Zoonotic Spillovers; DNA and RNA Testing for Cancer Risk

Derick Alison
Derick Alison
17 Min Read

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include rate of zoonotic spillovers, DNA and RNA testing for cancer risk, genes and health conditions among Icelanders, and primary care assessment for dental conditions.

Program notes:

0:40 Oral health and primary care

1:40 90% of adults affected by dental caries

2:41 Primary care doc burden

3:37 DNA and RNA sequencing in hereditary cancer risk

4:38 Variant reclassified as pathogenic

5:38 DNA may not be as predictive

6:30 Actionable genotypes and lifespan

7:32 Lifespan 3 years shorter

8:31 Screen at younger ages

9:01 Zoonosis spillover

10:01 About 9% annual increase

11:00 Livestock farming

12:31 End

Transcript:

Elizabeth: Should we test both DNA and RNA in those at risk for cancer?

Rick: Do actionable genetic differences actually affect lifespan?

Elizabeth: Are infections that arise in animals increasingly impacting people?

Rick: And what do we know about screening and preventive interventions for oral health?

Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I’m also dean of the Paul L. Foster School of Medicine.

Elizabeth: Rick, I think in reverence, if you will, to the number of papers that are all part of this issue of oral health in JAMA this week, why don’t we turn first there?

Rick: Okay. Our listeners have oftentimes heard us report on information gathered from the USPSTF — that’s the United States Preventive Services Task Force. This particular time they looked at oral healthcare in children and adolescents, and then a separate paper in adults with regard to screening. How effective is screening for oral health when it’s performed by primary care clinicians in order to prevent negative oral health outcomes? Secondly, how accurate is screening for oral health when it’s performed by a primary care clinician in identifying people who have oral health issues or are at an increased risk?

When they looked at that data for both adults and children, they came to the same conclusion. There is insufficient data; that’s with regard to screening. Okay. Well, what about in terms of intervention? They came to the same conclusion, there is really insufficient data. I’m actually surprised.

Now with regard to kids, kids lose 51 million hours of school time because of oral health issues; 90% of adults are affected by caries and about a fourth of them are untreated. They are either in a minority population or they’re in a rural setting or an urban, underserved setting where there just aren’t dentists available.

Elizabeth: The notion that we’re somehow going to be able to put together a study that’s going to look at interventions versus no interventions in these groups of people — both children and adolescents who are at risk for dental caries, and adults who are at risk for that and also periodontal disease — seems unlikely to me.

Rick: Let me take a step back, Elizabeth. We know there are things that are effective, but they are mostly in the setting when they are applied by dentists. But we need to take it a step further. For those people that don’t have access to a dentist, can we do at least some of these primary things in a primary care setting? That’s what the urge is for the USPSTF. They say, “OK, this is a knowledge gap. Let’s try to fill that.” They actually make some recommendations about how those studies should evolve, so we can get that information.

Elizabeth: Two things. One thing is it occurs to me that primary care docs once again being asked to do yet one more thing that is related to overall health. The other thing is, per overall health, it’s always been sort of interesting to me that somehow we have the mouth, that somehow we have the feet, somehow we have the eyes — these body parts that we seem to treat as if they were separate entities.

Rick: Well, Elizabeth, your point is well taken because we know that oral health affects the incidence of infection. It affects the incidence of diabetes and hypertension. Because poor oral health results in inflammation, that inflammation isn’t limited to the mouth. It affects all other organs.

Elizabeth: I’m surprised you didn’t mention cardiovascular disease where there is a very solid line relationship.

Rick: You’re actually right. For a long time, people didn’t understand that inflammation plays an important role in cardiovascular disease. Oral inflammation can contribute to that as well, so I’m glad you mentioned that.

Elizabeth: OK. Let’s turn to JAMA Oncology. This is a look at diagnostic outcomes of concurrent DNA and RNA sequencing in people who are undergoing hereditary cancer testing. Let’s distinguish that right off the bat from those folks who are having it done because they have presented with cancer and we’re taking a snapshot of where their particular cancer is from a genetic standpoint.

These are folks who are known to have this hereditary cancer predisposition. They have what’s called germline genetic testing, which is “What were you born with? What did your parents give you?” They looked at this cumulative association of paired DNA and RNA testing for a look at resolution of what they call variants of uncertain significance, they abbreviate VUS.

A pretty robust data set here, 43,000+ individuals. The mean age at testing was 54 and largely female. They made significant upgrades based on their variant classification in 97 individuals, including 70 who had a variant that was reclassified from “unknown significance” to “pathogenic” or “likely pathogenic.” There were also 27 individuals who had a novel deep intronic variant that would not have been detected using DNA sequencing alone.

Interestingly, they also noted an increase in positive rate and decrease in this variance of unknown significance that was higher in Asian, Black, and Hispanic individuals compared with white individuals. They assert that this is an advancement in germline genetic testing that ought to be employed.

Rick: Some of our listeners may not know the association between DNA and RNA. DNA is the genetic building block that ultimately is translated into a protein. How do you get from DNA into a protein? DNA is transcribed into RNA. You can actually identify the pathogenicity of a trait from not only looking at the DNA, but also looking at the mRNA — is it abnormal? Sometimes our DNA testing isn’t quite as accurate or predictive as we’d like. Therefore, we have these variants of unknown significance. But by looking at the mRNA, we are actually able to drill down and make it more predictive. It does involve simultaneous testing.

