Interaction between polygenic risk score and reproductive factors in relation to lung cancer risk among Singaporean Chinese women

Objectives

Studies have shown that reproductive factors can influence hormone levels in females, potentially affecting the risk of developing lung cancer. However, it remains unclear whether this association is modified by genetic variants.

Study design

Age-matched case-control study.

Methods

Reproductive factors included menopausal status, age at menopause, hormone use, hysterectomy and oophorectomy. Odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between reproductive factors and lung cancer risk were estimated using a multivariable conditional logistic regression model. A polygenic risk score (PRS) was calculated using a clumping plus thresholding approach. Gene-environment interactions between reproductive factors and PRS on lung cancer risk were evaluated.

Results

Our analysis included a total of 2910 female participants (1455 cases and 1455 controls). Compared to women with no surgical history, those who had undergone hysterectomy (OR = 1.41, 95 % CI = 1.10–1.82) or oophorectomy (OR = 1.52, 95% CI = 1.15–2.02) were associated with an increased risk of lung cancer. A PRS for lung cancer derived from 7 genetic variants showed a linear association with lung cancer risk (P_trend < 0.001). After adjusting for false discovery rate (FDR), we found a borderline non-significant interaction between hormone use and PRS on lung cancer risk (P_{interaction-FDR} = 0.05).

Conclusions

Women with a history of hysterectomy or oophorectomy had a higher risk of lung cancer compared to those without such surgical history, highlighting the need for targeted prevention strategies in this high-risk population. No significant effect modification by the lung cancer PRS was observed in the associations between reproductive factors and lung cancer risk. Larger prospective studies are warranted to validate these findings.