P59.04 Sex-Related Differences in Genomic and Immune Profiling of Lung Adenocarcinoma

Abstract

The responses to therapeutic treatment can be finely tuned by sex-related cellular and/or molecular biology. Such sex determination for the disease onset and progression has been recognized in many tumor types. However, the sex disparities in genomic and immune profiles of lung adenocarcinoma (LUAD) remain poorly understood. The aim of this study is to explore the sex-associated biases in mutation and immune portrait across Asian and non-Asian LUADs. DNA sequencing (n=305) and mRNA expression profiles (n=172) of Asian LUADs are downloaded from OncoSG together with related clinical records. To assess possible interaction between sex and genetic background, the somatic mutational profiles (n=614) and mRNA expression profiles (n=425) of Non-Asian LUADs were also downloaded from The Cancer Genome Atlas. The relative abundance of different immune cells in tumor was determined using a method for deconvolving the cell composition of complex tissues from gene expression data. We then compared somatic mutation profiles and the abundance of tumor-infiltrating immune cells between male and female LUADs. Additionally, mRNA expression data from a Chinese CHOICE cohort (n=128 LUADs) were used to validate the sex-specific immune infiltrates deconvolved from OncoSG cohort. The major clinicopathological features of two cohorts are summarized in Figure 1. EGFR mutation was more frequent in smoker females than males across the two cohorts. While in non-smokers, EGFR mutation showed not significant gender disparities. A higher EGFR mutation frequency was observed in male non-smokers than smokers (P=0.004), regardless of ethnic origin. Interestingly, in the non-Asian cohort, EGFR mutation presented a significantly higher frequency in female non-smokers than female smokers (P<0.0001), but this divergence was not observed between Asian female smokers and non-smokers. Among smokers, EGFR mutation type in females can be described by the substitutions pointing out unique oncogenic etiologies including "UV light" (COSMIC Signature 7), “APOBEC” (Signature 2) and “Defective DNA MMR” (Signature 15), but not in males. While among non-smokers, “Smoking” signature (Signature 4) was preeminent in Asian males, but no in other subpopulations. Moreover, in silico analysis of cellular composition disclosed an increase of resting CD4 memory T cells and dendritic cells in Asian females compared to males. Additionally, Macrophages M2 were more abundant in Asian males compared to females. Our findings provided evidence that sex-related molecular and cellular components are involved in shaping tumor distinct genomic and immune features, which might have important impact on personalized targeted and immune therapy. Further research is warranted to identify the molecular mechanisms underlying sex-related differences.