Transcript Unit 5: Ethical Issues in Genetics

Unit 5: Cancer Genomics and
Ethical Issues in Genetics
5 days
November 25:
• Cancer Genetics and
Genomics
Cancer Genomics
• Cancer accounts for more than 20% of all
deaths
• Strikes more than a third of the population
• Accounts for more than 10% of all medical
costs
Cancer Genomics
• Molecular genetic studies demonstrate
that cancer is fundamentally a genetic
disease
• Also, cancer is not a single disease, but
rather a term to describe the more
aggressive forms of neoplasia
– Disease process characterized by
uncontrolled cellular proliferation
– Leads to formation of a neoplasm (mass or
tumor)
Cancer Genomics
• When a neoplasm becomes malignant its
growth is no longer controlled
• The tumor becomes capable of invading
neighbor tissues
• It can also metastasize (spread to more
distant sites)
• If a tumor is not malignant, it is benign and
not considered cancerous
Three Main Forms of Cancer
• Sarcomas
– Tumor arises in mesenchymal tissues such as
bone, muscle, or connective tissues
– Tumor arises in nervous tissue
• Carcinomas
– Originate in epithelial tissues such as intestine
lining, bronchi, or mammary ducts
• Hematopoietic and Lymphoid
– Arise in bone marrow, lymphatic system, and
peripheral blood
Classification
• Tumors are classified by site, tissue type,
histological appearance, and degree of malignancy
Oncogenesis
• The development of cancer results from
mutations in one or more genes that
regulate cell growth or programmed cell
death
Oncogenesis
• Cancer can come from a hereditary cancer
syndrome
• The gene mutation responsible is inherited
• Most cancers however are sporadic, and
arise in a single somatic cell
Oncogenesis
• Many cancers have been traced to specific
genes with Mendelian inheritance
• Others have no specific Mendelian
pattern, but family members have an
increased risk of also developing cancers
– Indicates complex inheritance traits combined
with environmental factors
November 26:
• Oncogenes
– A mutant gene whose altered function or
expression results in abnormal stimulation of
cell division and proliferation
Oncogenes
• The mutation can be an activating gain-offunction mutation in the coding sequence
of the gene itself
• It could be a mutation in its regulatory
elements
• It could be an increase in its genomic copy
number, which lead to heterochronic or
ectopic function
Oncogenes
• Often a single mutant allele is enough to cause a
malignancy
• It therefore has a dominant effect
Oncogenes
Tumor-Suppressor Genes
• Rather than promoting cancer formation
like mutations in oncogenes, tumorsupressor gene mutations can be
responsible for malignancy by a different
mechanism
– This is the loss of function of both alleles of
the gene
Tumor-Suppressor Genes
• TSG’s are highly heterogenous
• They suppress tumors by regulating the
cell cycle or by causing inhibition of growth
through cell-to-cell contact
• TSG’s regulate cell growth directly
Retinoblastoma
• This is the prototype
disease for TSG
mutations
• It is rare, and
malignant
• About 1 in 20,000
incidence
• Tumor of the retina in
infants
Retinoblastoma
• Typically diagnosis results in the removal
of the affected eye
• If the tumors are small, they can
occasionally be treated, so that vision is
preserved
Retinoblastoma
Retinoblastoma
• About 40% of cases are of a heritable form
• The child typically inherits one mutation
from a parental germline
• The second mutation happens in a
somatic cell, or the cell is altered in some
other manner
• This leads to inactivation of the normal
allele
Retinoblastoma
• A tumor then develops
• The disorder is inherited as a dominant
trait because there are a large number of
primordial retinoblasts
• They also have a rapid proliferation rate
– Means it is highly likely that a somatic
mutation will occur
Retinoblastoma
• Often people are affected with multiple
tumors
• Often both eyes are affected
• However, there is still a component of
chance, and some people never have a
somatic mutation event occur
• Penetrance is very high – but not complete
Retinoblastoma
• The remaining 60% of cases are sporadic
• Meaning 2 sporadic mutation events occur
• Typically this only occurs in one location
– 15% of people with unilateral retinoblastoma
actually have the heritable form, but by
chance only have it affecting one eye
Retinoblastoma
• The sporadic form typically presents itself
later than the heritable form
– Early childhood rather than infancy
Heritable vs. Sporadic
Which form?
