Transcript

DAVID THOMAS: I don’t think it’s quite like every other area of medicine, and we’re going to have to evolve at a legislative and ethical and social level and have more debate about how we, as a society, want to deal with that information. It’s so profound that I don’t think there’s an area of society that it doesn’t in some way touch.

MIC CAVAZZINI: Welcome to Pomegranate Health, a podcast about the culture of medicine. I’m Mic Cavazzini for the Royal Australasian College of Physicians.

If you’re relatively new to the podcast, you probably haven’t trawled all the way through the archive, that now goes back more than ten years. So, I thought I would do what a lot of other popular shows do and republish episodes from the back catalogue that have stood the test of time.

I’m calling this Pomegranate REWIND, and the first throwback takes us to 2017. Episodes 20 and 21 were titled Genomics for the Generalist, a topic that had been suggested by a member of the CPD committee who recognised that this was a huge and confusing field for a general physician to stay on top of. While there’s been a flood of genomic discoveries since this story was first published, it’s still a good primer on fundamental concepts and everyday challenges for the physician.

Some of you will remember the fanfare in April 2003 around the completion of the Human Genome Project, a mammoth collaboration of 23 labs over 13 years that cost about three billion dollars in total. In fact, researchers only got 92% of the way, as the technology of the day allowed them to decode only what’s known as euchromatin, the so-called “open chromatin” that is accessible to transcription machinery and usually makes up gene sequences. There were still as many as 400 gaps in the sequence from areas of tightly wound heterochromatin also known as “silent-DNA” which were filled in only in 19 years later.

On March 31, 2022, the Telomere-to-Telomere consortium announced that they had produced the first truly complete human genome sequence. These days we understand a lot more about the importance of non-coding DNA for the targeting and timing of gene expression. 

And now a person's DNA can be sequenced in two weeks by a single lab. New disease markers are being identified all the time and as the research creeps along some of these lead to molecular targets for therapy. A new era in 'precision medicine' is certainly upon us, but the episode I’m replaying today only covers the principles of genome screening and the ethical minefield that comes with that. For example, what do you do if you uncover a genetic risk that a person wasn’t looking for, or disease that doesn’t have a treatment?

My guests have moved onto different roles since I first spoke to them so modern Mic will chime at some points with an updated studio narration. Otherwise, please forgive 2017 Mic for his very earnest tone more suited to a 60 Minutes inverstigation. To start with some first principles about gene-screening here’s Genetic Pathologist Leslie Burnett who at the time was CMO of the Genome One clinical sequencing facility at the Garvan Institute of Medical Research. He is now a Conjoint Professor with the UNSW School of Clinical Medicine and consults for Virtus Health.

LESLIE BURNETT: 20,000 genes in the human genome: we don’t know the function of all of those. So far we have a Mendelian base of about a third of them. Round about the 6,000 out of 20,000, we have a phenotype for which molecular basis is known, and probably we’ve found the relationship between the gene and the condition in half of those.

MIC CAVAZZINI: Mendelian conditions are those phenotypes that can be linked to a change in a single-gene, and whose inheritance can be traced through a family pedigree. One familiar example is cystic fibrosis, a disease that affects the lung mucosa. Those patients who have access to daily medical and physical therapy often survive childhood, but to a predicted life span of only 37 years.

The CFTR gene underlying cystic fibrosis was cloned in 1988, and targeted testing for mutations soon followed. There are hundreds of known mutations in this gene, the most common of which is so drastic that it stops the protein from ever folding into its functional shape. But clinical geneticist Michael Gabbett explains how outcomes can be drastically improved in individuals who carry a more subtle variant. I’m adding this note in 2026. Michael Gabbett is an Associate Professor at the Queensland University of Technology and consults privately through Mendel Genetics, though at the time of the original interview he was a staff specialist at the Royal Brisbane and Women’s Hospital.

MICHAEL GABBETT: So there’s a number of mutations, over a thousand in the CFTR gene, which lead to dysfunction and cause cystic fibrosis. Now, one of the more common mutations is one called G551D. This means that an individual produces the CFTR protein, just the protein doesn’t work quite as well as it does normally, and there’s medication which is now available to help that protein work better. So, if you find that someone has cystic fibrosis due to a G551D then that certainly changes management. It’s a bit of a success story in recent years.

MIC CAVAZZINI: Cystic fibrosis is a recessive condition, meaning that a mutant variant or allele must be inherited from both parents for an individual to express the phenotype. In people that carry only one mutant allele, the normal copy generates enough functional protein to mask the effects of the mutation. However, some genes are so critical to a molecular pathway that a mutation in even one allele of the pair is pathogenic. These are known as dominant conditions—Huntington's disease being the classic example. Testing for many Mendelian conditions has been going on for decades, but more and more conditions have been described which cannot be resolved by a single-gene analysis.

