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TB-related genes associated with lung cancer in Asian female never-smokers

Natalia Reoutova
29 Jul 2019

A recently published analysis of the world’s largest genome-wide association study (GWAS) of lung cancer among female never-smokers found a set of tuberculosis (TB)-related genes associated with lung adenocarcinoma in Asian women.

In order to evaluate whether genetic factors related to TB play a role in lung cancer development, researchers analyzed genome-wide data from 5,512 lung adenocarcinoma cases and 6,277 cancer-free controls from the Female Lung Cancer Consortium in Asia (FLCCA), which recruited never-smoking Asian female adult residents of mainland China, Hong Kong, Singapore, Taiwan, South Korea, and Japan. [Genomics 2019, doi: 10.1016/j.ygeno.2019.07.00]

The investigators, including eight researchers from Queen Mary Hospital and The University of Hong Kong, identified four TB-related genes that were significantly associated with lung adenocarcinoma in the FLCCA cohort.

Asian women have among the highest incidence rates of lung cancer in the never-smoker population worldwide. [PLoS Med 2008;5:e185] Previous genome-wide studies have identified multiple genetic loci that contribute to an increased risk of lung adenocarcinoma among never-smoking women, but the genetic variants identified to date explain only an estimated 12 percent of the heritability of lung cancer risk. [J Natl Cancer Inst 2015;107:djv279]

In addition to heritable causes, evidence from multiple epidemiological and clinical studies also suggests a link between pulmonary TB and lung cancer. [J Thorac Oncol 2011;6:32-37; Int J Cancer 2016;139:2447-2455] TB infection may contribute to increased lung cancer risk through biological mechanisms involving prolonged pulmonary inflammation, leading to tissue damage, fibrosis, scar formation and genomic damage. [Int J Cancer 2009;124:1183-1187; Oncogene 2009;28:1928-38]

“We conducted a pathway analysis in the largest GWAS of lung cancer among female never-smokers in the world to determine whether genetic factors related to TB contribute to lung adenocarcinoma development,” wrote the researchers. “To follow up on the pathway analysis and generate further evidence for a TB-lung cancer link, we conducted mendelian randomization to evaluate a possible causal association between TB and lung adenocarcinoma among never-smoking Asian women.”

The overall analysis set of 31 TB-related genes, which was compiled using known or suggestive TB-associated single nucleotide polymorphism from previous global GWASs, was shown to be associated with lung adenocarcinoma (ppathway=0.016) among never-smoking Asian women. Within the set, four genes, namely, forkhead-associated phosphopeptide binding domain 1 (FHAD1; p=0.001), zinc finger protein FOG family member 2 (ZFPM2; p=0.020), discs large MAGUK scaffold protein 2 (DLG2; p=0.017), and major histocompatibility complex class (MHC) II DQ alpha 1 (HLA-DQA1; p=0.009), were identified as having the greatest contribution to the TB-lung adenocarcinoma association.

HLA-DQA1 was one of the most notable contributing genes in the pathway analysis due to its central role in regulating adaptive immune response. A previous study found that variants of the HLA-DQA1 gene were associated with lung adenocarcinoma in a Japanese population. [Carcinogenesis. 2010;31:834-841]

“Our findings add to the evidence that TB is a causal risk factor for lung cancer development among never-smoking Asian women and contribute to the understanding of the biological mechanism underlying lung carcinogenesis independent of cigarette smoking,” concluded the researchers.

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