DNA Damage In Early Life Linked To Lung Cancer

Using whole-genome sequencing techniques, researchers in South Korea have found that some lung cancer-associated mutations can occur decades before the disease presents itself.

AsianScientist (Jun. 18, 2019) – A team of scientists in South Korea has demonstrated that genomic anomalies during early childhood and adolescence can lead to the development of lung cancer in later years, even in non-smokers. Their findings are published in Cell.

Lung cancer is a leading cause of cancer-related deaths worldwide, and lung adenocarcinoma is the most common subtype of lung cancer. Most lung adenocarcinomas are associated with chronic smoking, but about a fourth develop in non-smokers. Precisely what happens in non-smokers to allow cancer development is not clearly understood.

In the present study, researchers led by Professor Ju Young-Seok at the Korea Advanced Institute of Science and Technology, South Korea, analyzed the genomes of 138 lung adenocarcinoma patients, including smokers and non-smokers, using whole-genome sequencing technologies. They explored DNA damage that induced uncontrolled cell growth and malignant 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, were male and had more frequent mutations in a cancer-related gene called KRAS.

The researchers also noted that cancer genomes in the S4-high group were hypermutated with simple mutational classes, such as the substitution, insertion or deletion of a single DNA base. In contrast, 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 cells.

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.

“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?” said Ju.

The research team plans to delve into the molecular mechanisms that stimulate complex rearrangements in the body by screening the genomic structures of fusion genes in other cancer types.

The article can be found at: Lee et al. (2019) Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma.


Source: Korea Advanced Institute of Science and Technology; Photo: Shutterstock.
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