive genotyping is slow and the uptake by

physicians has been low.physicians has been low.

““Pre-emptive” Genotyping in Pre-emptive” Genotyping in PharmacogenomicsPharmacogenomics

– However, programs for However, programs for “pre-emptive” “pre-emptive” genotyping genotyping are being developed whereby are being developed whereby patients have extensive array based patients have extensive array based pharmacogenomic genotyping as part of their pharmacogenomic genotyping as part of their health supervision, the data being presented to health supervision, the data being presented to the physician only when a related drug is being the physician only when a related drug is being prescribed.prescribed.

At St. Jude’s, array based testing for 225 genes is At St. Jude’s, array based testing for 225 genes is performed, and results for those genes with the performed, and results for those genes with the strongest clinical evidence are placed in the EHR.strongest clinical evidence are placed in the EHR.

–

Diagnostic Genome SequencingDiagnostic Genome Sequencing

Whole exome (the protein coding exons) and Whole exome (the protein coding exons) and whole genome sequencing are now clinically whole genome sequencing are now clinically available through CLIA certified laboratories.available through CLIA certified laboratories. Whole exome Whole exome sequencing has revealed the sequencing has revealed the

etiology of many rare single gene disordersetiology of many rare single gene disorders Whole genome Whole genome and RNA (transcriptome) and RNA (transcriptome)

sequencing are necessary in oncology, since sequencing are necessary in oncology, since genetic material other than exomes (e.g., genetic material other than exomes (e.g., regulatory genes) often drive cancer.regulatory genes) often drive cancer.

Next Generation sequencing Technology: Next Generation sequencing Technology: the Engine of “Genomic Medicine”the Engine of “Genomic Medicine”

The Cost of Genome Sequencing The Cost of Genome Sequencing is Decreasing Rapidlyis Decreasing Rapidly

Evolution of Genomic Sequencing Evolution of Genomic Sequencing in Clinical Laboratory Testingin Clinical Laboratory Testing

Bioinformatics and Next Bioinformatics and Next Generation SequencingGeneration Sequencing

BioinformaticsBioinformatics is the science of collecting and is the science of collecting and analyzing complex biological data.analyzing complex biological data.

In 2013, the sequencing of the genome has In 2013, the sequencing of the genome has become relatively routine.become relatively routine.

– The difficult part of its clinical application is sorting The difficult part of its clinical application is sorting out normal genetic variation from the DNA changes out normal genetic variation from the DNA changes that are clinically actionable.that are clinically actionable.

– Any CLIA certified whole exome or genome Any CLIA certified whole exome or genome sequencing laboratory must have access to such sequencing laboratory must have access to such bioinformatics skill.bioinformatics skill.

The goal of the 1000 Genomes Project is to provide The goal of the 1000 Genomes Project is to provide a comprehensive resource on human genetic a comprehensive resource on human genetic variation to aid with genomics research and clinical variation to aid with genomics research and clinical interpretation of sequencing data for genomic interpretation of sequencing data for genomic medicine.medicine.

The first phase is complete, with 1092 individual The first phase is complete, with 1092 individual genomes sequenced with low coverage.genomes sequenced with low coverage.

Subsequent work will provide deep coverage and Subsequent work will provide deep coverage and more clinically applicable data.more clinically applicable data.

The 1000 Genomes ProjectThe 1000 Genomes Project

The project catalogs human DNA variants present at The project catalogs human DNA variants present at >>1% frequency, or within genes, at 1% frequency, or within genes, at >>0.5% frequency.0.5% frequency. Include not only SNPs, but also rearrangements, deletions, and Include not only SNPs, but also rearrangements, deletions, and

duplications.duplications. In its initial production phase, produced about 8.2 billion In its initial production phase, produced about 8.2 billion

bases/day (> two genomes/day).bases/day (> two genomes/day). Samples from: Europeans: British, Finnish, Italian, Spanish, Samples from: Europeans: British, Finnish, Italian, Spanish,

European Americans (Utah); Asians: Japanese, Chinese European Americans (Utah); Asians: Japanese, Chinese (Beijing and Denver); Africans: Yoruba, Maasai, African (Beijing and Denver); Africans: Yoruba, Maasai, African American (Los Angeles); Gujarata Indian; Mexican American American (Los Angeles); Gujarata Indian; Mexican American (Los Angeles).(Los Angeles).