LESLIE BURNETT: So, if you know what you’re looking for, you know a condition is caused by one gene—you look at the one gene. But increasingly, conditions are known to have a number of genes that may influence them. It may be a pathway where different parts of the pathway can be affected, it may be a condition where a number of contributing genes. So one bundles different groups of genes together into commonly-requested combinations and that’s basically a panel. You can buy off-the-shelf now a number of commercial kits that will do the most frequently requested genetic tests and simple panels. If you find your answer, great.

The second approach would be that if you drew a blank on the narrow panel you might look at an extended panel; these are genes that there’s a looser association or a looser correlation, the causation is less clear. And then you’ve got the third approach which is to look at the whole genome, and it may be more convenient for the patient, simpler for the diagnosis, faster, cheaper, to look at the collection of genes and look at it in one go.

MIC CAVAZZINI: The technique of exome sequencing involves pulling out only those regions that code for protein, which makes up one percent of the entire genome. But 70 per cent of the genome is actually transcribed to RNA, and it appears much of this is involved in regulating the timing and location of gene expression. Therefore, whole genome sequencing is used to process almost every strip of DNA—but you still need to choose which of the 20,000 genes to focus on in the bioinformatic analysis. The advantage of collecting all the data in one go is that you’re then able to reassess different panels of genes with each new diagnostic hypothesis. It's also much easier to adjust an analytic panel to the latest research findings than it is to develop a new sequencing array and have it validated for clinical use.

LESLIE BURNETT: So, we are starting by focusing on assisting with the diagnosis of rare or difficult-to-diagnose conditions that are suspected to be genetic but have, because of lack of knowledge, not yielded to the application of traditional genetic testing. Sometimes you may have 10 or 20 or 50 or 100 genes that may be involved. You can do it all in one go. Or you may want to do it once, and reinterrogate over time. So the beauty about the whole genome approach is you can actually apply, almost hypothesis-free, you can find diagnoses that weren’t suspected or weren’t even discovered at that point and yet being able to produce a diagnosis.

One of our early cases that was referred to us was the case of a young child who appeared to have some form of immune disorder, such that their platelet levels were falling and the child was extremely ill. And so we sequenced the child and other family members and we were able to find that indeed there was a fault in a plausible gene that might explain this condition. But what was interesting is that this gene lay on a pathway for which there was a medication available—but not for this particular presentation, but rather a quite different medical condition. So the clinicians decided that it was ethically defensible to apply for permission to apply this medication and the child left ICU to watch the opening of Star Wars only some two weeks later. And I think that’s one of the remarkable success stories and our dream, it was almost our very first patient coming through.

MICHAEL GABBETT: Paediatrics is probably where a lot of the clinical genetics grew up in. It’s not all about genetic testing; so there is clinical acumen involved as well. So, we do have children that walk through the door and they have a pattern of facial features that you recognise, and if you’ve got a very well-defined clinical phenotype and there are a number of genes associated with that phenotype then that might be all you look at. Certainly if there is no obvious condition apparent then there are, I guess, what you could consider screening tests. The literature says we’re probably getting a diagnosis, say, 25 per cent of the time if they come through the door cold. But the things I see are rare and esoteric; we’re talking about conditions where there are only a handful reported in the world. Having said that, I’ve certainly witnessed conditions where they’ve previously been unreported and a colleague has described it and then all of a sudden they sort of fall out of the sky and everyone else starts to recognise it.

MIC CAVAZZINI: Some developmental conditions result from incorrect replication of chromosomes in the gametes, and are easy to detect by techniques such as karyotyping or fluorescence in situ hybridisation. Examples include Turner syndrome and the microdeletion syndromes. But even where diagnosis of a genetic condition doesn’t lead to treatment for a given paediatric patient, the benefit to the family can be tremendous, says Associate Professor Kristine Barlowe-Stewart, Director of the Master of Genetic Counselling program at the University of Sydney.

KRISTINE BARLOWE-STEWART: I’m sure you’ve heard about genomics ending the diagnostic odyssey. What parents want is an answer. They need to know, “Did I do this to my child? Was it my fault? Was it something that I did in pregnancy?” And so, having a genetic diagnosis relieves that guilt, that blame that was often there. So, it’s important for a whole lot of reasons, it can affect how they feel about themselves and their family.

