The Hidden Causes of Lung Cancer: Why Non-Smokers Are Still at Risk
Why do some people develop Lung cancer despite never smoking? New global research points to hidden culprits—especially Air pollution—that can trigger DNA mutations and drive cancer development. By analyzing hundreds of cases worldwide, scientists uncovered clear links between pollution levels and tumor mutations, along with surprising risks from certain traditional medicines. The findings reveal that lung cancer in non-smokers may often be preventable—and that cleaner air could be a powerful form of protection.
Transcript
00:00:00 I'm Ludm Alexandro, a professor in cellular and molecular medicine and bioengineering at UC San Diego. When we started this study, we wanted to answer the question, what causes lung cancer in people that have never smoked? Uh we know in smoking lung in smokers lung cancer is preventable, but we were not sure whether in never smoker lung cancer is preventable. So we wanted to
00:00:27 understand that and perhaps the most important thing of this study is we have identified a number of processes that can allow us to prevent lung cancer and never smokers. Never smokers are people who have never ever had tobacco cigarettes or have had less than 15 tobacco cigarettes in their lifetime. Now they may have smoked they may have done electronic cigarettes.
00:00:55 They may have smoked other substances but when it comes to tobacco cigarettes they have had uh either none or less than 15 cigarettes in their lifetime. It's people telling you I have never ever smoked and people sometimes don't remember they have smoked in their lifetime and actually from the genetic material of the cancer and their lung tissue we can say whether they have
00:01:17 smoked before or not because smoking leaves a very specific patterns of mutation and molecular changes. So we have the self-reporting type of information but in addition to that we can actually trace it back and say hey we see some genomic signatures there are you sure you've never smoked and some of them have come and said oh actually I smoked when I was a teenager but
00:01:37 completely forgot about it now I'm 75 and and so it's the self-reporting plus double and triple checking. We actually collected samples from uh lung cancer patients that have never smoked. Uh and we collected it from 28 different locations around the world. And we collected almost 900 such samples. And we specifically designed the study in such a way that people were coming from
00:02:01 places that have low air pollution and places that have higher pollution allowing us to compare what is different in their cancers. In addition for that, for some of those people, about 450 of them, we had an information whether people were smoking in their household or not, which allowed us to do the additional comparison of passive smoking or secondhand smoking to see whether it
00:02:26 does anything uh uh to the cancers. How does one quantify air pollution? If I were to ask you, what's the air pollution you have been exposed in your lifetime? It's a very hard question to answer. But what you can do is you can look at the addresses a person has lived on the locations and then one can use satellite images that can measure the
00:02:49 air pollution at different times and then one can derive an average index or an average value of the air pollution one has been exposed throughout one's lifetime. So essentially that's what we did for these 800 and something patients. We use satellite images with ground measurements to derive an individual air pollution index and we wanted to see whether that associates
00:03:11 with any mutations or any genomic changes that we see in the cancers of these people. So specifically we looked at PM2.5 particles which are particles that are 2.5 micrometers or less in diameter uh and which have been previously implicated or it was suggested that they're implicated in lung cancers. We have had air pollution for a long
00:03:36 time. Uh but there are also we have had tobacco smoking being quite prevalent for a long time. So in the last several decades the tobacco smoking associated lung cancers have decreased and we have been able to see the emergence of lung cancer in never smokers. Lung cancer in general has been traditionally associated with tobacco smoking. Indeed 70 to 80% of all lung
00:04:01 cancers are associated with tobacco smoking. Now in the past few decades we have made significant advances towards reducing tobacco smoking and we are now seeing more and more lung cancer in never smokers. They're emerging uh as one of the dominant uh uh uh lung cancer types because less people are actually smoking. But not only that, we're thinking that we think that they're
00:04:25 increasing and this could be due to the increase of number of habits or a number of environmental uh factors such as air pollution. Uh but it could be due to other things that we haven't previously measured. Previously what we have known about air pollution and lung cancer in never smoker is we have known that there is an epidemiological association between
00:04:51 those two uh factors and we have also known from work in mouse models we have known that this could be reproduced experimentally but we haven't been sure how this occurs in humans or what does air pollution causes in human beings. Now in this study we had that power to understand that and in fact we can see that the more polluted region one lives in or the
00:05:18 more polluted region one comes from uh the more mutation one has in their lung. We don't only see that difference between low and high polluted areas. We also see a very very strong dose response association and we also see that the some of the main drivers that cause lung cancer are in fact being enriched in people who come from these highly polluted areas. So now in
00:05:43 addition to the associations that we have we have a mutogenic mechanism that air pollution is associated with mutagenesis in lung cancer which is causing the mutations and driving the cancer development and cancer evolution. But in addition to that, we found at least two things that we found that we thought are very exciting and completely unexpected. Uh the first one that we
00:06:06 found was that um uh in in uh in Taiwan we would see a very specific sets of mutations in the lung cancer of never smokers and indeed we know the cause of this and that's a Chinese traditional medicine that contains something called some plants uh withic acid and we do not know the exact mechanism by which the people take that but we suspect that they may be inhaling
00:06:33 them as part of uh traditional practices and that is mutating their lung and again increasing their uh uh their chance of developing lung cancer. So now we are talking about a very specific regional exposure or even in a country level exposure because we saw it in almost all samples that we look at from Taiwan. Uh that is potentially preventable here. One can have an
00:06:58 immediate personal action of not inhaling such traditional medicine. Uh but one can also have also regulation and changes that can be implemented. The second thing that was unexpected was across most of the lung cancer in never smokers, we found an unknown mutational process. We don't know what causes it. The fact that it's across all of them tells you that it's probably something
00:07:19 endogenous to the lung, but it tells you that there is something that's accumulating mutations like a ticking time bump with age and that's generating many of the potential cancer drivers. So again, something very interesting, something potentially preventable. it was seen regardless of where they live. That signature of a known region was seen everywhere. So it's something
00:07:40 globally ubiquitous because we have 28 locations around the world across number of countries. So everyone had them but they had them at different rates in the different countries. So it tells you that there's something that can be modulated. So probably something inside the lungs, something inside of the lung cells that can be affected by the environmental factors.
