A whole genome analysis of lung adenocarcinoma tissue shed light into one of the mechanisms by which cancer is developed. Authors identified specific types of mutations and the order in which they happen that lead to developing lung adenocarcinoma.
About the author: Sofia Doune Bosch
This web page was produced as an assignment for an undergraduate course at Davidson College.
With an estimate of 238,340 new cases and 127,070 deaths in 2023, lung cancer is one of the most common cancers in the United States (American Cancer Society; National Cancer Institute). The American Cancer Society and the National Cancer Institute state that although it remains one of the leading causes of death in the country, lung cancer cases have decreased at a steady rate. Factors like tobacco smoking, poor diet, high exposure to air pollution, and genetic susceptibility are key on the development of cancer. Specifically, lung adenocarcinoma accounts for half of the lung cases reported. Lung adenocarcinoma grows around the small air sacs in charge of exchanging oxygen and carbon dioxide on the lungs, the alveoli, prejudicing their functionality (National Cancer Institute 2011; Kuhn et al.). A lot is known about what lung adenocarcinoma is and how to treat it, but what are the genetic processes behind developing lung adenocarcinoma? This is the question that motivated Yasuhiko Haga and his team to sequence the whole genome of lung adenocarcinoma tumors and to analyze the genetic mechanisms by which the condition is developed.
Haga and his team extracted and sequenced the DNA 76 lung cancer tumors. The researchers then compared the DNA sequences to the genomes of healthy cells to identify the mutations that lead to the growth of cancerous cells. The authors curated a list of genes that showed different expression levels compared to normal tissue and explored them in more depth. They hypothesized that changes in the identified genes could be the operators behind the transformation of healthy cells to a cancerous state, also known as tumorigenesis. The authors also looked at the regulatory mechanisms of gene expression to identify any modifications that could facilitate the mutations they listed before. Lastly Haga et al. studied the order and combinations in which the mutations happen, and in which cases the changes in regulatory mechanisms facilitate tumorigenesis.
The authors found that there are a set of “driver mutations” that are usually acquired in the early stages of cancer development. After that, deletions of genes that suppress tumor growth accelerate tumorigenesis. The deletions are especially seen in more advanced adenocarcinoma cases that have a poor recovery projection. The combination of at least one driver mutation and one deletion are essential features of adenocarcinoma development. A third key aspect are the changes that happen in metabolic processes surrounding the tumor. These modifications in the environment surrounding the tumor facilitate the growth of the tumor outside of the alveoli, which drives the spread of the cancerous cells to adjacent tissues. Haga and his team identified multiple groups of mutations that seem to be inherited and triggered together. Lastly, they also pointed out a distinct order in which most lung adenocarcinoma cases seem to develop; first a driver mutation allows for the first cancerous cells to appear, followed by a deletion that drives growth of the tumor, finally the changes in the environment help the tumor survive outside of its place of origin.
Haga et al. did a great job at identifying all the variants that contribute to the development of lung adenocarcinoma. This study shed light to the complexity of this type of cancer, showing how many factors are involved in its development. However, the authors addressed how complex it was to carry this project out given the scarce number of samples available to them and how small the tumors from which the DNA needs to be extracted are. Still, they state how significant it is to have this information, how they want to conduct further analysis on the matter. This is of outmost importance because although the data they have collected is significant and opens the door to development of therapies that target these modifications, it is true that more samples are required to cover a broader spectrum of genetic variance. To address this more surgical lung adenocarcinoma cases need to be collected, plus good DNA recollection must be achieved. This presents two difficulties to the expansion of the data. First, not many lung adenocarcinoma cases are treated surgically. Second, extracting DNA in a high enough quality and concentration for sequencing is difficult when dealing with small amounts of tissue as they are in here because the size of the tumors being extracted (Haga et al.2023). Haga et al. opened the door to a deeper understanding of lung adenocarcinoma that will allow researchers and physicians to treat the condition with more specificity. Although much research needs to be conducted still, this is a great start to new ways of treatment.
Works Cited
American Cancer Society, Lung Cancer Statistics | How Common is Lung Cancer?
Haga Y., Y. Sakamoto, K. Kajiya, H. Kawai, M. Oka, et al., 2023 Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma. Nat Commun 14: 8375. https://doi.org/10.1038/s41467-023-43732-y
Kuhn E., P. Morbini, A. Cancellieri, S. Damiani, A. Cavazza, et al., Adenocarcinoma classification: patterns and prognosis
National Cancer Institute, 2011 Definition of alveoli – NCI Dictionary of Cancer Terms – NCI
National Cancer Institute, Cancer of the Lung and Bronchus – Cancer Stat Facts. SEER.
© Copyright 2022Department of Biology, Davidson College, Davidson, NC 28036.
Hello, wonderful article! The paper you wrote from is an extremely technical one with lots of abbreviations and terms that may be difficult for the layperson to understand. You also picked up on the major takeaways, which are the driver mutations (as emphasized on page 3), deletions, and epigenetic/transcriptomic changes. I also agree that sequencing MIA tumors would be difficult, especially since they are less likely to cause serious symptoms that prompt medical investigation. However, the ability to treat adenocarcinoma at such an early stage with genetic therapies would be great and prevent the cascade of mutations.
This is a well-written summary. I would like to take a moment and appreciate how you touched on the most important parts of the article in such a clear and simple manner. It was interesting to learn that there is a genetic component to developing lung cancer and the mechanisms of specific mutations that drive tumorigenesis. I wonder how some habits like smoking exacerbate the frequency of these mutations and variants. I agree with Sofia that the discovery and deep understanding and these variants might potentially to lead better treatments for lung cancer.