Elizabeth: One of the things that they don’t mention in this paper is the cost. If it’s way more expensive, the likelihood that we’re going to be performing this on everyone is really low. The other thing is, what’s the timeline?

Rick: Yeah. Both of these things are usually done fairly rapidly. Now, apropos to the cost, you’re right, this particular study did not address that. Whatever the cost is today, you and I both know that the cost 6 and 12 months from now will be much less. You also have to factor in not only the analysis, but can you do something about it? Can you either screen or perhaps apply some treatment? The cost of the test has to be weighed against the benefit.

Elizabeth, the next topic we’re going to talk about is a study in the New England Journal of Medicine where it looked at what is called “Actionable Genotypes and Their Association with Life Span in Iceland.” Back in 2021, the American College of Medical Genetics and Genomics (ACMG) recommended reporting actionable genotypes in 73 different genes associated with diseases. These are diseases that we have preventive or therapeutic measures that are available. Those genetic abnormalities centered around four particular disease processes: cancer, cardiovascular, metabolic diseases, and then a pool called miscellaneous. They looked at almost 58,000 Icelanders. They queried these 73 particular genes to ask which of them had the variants that would result in the disease you could potentially do something about. What they found is 1 in 25 Icelanders had one or more of those genetic abnormalities.

Okay, we identify it. Does it actually affect lifespan? In fact, it does. Those carrying an actionable genotype and a cancer gene had a survival that was 3 years less than those that didn’t have that actionable gene. The overall population, those that had a genetic abnormality, lived 1 year less than those that didn’t have it. Most of that was related to cancer genes, but there were a couple cardiovascular genes — one that regulates cholesterol, one that regulates heart muscle — that would also associate with the decreased lifespan. So the first evidence we have that these actionable genes result in a decrease lifespan, at least in this large population of Icelanders.

Elizabeth: Icelanders, of course, are very interesting because they are geographically isolated and they also haven’t changed a whole lot over the years. My question is, “OK, what does that mean, ‘actionable?'” You’re not going to be changing your DNA sequence.

Rick: No, you don’t do that. For example, if you know you have a gene that predisposes to cancer, then you’ll start the screening process either earlier or you do it more frequently. With regard to cardiovascular disease, genes that predispose to hypercholesterolemia, we can identify that early as well and screen individuals at a young age and also put them on therapy as well.

Elizabeth: Clearly, the next question is, how about in the population at large? Does this beg the question of examining for these variants in everyone?

Rick: That’s one interesting question. As you know, Elizabeth, there are a couple cohorts outside of Iceland. One in the United Kingdom. They have over, gosh, half a million people. You’ve got a couple cohorts in the United States as well. They’re testing 1 to 5 million individuals.

Elizabeth: Finally, let’s turn to the BMJ Global Health. This is a paper entitled “Historical trends demonstrate a pattern of increasingly frequent and severe spillover events of high-consequence zoonotic viruses.” Zoonotic viruses, of course, those that lurk about in animal populations. As we’re destroying so much of our ecology, let me say, and we are experiencing climate change, this study is attempting to use historical data to see whether or not these spillover events from those animal populations that are struggling in their habitat as it’s destroyed increasingly interacting with humans and then infecting us with viruses that are normally among them — is this happening more often?

Looking at this historical data, they do show that the number of spillover events and reported deaths have been increasing by just shy of 5% during their study period and just shy of 9% annually, respectively. They also took a look at the number of deaths caused collectively by this subset of pathogens and what they include in here is SARS Coronavirus 1, filoviruses, Machupo virus, and Nipah virus. They find that these number of deaths have been increasing at an exponential rate from 1963 to 2019. If this trend that they have observed continues, these pathogens can be expected to cause four times the number of spillover events and 12 times the number of deaths in 2050 compared with 2020.

Rick: The authors contend, and I wasn’t aware of this, that these zoonotic events aren’t just random, but they actually follow a multi-decade trend in which the epidemics occur and they become larger and more frequent. These viruses jump from animals into humans through things like hunting or we’re in the same habitat, or we do intensive livestock farming. The author suggests that climate change and environmental changes are what’s causing these things to occur. I wasn’t aware that these emerging zoonotic viruses cause most of the 20th century pandemics and account for 60% of all emerging human diseases. Any thoughts about how to address this?

Elizabeth: I was looking this morning, before we started to record, at a program that the CDC has underway in domestic airports where they are looking at random samples of people who agree to be tested, looking for a plethora of viruses. They are also testing wastewater in those locations to see if they can discern it there. Clearly, surveillance has to be something that we maintain. We also obviously have to look at deforestation and climate change and standard operating procedures, if you will, and how we respond to these public health threats, which I think is also really critical and the authors point out.

Rick: I think those are great suggestions, early, active and passive detection — that is, surveillance — and also getting the information out. I would say that one other major advancement is the rapid development of messenger RNA vaccines, which proved very helpful in COVID.

Elizabeth: On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.

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