The 1000 Genomes ProjectThe 1000 Genomes Project

Integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491:56-65

The Multiplex InitiativeThe Multiplex Initiative

Investigates the interest of 1,000 healthy, young adults Investigates the interest of 1,000 healthy, young adults in genetic testing for eight common conditions: type 2 in genetic testing for eight common conditions: type 2 diabetes, coronary disease, hypercholesterolemia, diabetes, coronary disease, hypercholesterolemia, hypertension, lung cancer, osteoporosis, colorectal hypertension, lung cancer, osteoporosis, colorectal cancer, and malignant melanoma.cancer, and malignant melanoma.– Evaluates responses to offer of free genetic testing to learn Evaluates responses to offer of free genetic testing to learn

about influences on deciding whether to be tested and how about influences on deciding whether to be tested and how individuals who are tested interact with the health care individuals who are tested interact with the health care system. system.

– Research team combines scientists in NHGRIResearch team combines scientists in NHGRI’’s intramural s intramural program and at Henry Ford Health System in Detroit and program and at Henry Ford Health System in Detroit and the Group Health Cooperative in Seattle.the Group Health Cooperative in Seattle.

Two Case Illustrative Case Two Case Illustrative Case Studies Studies

Case #1: Sara’s Story in 2020Case #1: Sara’s Story in 2020

Sara completes the Surgeon GeneralSara completes the Surgeon General’’s family s family history tool at age 14, learns of uncles with history tool at age 14, learns of uncles with early heart diseaseearly heart disease

She consults her health care provider who She consults her health care provider who suggests complete genome sequencing at suggests complete genome sequencing at age 18 for $500age 18 for $500

She inquires about the risk of genetic She inquires about the risk of genetic discrimination, but her pediatrician tells her discrimination, but her pediatrician tells her that federal legislation has outlawed thisthat federal legislation has outlawed this


At 18, she is found to have four genetic At 18, she is found to have four genetic variants that well validated studies have variants that well validated studies have conclusively shown increase risk of early conclusively shown increase risk of early heart attack five-foldheart attack five-fold

She and her health care team design a She and her health care team design a program of prevention based on diet, program of prevention based on diet, exercise, and medication, at age 35, precisely exercise, and medication, at age 35, precisely targeted to her genetic makeuptargeted to her genetic makeup


Sara does well until age 75Sara does well until age 75 She develops left arm pain that she assumes She develops left arm pain that she assumes

is due to gardening, but her primary care is due to gardening, but her primary care provider knows her higher risk and provider knows her higher risk and diagnoses an acute MIdiagnoses an acute MI

Referring to her genome sequence, the drugs Referring to her genome sequence, the drugs that will work best to treat her are chosenthat will work best to treat her are chosen

She survives and is alive and well in the 22She survives and is alive and well in the 22ndnd centurycentury

Case #1: Sara’s Story…An Case #1: Sara’s Story…An Alternative RealityAlternative Reality

The Surgeon GeneralThe Surgeon General’’s Family History s Family History Initiative never really takes off and her Initiative never really takes off and her pediatrician is too busy filling out insurance pediatrician is too busy filling out insurance forms to ask about family history, so Sara forms to ask about family history, so Sara never learns about her family historynever learns about her family history

Sara is offered genome sequencing, but after Sara is offered genome sequencing, but after seeing her brother lose his disability seeing her brother lose his disability insurance from this information, she declinesinsurance from this information, she declines


Sara eats an unhealthy diet, gains weight, Sara eats an unhealthy diet, gains weight, and develops hypertensionand develops hypertension

While tests to predict which drug would be While tests to predict which drug would be most effective for Sara have been proposed, most effective for Sara have been proposed, they have never been validated, and are not they have never been validated, and are not reimbursedreimbursed

SaraSara’’s hypertension is treated with a drug s hypertension is treated with a drug that causes a hypersensitivity reaction, so that causes a hypersensitivity reaction, so she stops treatmentshe stops treatment