MICHAEL GABBETT: The prenatal question, that’s one of the big questions we’re asked, what’s the chance of this happening again if this couple were to have another child? I guess from a medical point of view it’s important to give people answers, give them a sense of owning their own destiny in a way, empowering people to plan for their future. Now for some couples that’s not an issue, they’re quite happy, and if fate affords them another child with a developmental disability they’re not that fussed on necessarily getting an answer.

KRISTINE BARLOWE-STEWART: The ideal, of course, is preconception screening—what we’ve done in the Jewish community with the high school program; I’ve been involved in that since 1995. You know, there has been no child born with Tay-Sachs Disease in Australia to any couple screened.

And so, you know, we would really encourage taking a greater, more in-depth family history and updating it as well. But many of these recessive conditions like cystic fibrosis there is no family history, so asking about ancestry is very important. Like with Tay-Sachs, like the whole range of other conditions that are common in the Jewish community. If you’re of Caucasian background then testing for cystic fibrosis would be appropriate. If you are of Mediterranean, Southeast Asian, Chinese, then thalassemia screening is very important as well.

MIC CAVAZZINI: The entire genome is about 3 billion nucleotides bases long, and any two individuals differ from each other at one position in a thousand. To study the sequence genome the lab starts by breaking the chromosomes down into fragments of a few hundred kilobases that can be read with consistency by the biochemical reagents. The computational challenge is to put the snippets back together like a colossal jigsaw puzzle.

There are many stages in the process where errors can be introduced, and the Genome One facility is only the second in the world that has been accredited to meet the national standards of a clinical pathology service. It’s an impossible task for a single person to be on top of all the latest advances in the technology and the genetic research. Oncologist David Thomas explains what the general physician need consider during a consultation that might require genetic testing. Update for 2026, Professor Thomas is inaugural Director for the Centre for Molecular Oncology at the University of New South Wales.

DAVID THOMAS: So, my name is David Thomas. I’m Director of the Kinghorn Cancer Centre, I’m Head of the Cancer Division of the Garvan. I’m a medical oncologist with a specific interest in the applications of genomics to cancer care.

So, I imagine that the average physician needs to be able to separate out the conventional from the unconventional and then where to go when it gets unconventional. And that’s about referral patterns. And the vast majority of things will be canonical and, you know, there’ll be Stage 1 breast cancer which needs a surgeon and it needs chemotherapy to reduce the chance of the tumours coming back, and that will be perfectly standard.

It’s when the woman comes back the third time with advanced disease and you need to understand, now that the chemotherapy has stopped working, which test do you perform, what does it mean when you get the results and what do you do next? It’s about knowing who to go to who may have a specialist interest and provide advice. And I mean that’s part and parcel of clinical practice, I guess.

MICHAEL GABBETT: The generalist is I guess the phenotyper, so the most important job is: “Look, I think this is a genetic condition, these are the features. There might be a differential diagnosis; could you do a genetic test?” And that’s where, increasingly, genetic pathologists and clinical geneticists can help send the DNA off to the right lab and know what’s available locally or internationally, what’s the cheapest test, what the implications of a test may mean for other family members.

Genetics obviously involves your whole body; you can’t hold that knowledge in your head on every single genetic disorder. A lot of what we do is work with organ-specific specialists. Now, you’re not expecting your average specialist to be reading Nature Genetics, of course, but specialists will learn about these discoveries in the following year or two and they bring this knowledge to the genetics clinic. You often find that in the larger units that clinical geneticists do take up special interests. Two of my colleagues, one’s interested in cardiac genetics and one’s interested in renal genetics, and it’s not uncommon for us to get on the email and email the world expert on X, Y or Z for their opinion.

KRISTINE BARLOWE-STEWART: But people still see their doctor as the one to go, they want to talk to someone. And so we have to make sure that the doctors that they go to see can answer the questions they will increasingly ask. And the genetic counsellors are going to be pivotal in liaising with non-genetic specialist health professionals.

So, I founded the Centre for Genetics Education and on the website is every genetic service in Australia and New Zealand. The Human Genetics Society of Australasia also. Some states in Australia have a sort of a hub model and they would fly out to do clinics. And there are three main hubs in New Zealand, two in the South Island and one in the North. New South Wales has always been a bit different, in that we have genetic services in a lot of the major hospitals, but there is a huge workforce shortage.

MIC CAVAZZINI: Another outcome of next generation genomics is precision medicine—the idea that drug or lifestyle interventions could be tailored to a person’s particular gene profile. For example, blood-pressure lowering medications like ACE inhibitors are less effective in people that carry mutations in the renin-angiotensin-aldosterone pathway. And allopurinol therapy for gout can actually cause adverse cutaneous reactions in those that carry a variant of the HLA-B gene, common to East Asian populations. David Thomas explains how pharmacogenomics could be used to find more appropriate medications.

