Genetic screening for sporadic cancers and other diseases of complex etiology

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Genetic screeningfor sporadic cancersand other
diseases of complex etiology
School of MedicineUniversitat Autònoma de
BarcelonaBarcelona, Catalonia, Spain

• Miquel Porta, MD
• Institut Municipal dInvestigació Mèdica,
• Universitat Autònoma de Barcelona and
• University of North Carolina at Chapel Hill

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Misconceptions about the use of genetic tests
in populations Paolo Vineis, Paul Schulte,
Anthony J McMichael  THE LANCET Vol 357 March
3, 2001 709-712 Gene-environment interactions
in cancer Holtzman NA, Marteau TM. Will genetics
revolutionize medicine? N Engl J Med 2000 343
141-144 N Engl J Med 2000 343 1496-1498
(Correspondence)
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Population screening
Early clinical detection
Population context
Health care context
NHS invites individual
Individual seeks help
Signs, symptoms? NO
Signs, symptoms? Often, YES (less so, no)
Needs strong scientific evidence of effectiveness
Needs usual strength of scientific
evidence (gray zones persist)
Requires good functioning of health care system
Strengthens population (real) screening
National Health System
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Population screening
Early clinical detection
Community ethics
Individual ethics
Social impact
Individual impact
Clinical medicine
Public health
The rules of the game are different.
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Misconceptions about the use of genetic tests in
populations Paolo Vineis, Paul Schulte, Anthony J
McMichael  THE LANCET Vol 357 March 3, 2001
709-12

• The prospect of genetic screening for preventable
  or deferrable disease is becoming real. As the
  cataloguing of the human genome proceeds, the
  rate at which specific genes are being implicated
  in disease processes is increasing.
• Proposals to introduce genetic testing as a
  solution for common health problems abound.
• Claims for the potential benefits of genetic
  screening may be overstated.

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Misconceptions about the use of genetic tests in
populations Paolo Vineis, Paul Schulte, Anthony J
McMichael  THE LANCET Vol 357 March 3, 2001
709-12

• The relation between the frequency of a variant
  and its penetrance is almost inverse the more
  penetrant (i.e., deleterious) a mutation, the
  less frequent in the population.
• Gene-environment interactions are intrinsic to
  the mode of action of low-penetrant genes.

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• The relation between the frequency of a variant
  and its penetrance is almost inverse the more
  penetrant (i.e., deleterious) a mutation, the
  less frequent in the population.
• Gene-environment interactions are intrinsic to
  the mode of action of low-penetrant genes.

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Misconceptions about the use of genetic tests in
populations Paolo Vineis, Paul Schulte, Anthony J
McMichael  THE LANCET Vol 357 March 3, 2001
709-12

• The relation between the frequency of a variant
  and its penetrance is almost inverse the more
  penetrant (i.e., deleterious) a mutation, the
  less frequent in the population.
• Gene-environment interactions are intrinsic to
  the mode of action of low-penetrant genes.
• The NNS to prevent 1 case is ? ? for
  low-penetrant polymorphisms and for
  highly-penetrant mutations in the general
  population.

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Misconceptions about the use of genetic tests in
populations Paolo Vineis, Paul Schulte, Anthony J
McMichael  THE LANCET Vol 357 March 3, 2001
709-12

• Penetrance depends on at least 6 factors
• 1 importance of the function of the protein
  encoded by the gene (eg, in key metabolic
  pathways, in the cell cycle)
• 2 functional importance of the mutation (e.g.,
• a deletion vs. a mild loss of function due to
  a point mutation)

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Penetrance depends on

• 3 interaction with other genes.
• 4 onset of somatic mutations.
• 5 interaction with the environment.
• 6 existence of alternative pathways that can
  substitute for the loss of function.

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Genetic Penetrance Environmental Factors

• The relation between the frequency of a variant
  and its penetrance is almost inverse
• The more penetrant (i.e., deleterious) a
  mutation,
• the less frequently we expect to find it in the
  population although it may be concentrated in
  particular groups or families.

