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Gregory J. Riely, MD, PhD
Gregory J. Riely, MD, PhD
Posted: Monday, April 28, 2025
In a genetic association study, researchers found that individuals with higher genetically estimated sensitivity to environmental stress and adversity face a significantly increased risk of lung cancer. Specifically, participants of European ancestry had increased risk for squamous cell carcinoma, while those of East Asian ancestry had increased risk for adenocarcinoma.
Using Mendelian randomization methods, Yingxi Chen, MD, PhD, of the National Cancer Institute at the National Institutes of Health in Rockville, Maryland, and colleagues identified associations across ancestries and histologic subtypes, which provided new insights into the potential psychosocial contributors to lung cancer risk.
The analysis, which was recently published in JAMA Network Open, combined data from 351,827 participants in the U.K. Biobank, as well as genome-wide summary statistics from 61,047 lung cancer cases and 947,237 controls from the International Lung Cancer Consortium, to identify genetic variants associated with sensitivity to stress and adversity. European, East Asian, and African ancestries were represented in the data.
The researchers defined stress sensitivity based on a cluster of personality traits related to neuroticism (e.g., emotional reactivity, guilt, worry) and selected 37 independent genetic variants (single-nucleotide variants [SNVs]) that were not linked to smoking or carcinogen exposure to serve as instruments in the Mendelian randomization (MR) analysis. They used the robust adjusted profile score as the primary MR method, supported by debiased inverse-variance weighted and MR median sensitivity analyses. Genetic variants were selected based on genome-wide significance (P < 5 × 10⁻⁸), followed by linkage disequilibrium clumping and the exclusion of SNVs linked to smoking behavior.
The investigators found that individuals with high genetically estimated sensitivity to environmental stress had a 49% increased risk of lung cancer. In their cross-ancestry analysis, they found a 45% increased risk, though no statistically significant associations were observed among those of East Asian ancestry (odds ratio [OR] = 1.26, 95% confidence interval [CI] = 0.66–2.41; P = .48) or African ancestry (OR = 1.33, 95% CI = 0.50–3.55; P = .57).
Those of European ancestry had an odds ratio of 1.69 for squamous cell carcinoma (95% CI = 1.06–2.70; P = .03), but no statistically significant associations for adenocarcinoma and small cell lung cancer.
In comparison, those of East Asian ancestry had an odds ratio of 2.04 for adenocarcinoma (95% CI = 1.00–4.18; P = .05), but no other significant associations for other lung cancer subtypes. Those of African ancestry had no significant associations across any subtypes.
The researchers also briefly discussed the prolonged process of malignancy development and cancer dormancy. “Cancer risk may be elevated both through disease initiation and through escape from dormancy or accelerated progression to clinical manifestation,” they wrote. “Further research is warranted to elucidate the underlying mechanisms driving the observed associations among humans.”
Study limitations included the genetic instruments for stress sensitivity, which were derived primarily from individuals of European ancestry. The smaller sample sizes for African and East Asian participants also limited statistical power for subgroup analyses, and the analyzed stress-related trait represents a narrow slice of broader psychosocial adversity.
The investigators concluded, “These results not only contribute to our understanding of lung cancer’s multifaceted nature but also underscore the necessity for further research into the nuanced association between psychosocial stress and cancer risk, with a particular focus on diverse populations.”
Disclosures: Disclosures can be found at jamanetwork.com.
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