DAVID THOMAS: So there’s certainly lots of examples where a drug’s response or efficacy will be determined by a genetic background and differ between populations. Another example of a drug reaction is the gene dihydropyrimidine dehydrogenase, which is important in metabolism of the drug 5-fluorouracil—which is a 40, 50-year-old chemotherapy used frequently in, for example, bowel cancer. And people who have got mutations in that gene have really dire, life-threatening side-effects to a drug which is generally innocuous. So you could imagine that in some future if we all have whole genomes at birth, that the clinician who had that information for every patient on their computer would say, “I need to treat somebody with hypertension.” You would then get an alert that comes up saying, “This person has a variant and the renin-angiotensin pathway which makes them resistant to this particular drug. Use drug X instead.”

MIC CAVAZZINI: Genetic Pathologist Leslie Burnett, once more:

LESLIE BURNETT: And certainly we will be very keen to explore the move from curative or treatment to preventive medicine—well, it’s already happening now that a number of people are having the genome sequence at some point early in life, and we would imagine that somewhere between one and five per cent of the population will be carrying some variant that is going to potentially put them at increased risk of a condition they might otherwise not have been aware of, and so those patients will be able—well, not patients yet—those referrers potentially could become patients at that point and might be able to be offered early monitoring or early intervention so they never will actually get those conditions. And that is, I think, one of the enormous potentials yet to be explored. Then having the extraordinary tool of having one’s genome and being able to re-interrogate it, it really opens one’s eyes to the possibilities of what may be done down the track. Some of this is hype and some of this is prediction and some is reality, and I’m sure the future is not as far in the future as many of us would think it might be.

KRISTINE BARLOWE-STEWART: Of course, if you find a hereditary cancer then who looks after the unaffected relatives? That is a big issue in terms of health delivery. Physicians, GPs, other specialists, they’ve got sick people in their waiting rooms. You’ve got a well woman coming in. Will they want to see them? That’s the ripple effect in terms of health delivery.

MIC CAVAZZINI: One concern about handing out genetic diagnoses to otherwise health people is the anxiety conveyed by such a verdict. Genetic counsellor Kristine Barlowe-Stewart explains how one might guide a patient through this.

KRISTINE BARLOWE-STEWART: People certainly are affected psychologically in the short term, but that does not last—for the vast majority, 12 months later people have incorporated that information into their lives. And as part of genetic counselling we make sure that people are as well prepared psychologically for this information as they can be. And we then support them and we’ll refer them for extra assistance. But the bottom line is the pre-test preparation is so important. You’ve got to manage expectations, prepare them for uncertainty, prepare them for unexpected findings, prepare them for no answer.

MIC CAVAZZINI: And does that message, that pre-test message that you give, change very much depending on the condition they’re interested in and whether it’s treatable or not?

KRISTINE BARLOWE-STEWART: Yes. If it’s treatable the interest in it is higher, but that doesn’t mean to say that people still won’t want to know even if it’s not treatable, because people like to prepare their lives. When the test for Huntington’s disease, when we first isolated that gene and it was possible to test for it, 60 per cent of people on average said, “Yes, I want it.” Only about 20 per cent of people turned up to have it. But some people turned up years later, after they’d thought about. So you cannot look at a person and say they will or they won’t.

MIC CAVAZZINI: And as a counsellor you’re agnostic about what the best strategy for wellbeing and psychological preparation is. You can’t say what is the best approach?

KRISTINE BARLOWE-STEWART: No, you can’t. It’s called patient-centred counselling. You just work with a patient in front of you, walk alongside them.

MIC CAVAZZINI: Whole genome sequencing is not directly funded on either side of the Tasman. Australia’s MBS only lists specific tests for haemochromatosis, Factor V Leiden thrombophilia, protein C or S deficiencies, and antithrombin 3 deficiency. As well as diagnostic testing of a patient, screening of a first-degree relative is also permitted. In New Zealand, the Genetic Health Service is federally funded, and will assess referrals for a much broader range of conditions. Michael Gabbett describes the comparative costs of analysing gene panels from a whole genome sequence.

MIC CAVAZZINI: Since this story was first published, the number of gene screening tests subsidised by Australia’s Medical Benefits Schedule, or Pharmac in New Zealand, has greatly expanded. The MBS now covers gene panels for known drivers of familial melanoma, lung cancer, colorectal cancer, the BRCA breast cancer mutations, the cystic fibrosis transmembrane conductance regulator, Alport syndrome and familial Hypercholesterolemia. Not just patients, but first degree relatives are also usually covered. And even whole Exome Sequencing is funded for children diagnosed with intellectual disability or global developmental delay of suspected monogenetic origin. Michael Gabbett explains what sequencing would cost if paid for privately out of pocket.  

