Some teenagers harbor catastrophic changes to their genomes that can lead to lung cancer later on in life, even if they never smoke
< 20190603153641_81541_999037498.jpg >
< 20190603153641_81541_999037498.jpg >
(Professor Young Seok Ju at the Graduate School of Medical Science and Engineering)
Catastrophic rearrangements in the genome occurring as early as childhood and adolescence can lead to the development of lung cancer in later years in non-smokers. This finding, published in Cell, helps explain how some non-smoking-related lung cancers develop.
Researchers at KAIST, Seoul National University and their collaborators confirmed that gene fusions in non-smokers mostly occur early on, sometimes as early as childhood or adolescence, and on average about three decades before cancer is diagnosed. The study showed that these mutant lung cells, harboring oncogenic seeds, remain dormant for several decades until a number of further mutations accumulate sufficiently for progression into cancer. This is the first study to reveal the landscape of genome structural variations in lung adenocarcinoma.
Lung cancer is the leading cause of cancer-related deaths worldwide, and lung adenocarcinoma is its most common type. Most lung adenocarcinomas are associated with chronic smoking, but about a fourth develop in non-smokers. Precisely what happens in non-smokers for this cancer to develop is not clearly understood.
Researchers analyzed the genomes of 138 lung adenocarcinoma patients, including smokers and non-smokers, with whole-genome sequencing technologies. They explored DNA damage that induced neoplastic transformation.
Lung adenocarcinomas that originated from chronic smoking, referred to as signature 4-high (S4-high) cancers in the study, showed several distinguishing features compared to smoking-unrelated cancers (S4-low).
People in the S4-high group were largely older, men and had more frequent mutations in a cancer-related gene called KRAS. Cancer genomes in the S4-high group were hypermutated with simple mutational classes, such as the substitution, insertion, or deletion of a single base, the building block of DNA.
But the story was very different in the S4-low group. Generally, mutational profiles in this group were much more silent than the S4-high group. However, all cancer-related gene fusions, which are abnormally activated from the merging of two originally separate genes, were exclusively observed in the S4-low group.
The patterns of genomic structural changes underlying gene fusions suggest that about three in four cases of gene fusions emerged from a single cellular crisis causing massive genomic fragmentation and subsequent imprecise repair in normal lung epithelium.
Most strikingly, these major genomic rearrangements, which led to the development of lung adenocarcinoma, are very likely to be acquired decades before cancer diagnosis. The researchers used genomic archaeology techniques to trace the timing of when the catastrophes took place.
Researchers started this study seven years ago when they discovered the expression of the KIF5B-RET gene fusion in lung adenocarcinoma for the first time. Professor Young-Seok Ju, co-lead author from the Graduate School of Medical Science and Engineering at KAIST says, “It is remarkable that oncogenesis can begin by a massive shattering of chromosomes early in life. Our study immediately raises a new question: What induces the mutational catastrophe in our normal lung epithelium.”
Professor Young Tae Kim, co-lead author from Seoul National University says, “We hope this work will help us get one step closer to precision medicine for lung cancer patients.”
The research team plans to further focus on the molecular mechanisms that stimulate complex rearrangements in the body, through screening the genomic structures of fusion genes in other cancer types.
This study was supported by the National Research Foundation of Korea (NRF), Korea Health Industry Development Institute (KHIDI), Suh Kyungbae Foundation, the College of Medicine Research Foundations at Seoul National University and others.
- Researchers report minimalistic principles for designing small molecules with multiple reactivities against dementia. - Sometimes the most complex problems actually have very simple solutions. A group of South Korean researchers reported an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents against neurodegenerative disorders. The team developed redox-active aromatic molecular reagents with a simple structural composition that ca2020-05-11
A team of South Korean researchers found that lactation can lower the incidence and reduce the risk of maternal postpartum diabetes. The researchers identified that lactation increases the mass and function of pancreatic beta cells through serotonin production. The team suggested that sustained improvements in pancreatic beta cells, which can last for years even after the cessation of lactation, improve mothers’ metabolic health in addition to providing health benefits for infants. Pre2020-04-29
Solar cells convert light into energy, but they can be inefficient and vulnerable to the environment, degrading with, ironically, too much light or other factors, including moisture and low temperature. An international research team has developed a new type of solar cell that can both withstand environmental hazards and is 26.7% efficient in power conversion. They published their results on March 26 in Science. The researchers, led by Byungha Shin, a professor from the Department of Materia2020-03-27
- Biologically inspired ultrathin arrayed camera captures super-resolution images. - The unique structures of biological vision systems in nature inspired scientists to design ultracompact imaging systems. A research group led by Professor Ki-Hun Jeong have made an ultracompact camera that captures high-contrast and high-resolution images. Fully packaged with micro-optical elements such as inverted micro-lenses, multilayered pinhole arrays, and gap spacers on the image sensor, the camera boasts2020-03-23
KAIST researchers have developed a novel wearable strain sensor based on the modulation of optical transmittance of a carbon nanotube (CNT)-embedded elastomer. The sensor is capable of sensitive, stable, and continuous measurement of physical signals. This technology, featured in the March 4th issue of ACS Applied Materials & Interfaces as a front cover article, shows great potential for the detection of subtle human motions and the real-time monitoring of body postures for healthcare appl2020-03-20