00:08:03 So the story of arislloic acid is a very interesting story. We have first learned about it from a Belgium weight loss clinic in the '9s. Women were taking specific Chinese herbal medicine to lose weight. Well, it turns out that herbal medicine is very mutogenic and very carcinogenic. So causes mutations in cancer. So these women started having kidney failures and started developing
00:08:25 kidney and liver cancers. And that's when we learned about this Chinese herbal medicine causing many cancer types. Subsequently, it's been shown to be a big problem in Southeast Asia, in Eastern Europe, uh where we are seeing most of the kidney cancers, most of the liver cancers having this exposure. So, we're talking about nationwide or populationwide
00:08:48 exposure to this specific Chinese herbal medicine. In Southeast Asia, in China, we know they cons this is being consumed through traditional medicine. We see it in Eastern Europe and we have honestly no idea how this is being consumed there. It's not through traditional medicine. It might be through brewing specific moonshines and things like that. But it's it's quite fascinating to
00:09:09 think about. Again, we're talking about whole countries being exposed to that. Now, we have known that this causes kidney. We have known that this causes liver. We have had some reports it causes bladder cancers. By far this is the first report saying that it causes lung cancer um and specifically lung cancer in never smokers. Now we do not think that just
00:09:28 consuming it will cause lung cancer which needs we think that there needs to be an inhalation process. So we suspect that there is some inhalation of this Chinese herbal medicine that's mutating the lung of people. We see it very strongly in Taiwan. We do not see it in samples from Hong Kong. Uh and we don't have samples from mainland China. We suspect we'll see it, but we just don't
00:09:49 have the the samples there. So, we we know it's something cultural, something related to to to most likely Chinese traditional medicine, but you know, honestly, we don't understand it at this moment. Uh, and we also know that Eastern Europeans don't have it because we have cancers from them. Lung cancer in general is when we think about it, we think of disease of
00:10:14 smokers. most of the time this will be males who smoke a lot. Lung cancer in never smokers interestingly enough is mostly a disease of females and more specifically we see a very high enrichment of females of Asian origin. Now we do not know whether that's because of genetics of the genetics of of person being Asian or because of the people who lived in
00:10:39 China, Southeast Asia. So it's an environmental but we very very clearly see that specific enrichment. So we have a very specific population. Now again we will see lung cancer in never smokers in Caucasian females in African-American in males as well. But the predominant set of uh uh individuals that will see it or the the the enriched population will be Asian females. There's some region
00:11:02 specific hypothesis when it comes to Southeast Asia, when it comes to Taiwan, women cooking on open fire uh uh or women doing maybe more inhalations than males. But the reality is we don't know uh because again even when it comes to air pollution, well males and females would live exactly in the same air pollution. It's it's it's not like females breathe more of the air
00:11:28 pollution than males. So that part is a bit mysterious. that part we don't understand. So what can we do based on the information of fair pollution is a great question. Uh the simple answer is on an individual level there is little one can do on a more community city government level. One can needs to start thinking more about
00:11:55 regulating more about reducing air pollution more about making sure that some of the big cities are not that air there's not so much pollution because in addition to many other uh uh lung diseases now we know that this is also very strongly causing mutations in the lung and causing lung cancer. So there is a lot when it comes but it's a lot that can be done but it doesn't come on
00:12:20 the individual level unfortunately it comes on the level of we need to be able to reduce the air pollution and essentially have clean air so we and our children breathe better. This study has a number of limitations that we need to keep in mind. Um the first limitation is when it comes to air pollution we have derived a personalized index and this is an estimation. Ideally
00:12:45 one would wish to have every person wear a specific device that measure how much the air pollution they consume or they inhale during their lifetime. Practically it's not a very realistic thing to do or such data doesn't exist. Similarly for the secondhand smoke we have relied on multiple surveys of people self-reporting it. Again, people can make mistakes, people can misreport
00:13:06 it, and we have tried to account for that, but there is always the chance that there is some misreporting in the data. Um, the other and third limitation I should point out is there's other known factors that cause lung cancer such as radon exposure or such as some industrial exposures or occupations. We did not explore that specifically. Uh, and that's something that we're hoping
00:13:26 to do in future studies. In this study, we have focused to understand specifically air pollution and secondhand smoking. Um, and we have found interesting things related to Chinese herbal medicine and potentially unknown mutogenic process. Uh, but we haven't explored several things which we are hoping to explore in the future. The first thing that we haven't explored is
00:13:51 specific exposure such as radon or specific occupations that may lead to higher uh lung cancer. never smokers. The other thing that we hope to explore is is electronic cigarettes and smoking marijuana because we are seeing the population changing their behavior from smoking tobacco cigarettes to actually vaping electronic cigarettes or to smoking marijuana and we want to
00:14:17 understand the risk. We know there will be risk. We know that there will be probably some increase in cancer risk and mutations. We just don't know what it is and that's one of the things we're actively working on.