Which form?
December 2:
• Ethical Issues in Medicine
Medical Ethics
• Human genetics has already had a huge
effect in many areas of medicine:
– Prenatal and pre-implantation diagnosis
– Personalized medicine
– Risk assessment
– Genetic counseling
Medical Ethics
• Many of these medicinal breakthroughs
also have led to ethical issues
• It is the job of the doctor or health
professional to maintain a personal and a
professional sense of ethics
Four Cardinal Principles
• Respect for individual
autonomy
– Safeguarding an
individual’s rights to
control his or her
medical care free of
coercion
Four Cardinal Principles
• Beneficence
– Doing good for the
patient
Four Cardinal Principles
• Avoidance of maleficence
– “first of all, do no harm”
– Hippocratic Oath
Four Cardinal Principles
• Justice
– Ensuring that all individuals are treated
equally and fairly
Medical Ethics
• When one or more of these principles are
in conflict with each other, major ethical
dilemmas arise
• The job of ethicists working with society
and medical genetics, is to weigh and
balance conflicting demands
– Each of the demands may have a claim to
legitimacy, based on one or more of the
cardinal principals
Medical Ethics
• Many ethical issues arising with
regards to genetics are interlinked,
and often need to be looked at
together, since they are
not able to be examined
independently
Prenatal Genetic Testing
• Geneticists are frequently asked
to help couples use prenatal
diagnosis or assisted
reproductive technology to
avoid having offspring
with serious hereditary
disorders
Prenatal Genetic Testing
• For some disorders, prenatal diagnosis is
controversial, especially when diagnosis
frequently leads to a decision to terminate
the pregnancy
• In the case of Tay-Sachs disease, more
people accept prenatal screening
• When a disorder is NOT an untreatable
fatal disease of infancy, the area is more
grey
Prenatal Genetic Testing
• The debate rages in the communities of
disabled, mentally retarded, and deaf
individuals and their families
• The question of whether prenatal
diagnosis and potential abortion for these
disorders is justified
Prenatal Genetic Testing
• The ethical dilemma comes between an
attempt to balance respect for the parent’s
autonomy of reproductive decision making
and an assessment of whether aborting a
fetus with a disability compatible with life is
fair to the fetus or the broader community
Prenatal Genetic Testing
• The dilemma also arises when parents
make a request for a prenatal diagnosis in
a pregnancy that is at risk for what most
people do NOT consider a disease or
disability
Prenatal Genetic Testing
• The motivation might be to avoid a recurrence of
a disorder associated with a mild or cosmetic
defect
• It could also be for
selection of sex
Prenatal Genetic Testing
• In general, gender selection is only widely
accepted for the avoidance of X-linked
disorders
• The concern is that many parents are
using sex selection techniques to balance
the genders of children in their families, or
for social and economic reasons prevalent
in their societies
Prenatal Genetic Testing
• In the future particular alleles and genes
that contribute to complex traits such as
intelligence, personality, stature, and other
physical characteristics may be known
• Will these non-medical criteria be viewed
as acceptable for prenatal diagnosis?
Prenatal Genetic Testing
• Parents already
expend enormous
amounts of energy
improving the
environmental factors
for their children
• Why shouldn’t they be
allowed to improve
the genetic factors as
well?
Prenatal Genetic Testing
• Should a physician have the right
to decide for parents when a trait
or disorder is not serious enough
to warrant the termination of a
pregnancy?
