Using Gene Regulatory Networks to Understand Sex Differences in Lung Cancer Gene Regulation

Rationale: Significant sex and gender differences occur in risk factors, incidence, clinical characteristics, progression, and therapeutic responses of lung cancer. Lung cancer risk is higher in women than men, although mortality rates are higher in men than in women. Despite the growing realization that we need to explicitly account for sex and gender differences in both basic and translational research, sex- and gender-based analyses of genomic data have been limited, thus neglecting an essential biological variable to advance precision oncology.

Methods: We developed a sex-specific network approach to integrate genomic data and model gene regulation in males and females. We used gene expression data from 497 male and 440 female study participants from GTEx and TCGA, and inferred subject-specific gene regulatory networks for normal lung tissue and for lung adenocarcinoma.

Results: First, we investigated whether there are regulatory processes in normal lung tissues that might explain sex differences in cancer risk. We identified oncogenes and tumor suppressor genes that are differentially targeted by transcription factors in males and females, including tumor suppressor genes that escape X chromosome inactivation in females. We found that sex-biased transcription factor master regulators target cancer-related pathways in females, including WNT, NOTCH, and p53 (FDR<0.05). Next, by comparing lung adenocarcinoma gene regulatory networks, we found marked sex differences in transcriptional regulatory processes relevant to lung cancer development and progression. Drug metabolism-cytochrome P450 and immune-related pathways were more highly targeted in females, while cancer-related pathways were highly targeted in males, such as WNT, NOTCH, and MAPK signaling pathways (FDR<0.05).

Conclusions: We found significant sex differences in transcription factor regulatory patterns in both normal lung and lung adenocarcinoma. Network medicine approaches revealed gene regulatory differences for cancer susceptibility in women and poor prognosis in men providing insights into sex-biased manifestation of lung cancer risk and outcome.