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-of-function 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, tumor-supressor 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

• 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

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

• 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 pre-symptom 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 for Predisposition to Disease

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 non-consensual 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