Rare genetic variants contribute to increased risk for lung cancer

In the United States, lung cancer is the main cause of cancer death in both male and female populations. Although lifestyle factors, such as smoking, and environmental factors can influence the risk for this disease, studies have estimated that 18% of lung cancer cases are caused by inherited genetic variants.

A new study headed by Baylor College of Medicine has now analyzed how genetic variants play a crucial role in the elevated risk of lung cancer.

The investigators carried out whole-exome sequencing on germline (inherited) DNA obtained from eight massive datasets, including 1,045 patients who have a family history of lung cancer or genetic risk of early-onset cancer. It is believed that these groups are more likely to carry genetic risk variants. Besides this, 885 control cases were also included in the study.

We were looking for variants that have a relatively high impact on risk but occur at relatively low frequency. If a variant occurs at low frequency, you have to look at many different large data sources to validate the variant. These results can be replicated in many different European populations.”

Dr Chris Amos, Director of Institute for Clinical and Translational Research, Baylor College of Medicine

Dr. Amos is also the study corresponding author and professor of medicine, Epidemiology and Population Sciences at Baylor College of Medicine.

The team detected 25 new rare variants of pathogens that are linked to lung cancer risk and verified five of these variants. Among the five pathogenic variants, two involved genes, such as MPZL2 and ATM, with familiar associations with lung cancer risk. Similarly, three pathogenic variants involved new genes, such as MLNR, STAU2, and POMC, associated with lung cancer risk.

According to Dr. Yanhong Liu, the co-first author of the study, whole-exome sequencing enabled the team to detect more numbers of variants that affect the function of cells and proteins.

Investigating the Contribution of Insertions or Deletions

Mutations of DNA where sections are either inserted or deleted have been understudied compared to single nucleotide variants, but they are also very important because they can result in truncated proteins. Of the 25 candidate variants we identified, two-thirds of them are insertions or deletions.”

Dr Yanhong Liu, Study Co-First Author and Assistant Professor of Medicine, Epidemiology and Population Sciences, Baylor College of Medicine

Dr. Liu is also a member of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine.

To find out how these candidate variants have an impact on cellular functions, the researchers from Baylor College of Medicine used endogenous DNA damage assays. These assays check the replications of specific types of DNA mutations.

The researchers proposed that lung cancer risk genes lead to an increased level of endogenous DNA damage in cells, resulting in genomic instability and, eventually, leading to cancer.

Many studies have looked at lung cancer risk genes, but the function of those genes has not been well understood. In our study, we found that dysregulation or mutations in these candidate genes showed increased DNA damage, suggesting that their potential cancer-causing role might be due to genome instability at the DNA level.”

Dr Jun Xia, Postdoctoral Associate, Department of Molecular and Human Genetics and Institute for Clinical and Translational Research, Baylor College of Medicine

Dr. Xia is also the co-first author of the study.

The study demonstrated that ATM, MLNR, and POMC genetic variants caused higher levels of DNA damage. The ATM variant is known to be a crucial first responder to DNA damage, and many such ATM genetic variants have been associated with an increased risk for numerous cancers.

According to Dr. Amos, figuring out which variants cause greater DNA damage could be crucial to identifying new treatments for these cancers.

We know from breast cancer that PARP inhibitors, drugs that prevent DNA repair, work in people with inherited BRCA1 and BRCA2 mutations because those cells already have some DNA damage due to the inherited mutation,” added Dr. Amos, who is also a member of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine and aCPRIT Scholar.

If you disable PARP, the cancer cells can't repair DNA damage and won't survive, It’s possible that people with inherited ATM mutations causing them to develop lung cancer may respond to those PARP inhibitors as well, and that is something that needs to be studied further,” Dr. Amos concluded.

Source:
Journal reference:

Liu, Y., et al. (2021) Rare deleterious germline variants and risk of lung cancer. npj Precision Oncology. doi.org/10.1038/s41698-021-00146-7.

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