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Genetic Profiles Affect Smokers’ Lung Cancer Risk

MADRID — Smokers with extreme phenotypes of high and low risk of developing tobacco-associated lung cancer have different genetic profiles, according to a multidisciplinary study conducted by specialists from the Cancer Center at the University of Navarra Clinic (CUN). The results were presented at the last meeting of the American Society for Clinical Oncology held in Chicago, United States. 

Ana Patiño García, PhD, director of the Genomic Medicine Unit at the CUN and a coordinator of the research, explained to Medscape Spanish Edition the main reason why this study was conducted. "This study came straight out of the oncology clinic, where we are constantly encountering patients with lung cancer who have never smoked or who have smoked very little, while we also all know people who have smoked a lot throughout their lifetime and have never developed cancer. This observation has led us to ask whether there are genetic factors that increase or decrease the risk of cancer and protect people against this disease."

José Luis Pérez Gracia, MD, PhD, oncologist, coordinator of the Oncology Trials Department at the CUN and another of the individuals responsible for this research, said, "This is the first study to validate genetic factors associated with people who appear to be resistant to developing tobacco-related lung cancer or who, on the other hand, are at high risk of developing this disease."

Pioneering Approach 

Earlier evidence showed that some smokers develop cancer, and others don't. "This is a very well-known fact, since everyone knows about some elderly person who has been a heavy smoker and has never developed lung cancer, said Pérez. "Unfortunately, we oncologists encounter young smokers who have been diagnosed with this disease. However, despite the importance of understanding the causes behind these phenotypes, it is a question that has never been studied from a genetic standpoint."

The study was conducted using DNA from 133 heavy smokers who had not developed lung cancer at a mean age of 80 years, and from another 116 heavy smokers who had developed this type of cancer at a mean age of 50 years. This DNA was sequenced using next-generation techniques, and the results were analyzed using bioinformatics and artificial intelligence systems in collaboration with the University of Navarra Applied Medical Research Center and the University of Navarra School of Engineering.

When asked how this methodology could be applied to support other research conducted along these lines, Patiño said, "The most novel thing about this research is actually its approach. It's based on groups at the extremes, defined by the patient's age at the time of developing lung cancer and how much they had smoked. This type of comparative design is called extreme phenotypes, and its main distinguishing characteristic — which is also its most limiting characteristic — is choosing cases and controls well. Obviously, with today's next-generation sequencing technologies, we achieve a quantity and quality of data that would have been unattainable in years gone by."

Speaking to the role played by bioinformatics and artificial intelligence in this research, Patiño explained that they are fairly new techniques. "In fact, these technologies could be thought of as spearheading a lot of the biomedical research being done today. They've also somewhat set the stage for the paradigm shift where the investigator asks the data a question, and in the case of artificial intelligence, it's the data that answer."

Pinpointing Genetic Differences

In his analysis of the most noteworthy data and conclusions from this research, Pérez noted, "The most significant thing we've seen is that both populations have genetic differences. This suggests that our hypothesis is correct. Of course, more studies including a larger number of individuals will be needed to confirm these findings. For the first time, our work has laid the foundation for developing this line of research." 

"Many genetic variants that we have identified as differentials in cases and controls are found in genes relevant to the immune system (HLA system), in genes related to functional pathways that are often altered in tumor development, and in structural proteins and in genes related to cell mobility," emphasized Patiño.

Many of the genetic characteristics that were discovered are located in genes with functions related to cancer development, such as immune response, repair of genetic material, regulation of inflammation, etc. This finding is highly significant, said Pérez. "However, we must remember that these phenotypes may be attributable to multiple causes, not just one cause."

Furthermore, the specialist explained the next steps to be taken in the context of the line opened up by this research. "First, we must expand these studies, including more individuals with, if possible, even more extreme phenotypes: more smokers who are older and younger, respectively. Once the statistical evidence is stronger, we must also confirm that the alterations observed in lab-based studies truly impact gene function."

Earlier Diagnosis 

The clinician also discussed the potential ways that the conclusions of this study could be applied to clinical practice now and in the future, and how the conclusions could benefit these patients. "The results of our line of research may help in early identification of those individuals at high risk of developing lung cancer if they smoke, so that they could be included in prevention programs to keep them from smoking or to help them stop smoking," said Pérez. "It would also allow for early diagnosis of cancer at a time when there is a much higher chance of curing it. 

"However, the most important thing is that our study may allow us to better understand the mechanisms by which cancer arises and especially why some people do not develop it. This [understanding] could lead to new diagnostic techniques and new treatments for this disease. The techniques needed to develop this line of research (bioinformatic mass sequencing and artificial intelligence) are available and becoming more reliable and more accessible every day. So, we believe our strategy is very realistic," he added.

Although the line of research opened up by this study depicts a new scenario, the specialists still must face several challenges to discover why some smokers are more likely than others to develop lung cancer.

"There are many lines of research in this regard," said Pérez. "But to name a few, I would draw attention to the need to increase the number of cases and controls to improve the comparison, study patients with other tumors related to tobacco use, ask new questions using the data we have already collected, and apply other genomic techniques that would allow us to perform additional studies of genetic variants that have not yet been studied. And, of course, we need to use functional studies to expand our understanding of the function and activity of the genes that have already been identified."

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