Study examines how genetic modifications contribute to increased risk of lung cancer

Lung cancer is the leading cause of cancer death in the U.S. for both men and women. Although environmental and lifestyle factors such as smoking may influence risk for this disease, studies indicate that 18% of lung cancer cases are due to inherited genetic changes. New research led by Baylor College of Medicine is examining how genetic changes contribute to an increased risk of lung cancer.

The researchers performed a complete exome sequence on germline (hereditary) DNA from eight big data sets, including 1,045 patients with a family history of lung cancer or early breast cancer. These groups are more likely to capture a variety of genetic hazards. The analysis also included 885 control cases.

We were looking for changes that will have a relatively high risk impact but that will occur at a relatively low frequency. If a variable occurs at low frequency, you need to look at many different big data sources to determine the variable. These results can be replicated in many different European groups. “

Professor Chris Amos, Associate Author, Professor of Medicine – Epidemiological and Population Sciences and Director, Baylor Institute for Clinical and Translational Research (ICTR)

The researchers identified 25 new rare pathogenic changes associated with lung cancer susceptibility and confirmed five of these variables. Of those five, two different types included genes with known links to lung cancer risk, ATM and MPZL2. Three modifications included lung cancer vulnerability genes, POMC, STAU2 and MLNR. According to the co-author of the study, Dr. Yanhong Liu, exome sequencing allowed the researchers to identify further changes that affect protein and cell function.

Checking an insert or delete donation

“DNA mutations where fragments are either inserted or removed have been compared to single nucleotide mutations, but they are also very important because they can cause heating proteins,” said Liu, professor medicine – epidemiology and population sciences and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. “Of the 25 candidate changes we’ve announced, two-thirds are either submit or delete.”

To further understand the impact of these candidate differences on cell functions, Baylor researchers applied endogenous DNA damage assessments, which test for reactions of specific types of DNA mutations. They assumed that lung cancer risk genes lead to increased levels of endogenous DNA damage in cells, leading to genomic instability and ultimately causing cancer.

“Many studies have looked at lung cancer risk genes, but the function of these genes has not been well understood. In our study, we found that dysregulation or mutations in these candidate genes showed more DNA damage , suggesting that their potential cancer-causing role may be due to genome instability at the DNA level, “said Dr. Jun Xia, co-author of the study and co postdoctoral liaison in Baylor’s Department of Molecular and Human Genetics and ICTR.

The analysis showed that changes in POMC, MLNR and ATM increased levels of DNA damage. ATMs are known to be the first critical responder to DNA damage, and several ATM modifications are associated with increased vulnerability for many cancers. According to Amos, understanding what variables cause more DNA damage could be fundamental in solving treatments for these cancers.

“We know from breast cancer that PARP inhibitors, drugs that inhibit DNA repair, work in people with BRCA1 and BRCA2 mutations because some DNA damage to these cells is the result of imitation If you disable PARP, cancer cells cannot repair DNA damage and will not survive, “said Amos, a member of Baylor ‘s Dan L Duncan Comprehensive Cancer Center and CPRIT Scholar. “It is possible that people with inherited ATM mutations that lead to the development of lung cancer may also respond to these PARP inhibitors, which is something that needs to be explored further.”