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Genetic Penetrance Environmental Factors

• Penetrance of a gene describes
• the frequency with which
• the characteristic it controls (phenotype)
• is seen in people who carry it.
• Single, highly-penetrant mutations
• in so-called cancer genes
• cause only a small proportion of cancers.
• Vogelstein B, Kinzler KW. The genetic basis of
  human cancer. New York McGraw-Hill, 1998.

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PENETRANCE EXPRESSIVITY

• PENETRANCE, the percentage of individuals with a
  particular genotype that display the genotype in
  the phenotype.
• e.g., a dominant gene for baldness is 100
  dominant in males and 0 penetrant in most
  females, because the gene requires high levels of
  the male hormone for expression.
• Once a gene shows penetrance it may show a range
  of expressivity of phenotype.

Hale WG, Margham JP. Biology. Collins reference
dictionary. London Glasgow Collins, 1988.
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PENETRANCE EXPRESSIVITY

• EXPRESSIVITY, the degree to which a particular
  gene exhibits itself in the phenotype of an
  organism, once it has undergone penetrance.
• e.g., a penetrant baldness gene in man
• can have a wide range of expressivity,
• from thinning hair to complete lack of hair.

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PENETRANCE EXPRESSIVITY

• PHENOTYPE, the observable features of an
  individual organism that resuly from an
  interaction between the genotype and the
  environment in which development occurs.
• Hale WG, Margham JP. Biology. Collins reference
  dictionary. London Glasgow Collins, 1988.

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NNS NUMBER NEEDED TO SCREEN to Prevent 1 Case.

• A reasonable (low) NNS is attained only by
  screening for highly-penetrant mutations in
  high-risk families, not for such mutations in the
  general population or for low-penetrant
  polymorphisms.

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NNS NUMBER NEEDED TO SCREEN to Prevent 1 Case.

• A reasonable (low) NNS is attained only by
  screening for highly-penetrant mutations in
  high-risk families, not for such mutations in the
  general population or for low-penetrant
  polymorphisms.

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Main Points - 1

• ? Both environmental and genetic factors play a
  part in complex diseases.
• ? The proportion of diseases attributable to
  low-penetrant genetic traits is probably much
  lower than the burden of disease attributable to
  certain environmental agents.
• ? To credit genes with a major independent role
  in the causes of complex diseases is scientific
  misjudgement of the way genetics affects disease
  risk.

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Main Points - 2

• ? To assess the role of a gene-environment
  interaction and screening in a population we need
  to know (1) the penetrance of the genetic trait
  and (2) its frequency. 
• ? Gene-environment interactions are intrinsic to
  the mode of action of low-penetrant genes.

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Main Points and 3

• ? A reasonable (low) NNS is attained only by
  screening for highly-penetrant mutations in
  high-risk families, not for such mutations in the
  general population or for low-penetrant
  polymorphisms.
• ? Cost-benefit analysis is urgently needed for
  screening for single-gene diseases versus
  multigenetic diseases, and for genes of low
  versus high penetrance.

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Genetic Testing or Exposure Reduction? - 1

• Elimination of a single environmental exposure
  (eg, smoking) would reduce a large proportion of
  chronic diseases.
• Genetic traits can have a different relation with
  disease people with the NAT2-slow genotype have
  an increased risk of bladder cancer, but a
  decreased risk of colon cancer.

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Genetic Testing or Exposure Reduction? - 1

• Elimination of a single environmental exposure
  (eg, smoking) would reduce a large proportion of
  chronic diseases.
• Genetic traits can have a different relation with
  disease people with the NAT2-slow genotype have
  an increased risk of bladder cancer, but a
  decreased risk of colon cancer.

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Genetic Testing or Exposure Reduction? - 2

• Exposures that cause one disease and protect
  against another are very few.
• For low-penetrant genes one disease/many
  genotypes.
• The population will usually contain very few
  individuals carrying several high-risk
  polymorphisms and a large proportion with a
  balance between high-risk and low-risk genotypes.

