Download Genetic screening

School of Medicine
Universitat Autònoma de Barcelona
Barcelona, Catalonia, Spain
Genetic screening
for sporadic cancers
and other diseases of complex etiology
Miquel Porta, MD
Institut Municipal d’Investigació Mèdica,
Universitat Autònoma de Barcelona and
University of North Carolina at Chapel Hill
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)
Early clinical detection
Population screening
Health care context
Population context
Individual seeks help
NHS* invites individual
Signs, symptoms?
Often, YES (less so, no)
Signs, symptoms?
NO
Needs usual strength of
scientific evidence
(“gray zones” persist)
Needs strong
scientific evidence
of effectiveness
Strengthens
population (real)
screening
Requires good
functioning of
health care system
*National Health System
Early clinical detection
Population screening
Individual ethics
Community ethics
Individual impact
Social impact
Clinical medicine
Public health
The “rules of the game”
are different.
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.
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 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.
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 lowpenetrant polymorphisms and for highlypenetrant mutations in the general population.
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
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.
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
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.
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.
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.
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.
NNS: NUMBER NEEDED TO SCREEN
to Prevent 1 Case.
A reasonable (low) NNS is attained
only by screening for highlypenetrant mutations in high-risk
families, not for such mutations in
the general population or for lowpenetrant polymorphisms.
NNS: NUMBER NEEDED TO SCREEN
to Prevent 1 Case.
A reasonable (low) NNS is attained
only by screening for highlypenetrant mutations in high-risk
families, not for such mutations in
the general population or for lowpenetrant polymorphisms.
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
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-
Main Points – and 3
 A reasonable (low) NNS is attained
only by screening for highlypenetrant mutations in high-risk
families, not for such mutations in
the general population or for lowpenetrant polymorphisms.
 Cost-benefit analysis is urgently
needed for screening for singlegene diseases versus multigenetic
diseases, and for genes of low
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
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
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
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
NNS: NUMBER NEEDED TO SCREEN to prevent 1 case
GENETIC
TRAIT
A
B
C
LOW- penetrant
and COMMON in
the GENERAL POPULATION
HIGHLY penetrant
and COMMON
in some FAMILIES
HIGHLY penetrant
and RARE in the
GENERAL POPULATION
13.8 per 100
50 per 100
0.16 per 100
58 per 100
58 per 100
same as B
Lifetime risk of
disease among
carriers
14 per 1,000
37 per 100
same as B
Risk reduction
14 * 0.58 = 8
8 per 1,000
14‰  6‰
37 * 0.58 = 21.5
21.5 per 100
37%  15.5%
same as B
NNT
1000 / 8 = 125
100 / 21.5 = 4.5
same as B
NNS
125 / 0.138 = 906
4.5 / 0.5 = 9
4.5 / 0.0016 = 2,813
Prevalence of
carriers
Identific.  risk
Number needed to screen for a low penetrant gene
(GSTM1 in smokers),
and a highly penetrant gene (BRCA1)
Disease
Population
Gene
Relative risk
Breast cancer
General
population
BRCA1
Families
BRCA1
Lung cancer
Smokers
Smokers
GSTM1 null GSTM1 wild
5
10
1.34
1.0
Cumulative risk
40%
80%
13%
10%
Risk reduction
Cumulative risk
after intervention
Absolute risk
reduction
50%
50%
50%
50%§
20%
40%
6.5%
5%
20%
40%
6.5%
5%
5
2.5
15
20
0.2%
50%
50%
50%
5
30
40
NNT
Frequency
NNS
NNS in all smokers
2,500
––
35
The principle of
One Exposure,
Many Diseases
One Disease,
Many Low-penetrant Genes
A. 1 Exposure  Many Diseases
Exposure
Disease
Proportion
attributable
to exposure
Tobacco smoke
Lung cancer
90%
Bladder cancer
70% (men)
30% (women)
Larynx cancer
90%
Coronary Heart D
12.5%
Chronic bronchitis
80%
B. 1 Disease Resulting From
Low-penetrant Genes
Disease
Low-penetrant Odds ratio
genes
Lung cancer
CYP1A1 Msp I
CYP1A1 exon 7
Bladder cancer
Colon cancer
CYP2D6
GSTM1
NAT-2 slow
GSTM1
NAT-2 rapid
1.73 (Asian)
1.04 (white)
2.25 (Asian)
1.30 (white)
1.26
1.34
1.37
1.57
1.19
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.
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
a page”.
Lewison
J. The
performance of a lifetime:
a metaphor for the phenotype.
Perspect Biol Med 1999; 43: 112–127.
The seduction power of
Metaphors, 3a
The genome nucleotide sequence is the
score of a jazz composition.
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.
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.
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 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.
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.
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).
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.
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