MICHAEL GABBETT: I guess it’s a bit of a “you get what you pay for.” So 4,000 dollars is probably what the diagnostic labs in Australia would be charging to look at a single person’s genome and that would be the whole genome. I certainly can have a next-generation sequencing and have a panel done for, say, around 1,000 dollars. So I don’t need all that bioinformatics done to look at the rest of the genome, I just want to look at neuromuscular genes, for instance, and that will cost a lot less.

So, the bioinformatics is what costs a lot because that’s bringing in an actual person with the expertise. As good as computers are you still need a human brain to sort of look at the data and say, “Oh look, you know, our whole genome sequencing did not find a mutation in this gene, but I know from experience that this exon actually isn’t read very well from next-generation sequencing. We might have to go back and look at more traditional ways of gene sequencing just for this exon.”

LESLIE BURNETT: It’s not a mental image of pouring DNA in one end of a sequencer, pressing the button and out comes your diagnosis at the other. These are massive computational problems, and for very complex conditions, particularly if the gene has only recently been described and you’re not sure whether the variant is causative or not, you may need to look at how it associates with affected or unaffected individuals within the family. So, clearly the cost will go up because you’re looking at more and more individuals.

At the moment, the two sources of funding are the hospital or the health entity, as is the case of many other genetic tests that aren’t on the Medical Benefits Schedule. And in some cases the patient is not eligible as a public patient, and so the patient of a family is electing to fund it themselves and pays for the cost of the testing. But there are a number of conditions for which we’re trying to draw attention to the government that you can only make these diagnoses by whole genome sequencing—and a mechanism needs to be found to fund this.

MIC CAVAZZINI: This is where the first part of this series ended, and as I said at the beginning, we didn’t go into too many examples of specific therapies for identified genetic disorders. There are just too many different examples which, for the most part, work towards mitigating the consequences of disease.

But one remarkable evolution of the past couple of decades is correction of genetic errors themselves. Researchers have been conducting ex-vivo gene therapy since the 1990s and reintroducing modified cells to patients with rare disorders. A development in recent years has been to introduce modified DNA into diseased cells in situ using classic lab-proven transfection techniques.

You might have read about the recent presentation of a Breakthrough prize to the creators of a treatment for the retinal disease Leber congenital amaurosis. Left untreated, LCA leads to degeneration of photoreceptors and complete blindness by adulthood. To address this, clonal DNA for a corrected retinal pigment epithelium gene is injected into the patient’s paper-thin retina, along with a viral vector that permits its introduction into the diseased cells. This intervention has been shown to preserve retinal integrity and halt vision loss for several years, and was approved by Therapeutic Goods Administration in 2020.

Even more mindboggling is the CRISPR approach, borrowed from bacteria, that has allows editing of a patient’s very own genes. In early 2020 researchers published safety data from the three cancer patients who underwent modifications to genes for certain T-cell receptors. In December 2023 the Food and Drugs Administration approved the use of CRISPR technology in the USA to treat patients with Sickle Cell Disease and just over a year later such a treatment was delivered to a patient for the first time, in the Kingdom of Bahrain. 

It would take an entire new podcast to do these therapies justice, so let’s go back to the second part of my original 2017 series. This began by addressing public understandings of risk. Knowledge of an inherited risk can empower otherwise health people to adopt lifestyle changes to minimise the chance of disease. Or it can inform their decisions around parenthood. But few gene markers are as predictable as the BRCA1 mutation, say, which confer a 65% per cent lifetime risk of breast cancer. Most genetic associations have a much weaker influence, so what do you advise people who carry a such a variant? First you’ll hear from Michael Gabbett, and then Kristine Barlowe-Stewart who now also works as a senior genetic counsellor at the Children’s Cancer Institute.

MICHAEL GABBETT: I guess, one of the tenets of clinical genetics really is to take a position where you provide the information, help people process that information, but how they perceive the risk is something that is very individual. So certainly, I’ve had people when I’ve said, “The chance of this recurring again is 25 per cent,” they’ll say, “Oh, is that all?” I don’t know if it’s that they focus on the positive—that three in four chance of it not occurring is actually the positive that they like to focus on.

Conversely, I’ve had people where I’ve said, “Look, the chance is as close to zero as possible. I couldn’t put a number on it but it’s certainly less than one per cent,” but they are absolutely petrified of something recurring, then they’d like to take any steps possible to prevent that. And it’s good to have an understanding of your patient’s background. If you can come up with analogies that I guess are visually something that they can relate to quite easily, more so than if you use some esoteric example. And I try to put them in a comparative fashion. I guess one of the great analogies I always use in my counselling is there’s no such thing as a risk-free life. I could drive home from work today and get killed by a semi-trailer. You know—risk is inherent in life, risk is inherent in having babies. I can never take away risk.