December 3:
• Ethical Issues in
Medicine continued
Testing for Predisposition to
Disease
• Another area in which ethical dilemmas frequently
arise is the genetic testing of asymptomatic
individuals for diseases that may have an onset
later in life
Testing for Predisposition to Disease
• The conflicting ethical issues are
autonomy and beneficence
• A good example is Huntington’s Disease
– Late in life onset
– Degenerative
– Not curable
– Highly penetrant
Testing for Predisposition to
Disease
• Is knowing that you have Huntington’s Disease
early on more beneficial than harmful?
Or vice versa?
• There is no simple answer
Testing for Predisposition to Disease
• Studies show that some individuals would
rather know, and choose to receive testing
• Other individuals choose not to be tested
Testing for Predisposition to Disease
• Many people who test positive have a
transient period of depression
• A few suffer severe depression
• Many report the positive benefits of using
this information to make life choices
regarding marriage, procreation, and
career choice
Testing for Predisposition to Disease
• Many who test negative report positive
benefits of relief
• Some also experience guilt over not
needing to worry about a disorder that
affects or may affect many of their close
relatives
Testing for Predisposition to Disease
• Other questionable genes for presymptom testing include:
– APOE for Alzheimer’s
– BRCA1 and BRCA2 for breast and ovarian
cancers
• Does the availability of treatment change
the ethics behind early identification?
Testing Asymptomatic Children
• Additional ethical issues arise when
children are involved
• An added layer of complexity comes from
having to accommodate the ethical needs
and rights of both the child and the parent
Testing Asymptomatic Children
• Many times siblings of children with
disorders are tested
• Many argue that it is the parent’s job to
know and prepare their child for a future
with disease
Testing Asymptomatic Children
• Testing children carries the same risks of
psychological damage as it does with
adults
• It can also lead to stigmatization, as well
as insurance and employment
discrimination in the future
Testing Asymptomatic Children
• Most bioethicists feel that in cases where
there is no direct benefit for the child, and
the child is asymptomatic, the genetic
testing should be put off until the child has
reach a level of maturity to decide for
themselves
Duty and Permission to Warn
• A patient’s desire to have his or her
medical information kept confidential is
one aspect of patient autonomy
• Patient’s have a right to decide how and if
their medical information is communicated
to others
Duty and Permission to Warn
• Genetics however is concerned with both
the patient and the family
• A major ethical and legal dilemma arises
when a patient insists that their medical
information be kept private, but that
information could dramatically affect the
health of their relatives and children
Duty and Permission to Warn
• In the situation is the genetics practitioner
obligated to keep the information private
(autonomy) or is the practitioner obligated to
warn the family members (duty to warn)?
Duty and Permission to Warn
• Is telling the patient to inform their family
sufficient to alleviate the practitioner’s
obligation to warn?
• Or is the practitioner allowed to inform the
relatives without authorization (permission
to warn)?
Duty and Permission to Warn
• Guidelines from international health
organizations, individual national health
policy groups, and professional medical
organizations are not unanimous on this
issue
• Case law derived from lawsuits are also
not consistent with legislative and
regulative mandates (particularly HIPAA)
Duty and Permission to Warn
• The precedent-setting case involved the
murder of a young woman, and a
psychiatrist found negligent because he
did not take any measure to warn her, or
local police authorities, that one of his
patients had declared an intention to kill
her
Duty and Permission to Warn
• A court in New Jersey decided that a
physician had a duty to warn the daughter
of a man with familial adenomatous
polyposis (risk of colon cancer)
• “There is no essential difference between
the type of genetic threat at issue here and
the menace of infection, contagion, or a
threat of physical harm.”
Duty and Permission to Warn
• The court also found that simply telling the patient
that they needed to disclose the information was
not sufficient
December 9:
• Ethical Issues in Medicine continued
Employers and Insurers
• Justice is a major area of concern in
regards to genetic diagnosis and
insurance eligibility or employment
opportunities
Employers and Insurers
• Is it fair to penalize people who, through
no fault of their own, are found to carry a
genetic predisposition to disease?
