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 School of Medicine Universitat Autònoma de Barcelona Barcelona, Catalonia, Spain

Misconceptions about the use of genetic tests in populations Paolo Vineis, Paul Schulte, Anthony J McMichael THE LANCET Vol 357 March 3, 2001: Gene-environment interactions in cancer Holtzman NA, Marteau TM. Will genetics revolutionize medicine? N Engl J Med 2000; 343: N Engl J Med 2000; 343: (Correspondence)

Requires good functioning of health care system Strengthens population (real) screening Needs strong scientific evidence of effectiveness Needs usual strength of scientific evidence (“gray zones” persist) Signs, symptoms? NO Signs, symptoms? Often, YES (less so, no) NHS * invites individual Individual seeks help Population contextHealth care context Population screeningEarly clinical detection * National Health System

The “rules of the game” are different. Public health Clinical medicine Social impactIndividual impact Community ethicsIndividual ethics Population screeningEarly clinical detection

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:

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:

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. The NNS to prevent 1 case is   for low- penetrant polymorphisms and for highly- penetrant 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:

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

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. Penetrance depends on :

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.

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.

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 low- penetrant 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 low- penetrant 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 affects disease risk.

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.

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.

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.

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.

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.

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.

NNS: NUMBER NEEDED TO SCREEN to prevent 1 case

Number needed to screen for a low penetrant gene (GSTM1 in smokers), and a highly penetrant gene (BRCA1)

The principle of One Exposure, Many Diseases One Disease, Many Low-penetrant Genes

A. 1 Exposure  Many Diseases

B. 1 Disease Resulting From Low-penetrant Genes

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 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 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