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Genetic Testing or Exposure Reduction? - 3

• Polymorphisms require exposure to environmental
  factors to be effective i.e., the 12.6
  proportion is attributable to interaction, not to
  the genetic trait itself.
•  Overall, the proportion of diseases attributable
  to low-penetrant genetic traits is clearly
  difficult to establish and is probably much lower
  than the burden of disease attributable to
  certain environmental agents.

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NNS NUMBER NEEDED TO SCREEN to prevent 1 case
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Number needed to screen for a low penetrant gene
(GSTM1 in smokers), and a highly penetrant gene
(BRCA1)
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The principle of One Exposure, Many Diseases
One Disease,Many Low-penetrant Genes
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A. 1 Exposure ? Many Diseases
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B. 1 Disease Resulting From Low-penetrant Genes
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The seduction power of Metaphors, 1

• The emphasis on genetic testing (which has a
  clear commercial motivation) is based on false
  metaphors of the role of DNA and genes.
• One common metaphor compares the gene to a
  computer program i.e., the gene is a set of
  instructions to reach a certain goal.
• However, a computer program merely executes the
  instructions, without changing them on the basis
  of context.
• In fact the relations between genotype and
  phenotype are much more complex than usually
  depicted in popular accounts.

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The seduction power of Metaphors, 2

• If the genome can be seen as a text or a script,
  then its phenotypic expression can be seen as a
  performance of that script,
• bringing the text to vibrant and unique life
• just as actors on a stage bring life to the words
  on a page.

Lewis J. The performance of a lifetime a
metaphor for the phenotype. Perspect Biol Med
1999 43 112127.
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The seduction power of Metaphors, 3a

• The genome nucleotide sequence is the score of a
  jazz composition.

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The seduction power of Metaphors, 3a

• The genome nucleotide sequence is the score of a
  jazz composition. First, the jazz musician learns
  how to read and to play the score, and does so
  embedded in a sociocultural environment, and
  grows with music and musicians and partners of
  all sorts.

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The seduction power of Metaphors, 3a

• The genome nucleotide sequence is the score of a
  jazz composition. First, the jazz musician learns
  how to read and to play the score, and does so
  embedded in a sociocultural environment, and
  grows with music and musicians and partners of
  all sorts. Though her endowment and talents
  count, so do her colleagues, experiences and
  intuition the result of such interaction is
  seldom predictable.

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The seduction power of Metaphors, 3b

• Then, all over her life she continues to learn
  to master technique certainly but above all, to
  express her emotions and ideas among the many
  treasures that music holds.

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The seduction power of Metaphors, 3b

• Then, all over her life she continues to learn
  to master technique certainly but above all, to
  express her emotions and ideas among the many
  treasures that music holds. The genome is thus
  like the innumerable scores that a jazz
  aficionado would play during all her life, some
  with great fidelity to the original musical text,
  many just but deeply inspired by it, still many
  others almost totally invented, whether
  improvised or consciously crafted.

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The seduction power of Metaphors, 3c

• Surely the music that she expresses stems from
  the scores (through a marvellously complex
  process) but well beyond technique and script,
  every instant the unique music expresses what the
  musician knows, feels and wishes to play.

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The seduction power of Metaphors, 3c

• Surely the music that she expresses stems from
  the scores (through a marvellously complex
  process) but well beyond technique and script,
  every instant the unique music expresses what the
  musician knows, feels and wishes to play. (Once,
  the origin of the music is a scent she smelled in
  infancy once, a recent love loss often the
  source code is unknown).

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The seduction power of Metaphors, 3d

• And the music grows and evolves with time and,
  much more, with the people and places where it
  swells and flows. Stemming from the score.
  Sensitive to the other musicians with whom she
  plays.

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The seduction power of Metaphors, 3d

• And the music grows and evolves with time and,
  much more, with the people and places where it
  swells and flows. Stemming from the score.
  Sensitive to the other musicians with whom she
  plays. Delicately responsive to the audiences to
  whom and with whom she feels, every time of her
  lifetime.

Miquel Porta The genome sequence is a jazz
score International Journal of Epidemiology 2003