KRISTINE BARLOWE-STEWART: Risk perception is very personal. I often say to my students, “You have a ten per cent chance of winning the lottery. Stand up if you think that’s a good chance.” They all stand up. “You have a ten per cent chance of your child having a problem.” They’re not often the same people who think that’s a risk. If they have experience of a particular condition their perception of that risk is going to be different to someone who’s just read about it. People are not necessarily numerically literate, you can’t use percentages. You’ve got to present that number in a whole different way perhaps using the 100-person figure. And it takes time.

MIC CAVAZZINI: These discussions about risk are going to become more nuanced as the findings from genetic epidemiology research trickle down to the clinic. One sensitive tool is the genome-wide association study, or GWAS for short. These are large scale case-control studies in which researchers fish out thousands of single nucleotide polymorphisms that are common in the human population.

These common variants, known as SNPs, are not like the pathogenic mutations we’ve talked about until now. SNPs are usually harmless silent mutations, or fall outside protein-coding regions entirely. But they sometimes associate with a slight increase in disease risk, perhaps because they sit within an important regulatory sequence, or segregate with some unknown causal gene factor nearby. Research is only just beginning to make sense of these variants, says David Thomas.

DAVID THOMAS: A SNP is a change, a variant that is quite common typically amongst people, perhaps more than five percent of the population might have that SNP but the effect side is quite small. So many people, you know, ask themselves, “What’s the point of a genome-wide association study in terms of deriving clinically useful conclusions from something which has a 1.2-fold risk, a 20 per cent risk?”—for example.

But the reality is these things don’t operate as singletons, they’re not lone wolves—they hunt in packs. And because they’re so common, for individuals who have, say, not one disease-associated SNP but maybe five at once, all of a sudden the cumulative total risk for that person goes from 1.2-fold to maybe eight-fold.

And we certainly see that in breast cancer. There have been studies, including Australian studies actually by Paul James in Melbourne, which have shown the polygenic risk score—that is, using the genome-wide association study results and aggregating all of those the risk—is phenotypically indistinguishable from carrying a BRCA1 mutation. For the woman concerned it makes no difference whether you’ve got BRCA1 or five of these nasty SNPs together. And that’s a really interesting thing, which I think is still to enter into clinical practice in terms of risk stratification, but the data are unambiguous.

MICHAEL GABBETT: I guess commercial testing for these normal variants has been available for many years now. You know, you can hop on the internet and these companies use what information is available in the literature to look at your risk profile for, you know, dementia or heart disease. Now, as our understanding of normal variants increases that will become more powerful, but we’re looking at sort of relative risks of, you know, 1.5 times more likely to develop disease X, and if the background incidence of the disease is low then 1.5 times a small number is still a small number. So, I guess us clinical geneticists aren’t big fans of these commercial tests. Certainly next generation sequencing will be able to find all these normal variants and as our knowledge improves then we should be able to design algorithms to give a risk figure at the end of the day. But there’s still a lot we don’t know.

DAVID THOMAS: So, here’s something that might happen over the coming years. Typically people come into a familial cancer centre because they know that people in their family have had cancer. In a way you’re primed, you know—you’ve seen your sister, your mother get breast cancer and now you’re worried about breast cancer.

But increasingly we’re going to be discovering genetic causes that are not going to be dominant and Mendelian in their transmission patterns, which means there may not be a family history, and it might be quite different in terms of clinical genetics practice to give people information which they weren’t expecting because they’ve had no kind of conditioning for that.

MIC CAVAZZINI: Whole genome sequencing allows you to screen for every genetic risk factor in the book, but the problem of casting such a wide net is that you might detect disease markers you weren't expecting. How such incidental findings should be dealt with is one of the main ethical issues with the technology. The question becomes even more fraught in the context of prenatal screening, since foetal DNA can now sampled non-invasively from the maternal blood.

KRISTINE BARLOWE-STEWART: That’s the problem, these incidental findings. The chance is not high—one to two per cent, but it can happen. There will be enormous uncertainty generated from that because of our still-limited capacity to interpret what we find. Even if we find something and we know that it can cause a problem, it may not.

MIC CAVAZZINI: And is that a risk you explain to the patient that, “OK, we’re looking for this but we might turn up other things. Do you really want to go down that path?”

