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Early Genome Catastrophes Can Cause Non-Smoking Lung Cancer
Some teenagers harbor catastrophic changes to their genomes that can lead to lung cancer later on in life, even if they never smoke
(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.
Figure.
(Smoking-unrelated oncogenesis of lung cancers by gene fusions)
Publication.
Jake June-Koo Lee, Seongyeol Park et al., Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma
Cell 177, June 13 2019, online publication ahead of print at May 30, 2019
https://doi.org/10.1016/j.cell.2019.05.013
Profile: Prof Young Seok Ju, MD, PhD
ysju@kaist.ac.kr
http://julab.kaist.ac.kr
Associate Professor
Graduate School of Medical Science and Engineering (GSMSE)
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon 34141, Korea
Profile: Prof Young Tae Kim, MD, PhD
ytkim@snu.ac.kr
Professor
Seoul National University Cancer Research Institute
Department of Thoracic and Cardiovascular Surgery
Seoul National University Hospital Seoul 03080, Korea
2019.05.31 View 61816 -
KAIST Opens Cell Bench Research Center
KAIST opened a cell bench research center on the campus on Monday, Nov. 17, as a joint project with Samsung Electric Co. and Samsung Medical Center.
On hand at the opening ceremony were about 100 persons from the three organizations, including KAIST President Nam-Pyo Suh, Samsung Electric"s Chief Technology Officer (CTO) Byung-Cheon Koh and Samsung Medical Center Vice President Hyo-Geun Lim.
The newly-opened research center will be involved in the development of individually-tailored anti-cancer medicine using bio-inspired cell chips and technologies for clinical applications. Prof. Young-Ho Cho of the Department of Bio and Brain Engineering was named director of the research center.
"Top-notch professionals from the electronic industry, academia and the medical community have gathered together to establish this research center. We expect the center will open a new path for the science and technology community and the industry to combine their strengths and develop innovative anti-cancer therapeutics," said KAIST President Nam-Pyo Suh at the opening ceremony.
"The development of bio-cell chip technology represents a new challenge for the Samsung Electric which has focused on information technologies thus far. Through cooperation with KAIST and Samsung Medical Center, we expect to be able to develop a simple and efficient cure for cancer patients," commented Samsung Electric CTO Byung-Cheon Koh.
The research center will be initially concentrating on the development of cell chips for lung cancer, one of the primary causes of death for Koreans.
2008.11.17 View 23144