After 10 years of uncontrolled hypertension, After 10 years of uncontrolled hypertension, Sara develops left arm pain at age 45Sara develops left arm pain at age 45

Since she has no primary care physician, she Since she has no primary care physician, she presents to urgent care, where the physician, presents to urgent care, where the physician, unaware of her high risk, assumes her pain unaware of her high risk, assumes her pain to be musculoskeletal and prescribes restto be musculoskeletal and prescribes rest

Sara returns to the ER the next day in Sara returns to the ER the next day in cardiogenic shockcardiogenic shock


The absence of her genome sequence The absence of her genome sequence information prevents optimal choice of information prevents optimal choice of therapytherapy

Sara dies in the ERSara dies in the ER

Case #2: Genomic Medicine Case #2: Genomic Medicine in Oncologyin Oncology

A true case study from a few years ago:A true case study from a few years ago:− A young leukemia researcher is diagnosed with the A young leukemia researcher is diagnosed with the

cancer he had devoted his life to studying.cancer he had devoted his life to studying.− With no other treatment available, his colleagues With no other treatment available, his colleagues

decide to sequence his entire genome and his RNA, to decide to sequence his entire genome and his RNA, to see if they can find the gene(s) that are driving his see if they can find the gene(s) that are driving his cancer, adult acute lymphoblastic leukemia (ALL).cancer, adult acute lymphoblastic leukemia (ALL).

− The sequencing takes a month to complete and reveals The sequencing takes a month to complete and reveals multiple pathologic changes in several genes, none of multiple pathologic changes in several genes, none of which are in pathways responsive to existing which are in pathways responsive to existing medications.medications.

Case #2: Genomic Medicine Case #2: Genomic Medicine in Oncologyin Oncology

− However, RNA analysis points to a single gene which is driving However, RNA analysis points to a single gene which is driving overproduction of a protein that spurs growth of cancer cells.overproduction of a protein that spurs growth of cancer cells.

− A new drug, Sutent, blocks the effects of the gene. However, A new drug, Sutent, blocks the effects of the gene. However, the cost ($330 per day) is prohibitive. His insurance company the cost ($330 per day) is prohibitive. His insurance company will not pay for it, and despite two appeals, the manufacturer, will not pay for it, and despite two appeals, the manufacturer, will not grant him a supply through its compassionate use will not grant him a supply through its compassionate use program.program.

− After scraping up some money to buy a week’s worth, he begins 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 taking Sutent. His colleagues also pitch in to buy a month’s supply for him.supply for him.

− Two weeks later, bone marrow biopsy reveals a full remission.Two weeks later, bone marrow biopsy reveals a full remission.

ConclusionsConclusions

Primary care physicians must be familiar Primary care physicians must be familiar with the principles of genetics in order to:with the principles of genetics in order to:– Recognize genetic disease in their patients.Recognize genetic disease in their patients.– Provide effective health supervision for their Provide effective health supervision for their

patients with genetic disorders.patients with genetic disorders.– Answer patientsAnswer patients’’ questions about genetic vs. questions about genetic vs.

environmental factors in common diseases.environmental factors in common diseases.– Appropriately refer cases to clinical geneticists Appropriately refer cases to clinical geneticists

and genetic counselors for additional and genetic counselors for additional diagnostic evaluation.diagnostic evaluation.

ConclusionsConclusions

The fruits of the Human Genome Project and the The fruits of the Human Genome Project and the vast array of genetic testing available to vast array of genetic testing available to clinicians have greatly enhanced primary care clinicians have greatly enhanced primary care physiciansphysicians’’ ability to diagnose genetic disorders ability to diagnose genetic disorders and those disorders with a major genetic and those disorders with a major genetic predisposition.predisposition.

Genomic medicine is already being applied in Genomic medicine is already being applied in tumor-based screening, family history-oriented tumor-based screening, family history-oriented decision support, pharmacogenomics and decision support, pharmacogenomics and diagnostic genome sequencing.diagnostic genome sequencing.

BUT…this is only the beginning!BUT…this is only the beginning!

diving into the gene pool: genetics, genomics and primary care medical practice

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genetic disorderspractitioners

genetic testing

genetic effect

primary care medical

common diseases

nongenetic factors

study of complex diseases

patients symptoms