• Should employers be able to access
genetic data to help them make hiring
decisions, and increase their likelihood of
getting dependable individuals with lower
potential for absenteeism?
Employers and Insurers
• In particular, small business owners who
fund their employees health plans may go
bankrupt if they hire someone with a major
disorder that requires expensive treatment
• Should they have access to this
information prior to hiring?
Employers and Insurers
• Similarly, life insurance companies
calculate premiums based on all available
information
• They argue that they should have access
to all information that the patient is privy to
Employers and Insurers
• Premiums do not cover instances where
the person has concealed preexisting
conditions
• Doing this is called Adverse Selection
• If adverse selection was widespread then
insurance premiums would have to
increase for the entire population
Employers and Insurers
• It was shown that individuals who tested
positive for the APOE allele that indicates
a likelihood of developing Alzheimer’s
were nearly six times more likely to
purchase extra long-term care insurance
• There is no evidence that insurance
companies have ever participated in
genetic discrimination, but the fear has led
to proposals to ban the use of genetic
information
Employers and Insurers
• In the U.K. insurance companies have
voluntarily agreed to not use genetic
information except in the case of large
policies and Huntington’s Disease
– For which disclosure by the patient is required
• Can the insurance company require a
person to get tested?
Employers and Insurers
• Health insurance companies in the U.S.
already obtain medical histories, family
histories, and current phenotypic exam
results
• Is genetic testing different? Why?
Employers and Insurers
• HIPAA regulations specify that genetic
susceptibility without a current diagnosis of
illness cannot be considered a preexisting
condition – for which coverage can be
denied or premiums raised
• This concern over preexisting prejudice is
obviously not an issue in countries which
provide universal healthcare
Employers and Insurers
• Although the ultimate objective of genetic
screening is to improve public health,
there may also be unintended negative
consequences
• Stigmatization, adverse psychological
consequences, and discrimination are the
major concerns
Employers and Insurers
• Once widespread screening programs are
put into effect, how will we regulate that
the DNA is not later used for other nonconsensual purposes?
Eugenics
• The term eugenics was
introduced by Francis
Galton (Darwin’s cousin)
in 1883
• It refers to the
improvement of a
population by selecting
only its ‘best’ specimens
for breeding
Eugenics
• Plant and animal breeders have been
doing this since ancient times
• In the late 19th century Galton and other
scientists began promoting this practice to
improve the human species
Eugenics
• The ideal qualities that the eugenics
movement advocated spreading were
defined by social, ethnic, and economic
prejudices
• They were often fed by anti-immigration
and racist sentiments
Eugenics
• What we would consider now a lack of
education was then considered ‘familial
feeblemindedness’
• What is now rural poverty was called
‘hereditary shiftlessness’
• The lines between nature and nurture
were even grayer than they are today
Eugenics
• Eugenics was largely discredited when it
was used by the Nazis as justification for
genocide
• In North America and Europe, however,
involuntary sterilization was carried out on
institutionalized individuals deemed
incompetent or retarded
– This continued for many years after the Nazi
regime was destroyed
Dysgenics
• The opposite of eugenics is dysgenics
– The deterioration in the health and well being
of a population through practices that allow
the accumulation of deleterious alleles
• In the case of some single gene defects,
medical treatment has a dysgenic effect
– Selection against the gene is reduced, and it
is therefore proliferated throughout the
population
Dysgenics
Dysgenics
• For instance, if a treatment for DMD was
achieved, then males would potentially live
long enough to transmit DMD genes to
their daughters
• This would greatly increase the incidence
of carriers
Dysgenics
• As prenatal testing improves the termination of
pregnancies in which the fetus has inherited a
genetic defect may become more common
• This would obviously have an effect on the
prevalence of these alleles in the population
Dysgenics
• Genetic disease will never entirely go
away, due to new mutations and complex
inheritance patterns that may involve
environmental factors