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 Health care context Individual seeks help Signs, symptoms? Often, YES (less so, no) Needs usual strength of scientific evidence (―gray zones‖ persist) Strengthens population (real) screening
Population screening Population context NHS* invites individual Signs, symptoms? NO Needs strong scientific evidence of effectiveness Requires good functioning of health care system
*National Health System
Early clinical detection
Population screening
Individual ethics Individual impact Clinical medicine
Community ethics Social impact 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 highly-
penetrant 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 highly-
penetrant 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
A
LOW- penetrant and COMMON in the GENERAL POPULATION
TRAIT
C
HIGHLY penetrant and RARE in the GENERAL POPULATION
B
HIGHLY penetrant and COMMON in some FAMILIES
Prevalence of carriers Identific. risk Lifetime risk of disease among carriers Risk reduction
13.8 per 100 58 per 100 14 per 1,000 14 * 0.58 = 8 8 per 1,000 14‰ 6‰ 1000 / 8 = 125 125 / 0.138 = 906
50 per 100 58 per 100 37 per 100
37 * 0.58 = 21.5 21.5 per 100 37% 15.5%
0.16 per 100 same as B same as B
same as B same as B 4.5 / 0.0016 = 2,813
NNT NNS
100 / 21.5 = 4.5 4.5 / 0.5 = 9
Number needed to screen for a low penetrant gene (GSTM1 in smokers), and a highly penetrant gene (BRCA1)
Disease Population
Gene
Relative risk Cumulative risk Risk reduction Cumulative risk after intervention Absolute risk reduction NNT Frequency NNS NNS in all smokers
Breast cancer
General population BRCA1 5 40% 50% 20% 20% 5 0.2% 2,500 –– Families BRCA1 10 80% 50% 40% 40% 2.5 50% 5
Lung cancer
Smokers Smokers GSTM1 null GSTM1 wild 1.34 13% 50% 6.5% 6.5% 15 50% 30 35 1.0 10% 50%§ 5% 5% 20 50% 40
The principle of
One Exposure, Many Diseases One Disease, Many Low-penetrant Genes
A. 1 Exposure Many Diseases
Exposure Disease
Proportion attributable to exposure
90% 70% (men) 30% (women) 90% 12.5% 80%
Tobacco smoke
Lung cancer Bladder cancer Larynx cancer Coronary Heart D Chronic bronchitis
B. 1 Disease Resulting From Low-penetrant Genes
Disease
Lung cancer
Low-penetrant Odds ratio genes
CYP1A1 Msp I CYP1A1 exon 7 CYP2D6 GSTM1 NAT-2 slow GSTM1 NAT-2 rapid 1.73 1.04 2.25 1.30 1.26 1.34 1.37 1.57 1.19 (Asian) (white) (Asian) (white)
Bladder cancer Colon cancer
The seduction power of Metaphors, genetic testing (which has a 1 The emphasis on
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 on a page‖.
Lewis 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 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, 3a
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.
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, 3b
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