KRISTINE BARLOWE-STEWART: Yes, that’s a conversation we have because the consent forms now have that on them. We ask them, “Do you want to know this other information?” So people have a choice. If that’s what the patient wants—some patients will say, “I want to know everything.”

And I think that increasingly that choice is not given. Everyone has an ultrasound, and it’s a test, it’s a prenatal test. People don’t think it’s a prenatal test because they think they’re just getting a picture of the baby, but it’s a test. And because it’s a blood test, and they have zillions of blood tests in pregnancy, more and more there is the expectation that you will do these tests. And I think you have to tell them that this is a special blood test. But not everybody then wants to go down that path.

Making a decision to terminate a pregnancy, for example, is the most difficult decision anyone can ever make. But if we’re going to be doing whole genome sequencing, we’re going to find these babies are at risk for adult-onset conditions like Alzheimer’s disease and breast cancer and bowel cancer, in a foetus. And you know we, as a society, need to have the conversation about how appropriate is this, and should there be limits on the technology?

MIC CAVAZZINI: Genetic pathologist, Professor Leslie Burnett is more confident that systems are in place to avoid incidental findings from even coming to light.

LESLIE BURNETT: If we are searching for a narrow diagnosis and we know what we’re looking for, we will adjust the bioinformatics filters so we never see these things. We are, in effect, going in with deliberate blinkers, consciously applied, because we know that either the requesting clinician has asked us to look no further or the patient has not consented for us to look further. But for more difficult cases where the net necessarily has to be cast wider we will find unexpected findings, we’ll have to evaluate them and decide whether they’re relevant.

Look, the issue of incidental findings is very important. Some see it as an issue to be feared and avoided, others see it as an issue to be welcomed because if they’re present it’s a risk that the patient has and they should know about it. And this was brought to a head two or three years ago by the American College of Medical Genetics and Genomics which, I think very bravely, put out a list of 56 important findings that they claimed that one is professionally obliged to search for and include whether or not it had been requested. Because these were sufficiently important, would have an impact on the patient’s life, and you could do something about them, therefore don’t you have an obligation to inform the patient and the clinician?

Now, this caused much controversy and is still debated around the world, and I think, I respect them and support them for having made the statement, but it probably didn’t quite capture the consensus views of others working in the field around the world. And the current position is that this list is widely respected, but you don’t have an obligation to include it. One should seek the patient’s consent as to whether they wish to know about it or not, and one shouldn’t go searching for it just because one can.

Now, it’s not a black and white thing. I’ve had my genome sequenced—I was one of the early adopters, because I was doing this as an experiment to see how I would react. I discussed this around the dining room table with my family and my view was, “I want to know because if there’s something I can do about it, well, I’d be foolish to close my eyes, it’s not going to go away.” And my wife looked at me and she said, “Well, if you are going to be mad enough to have it, under no circumstances tell me anything.” And then my daughter, who works in a similar field, she said, “Oh, you’d be crazy not to know. Look, if you find anything you have an obligation to tell me because I share half my genes with you!”

DAVID THOMAS: Look, so actually this is an interesting point. You cannot consent someone in an informed way to the full implications of a whole genome test.

MIC CAVAZZINI: Medical oncologist, David Thomas once again.

DAVID THOMAS: You know, to consent somebody to the full spectrum of human disorders which might be identified or for which the information might be relevant would take far longer than is clinically feasible, and knowledge is changing so rapidly that you could consent at one point in time and it would become irrelevant 12 months later.

So I think what you’re consenting people to understand is that the information is changing rapidly and that we will use our best judgment, clinical judgment, and always putting the patient’s best interests at the forefront of our decision-making. Electing to return those results which we feel we have a duty of care to return to the patient, whether or not they express a certainty that they don’t want to receive that information or not.

And the reason I say that is there’s quite a lot of literature about people making a firm decision at one point in time and changing it the next, and the last thing want you do is take a result which might change the course of a person’s life and not return it to them because of a decision which couldn’t possibly, in retrospect, be called informed maybe some years ago. And of course, if it’s not relevant to you as the subject it’s relevant to children and sisters and brothers and so forth.

Dealing with uncertainty—it’s actually not an unusual feature of medical practice, you know. When you get a chest X-ray because somebody’s got some chest pain and you see an incidental spot in it, people don’t panic and think, “We needed to have consented people that we might identify a spot.” You just deal with it because you’ve got a duty of care to the patient to do what’s in their best interest. Those things are part and parcel of the way clinical practice evolved, and I think the same thing will apply with genomic information.

MIC CAVAZZINI: The apprehension some clinicians feel towards genomics testing will change with time, says clinical geneticist Michael Gabbett.

MICHAEL GABBETT: You know, with anything new you always have to tread a little bit carefully and there are certainly some traps I’ve seen generalists fall into and do quite a bit of damage by not providing adequate pre-test counselling or giving an erroneous interpretation to the families. But that, I guess, is a function of not being familiar with the test.

A good analogy I think of is HIV. So certainly when I went through medical school for someone to have an HIV test was a very big deal. There had to be significant pre-test counselling and then to give the result it was all very planned—you know, a quiet room, one-on-one. Now HIV testing is done quite, I would say willy-nilly, simply because people are more accustomed to knowing what HIV is, but also our ability to treat it is much, much better. So, the test itself hasn’t necessarily changed but the meaning of the test has changed and our familiarity has changed. And I think genetic testing is something similar. With next-generation sequencing there are a lot of caveats to the test, they are still a little bit special, but I have seen certain genetic tests over the years becoming less special as people get more familiar with them.

MIC CAVAZZINI: Another concern about collecting a person's entire genome sequence is what then happens to the information. Who has a right to gain access to it and what kind of decisions will it influence? Kristine Barlowe-Stewart was a founder of the Genetic Discrimination Project aimed at dealing with some of these questions.

KRISTINE BARLOWE-STEWART: So, what we’re talking about is being treated differently by a third party like insurer or employer. Access to a right that you would have normally had has been changed on the basis of your genotype rather than anything that you were presenting with.

And so, we investigated that and we certainly found in life insurance that’s where there was the greatest concern. In many other countries life insurers can’t ask you about your genetic information. Here, if you know your genetic test result you have to tell them—“Have you had a genetic test?”—on every form. And we got access to all of the applications that were disclosed, where a genetic test was disclosed, and basically most of the results were negative, but that’s because people are not really disclosing. I think the fear—

MIC CAVAZZINI: —and so you’re still pushing to have that requirement removed?

KRISTINE BARLOWE-STEWART: —no, look, I think it’s a problem if we start saying a genetic test is different from every other test. What I am pushing for is that if it is disclosed, the interpretation has to be evidence-based. If the data isn’t there, they shouldn’t be using it. So my message is, use your genetic counsellor as your advocate. If you are concerned, challenge the insurance company.

MIC CAVAZZINI: I’m going to spare you the last ten minutes of the original podcast about cancer genetics because there are more recent episodes that cover that terrain in more detail. Enormous progress has now been made not only in identifying germline mutations that predispose people to particular cancers but also the genetic profile of cancer tissues itself.

Eight years after I first spoke to Professor David Thomas I went back to him to talk about the state of the art in precision oncology. Episode 121 covers how the identification of moleculular vulnerabilities has led to the development of targeted immunotherapies that are much more effective than previous generations of chaemo.  You’ve probably heard of trastuzumab for HER2 positive breast cancers but other examples we discuss are dabrafenib against BRAF mutations and larotrectinib against NTREK fusions.

The revolutionary aspect of these drugs is that they’re not restricted to a classification of cancers defined by their tissue of origin. In episode 122 Professor Thomas goes on to describe how such “tissue agnostic” therapies give some hope to patients with rare cancers which get little or no interest from drug developers. He has founded the organisation Omico to provide these patients with genomic profiling to detect genetic targets that may be susceptible to approved pan-cancer therapies, or other experimental treatments further up the pipeline.

The best-known example of tissue-agnostic treatments are the immune-checkpoint inhibitors like pembrolizumab, although they are targeted at a predisposition for rapid mutation moreso than a particular genetic target. While they have found applications against a number of different cancer types, they were first developed against melanoma, as described in podcast episode 79 by Australian researchers at the cutting edge of this field.

I hope you find plenty more to listen to. Before I go I want to thank once again, Professor Leslie Burnett, Kristine Barlowe-Stewart, Michael Gabbett and David Thomas for their contribution to Pomegranate Health. There are some supporting readings listed at the website racp.edu.au/podcast then just click on episode 147. And at the top of the blurb you’ll notice a blue button saying “Add educational activity to MyCPD” that will prefill most of the details for an entry towards your continuing professional development.

At the website you can also sign up to an email alerts list for newly published episodes although it’s much to stay tuned with a pod browsing app like Apple Podcasts, Overcast, Spotify or Castbox. Just open the app, search for Pomegranate Health and click follow. And please do the same with your colleague’s phone if they don’t mind. Word of mouth and reviews makes the biggest difference in spreading the word to more listeners.

If you’ve got any feedback and suggestions send an email to podcast@racp.edu.au. The podcast was recorded on the lands of the Gadigal clans of the Yura Nation. I pay respect to their elders past, present and emerging. I’m Mic Cavazzini. Thanks for listening.