Genomic correlates with ancestry in lung squamous cell carcinoma

Abstract Many studies show racial and ethnic survival disparities in lung squamous cell carcinoma (LSCC), and self-identified African-Americans have significantly lower overall survival and progression-free survival than self-identified Caucasians. However, survival models based on genetic ancestry, rather than self-identified race, are needed to assess whether genetic ancestry influences this survival disparity or whether the cause of the disparity is largely socioeconomic. Using clinically annotated genomic data from 501 LSCC tumor samples in the Cancer Genome Atlas (TCGA), we compared clinical data, gene expression profiles, mutations, and copy number changes of tumors across ancestral groups to identify significantly differential events. We then applied the Cox Proportional Hazards model to predict overall survival as a function of genetic ancestry alongside other genetic, molecular, and clinical variables. We found a significant difference in metastatic stage between tumors from patients of African (AFR) and European (EUR) ancestry, which was significant in predicting survival. We identified increased copy number of chromosome arm 8q and locus chr8q24, as well as increased expression of MYC targets in AFR samples relative to EUR samples, all of which suggest a role for the MYC pathway in differential cancer progression. In addition, we found enrichment of amplifications at chr22q11 and chr16p11 in AFR samples compared to EUR samples. We identified top differentially mutated genes between groups, of which mutant SPRR3, PDGFA, FRS3, and C21orf62 correlate with survival. Notably, when survival was modeled as a function of both genetic ancestry and SPRR3 mutation, genetic ancestry was no longer significant as a predictor of survival. The PDGFRA receptor is also significantly differentially expressed between groups, suggesting a possible role of the PDGF axis in differential tumor growth. These results suggest potential genetic and clinical factors implicated in racial survival disparities. Further studies and more diverse sampling of cancer patient populations would allow validation of these differences and future elucidation of patient-specific treatment modalities. Citation Format: Sejal Jain, Alexandria Yao, Diane Allen-Gipson, Fatemeh Momen-Heravi, Alison M. Taylor. Survival disparities in lung squamous cell carcinoma: Clinical and genomic correlates with genetic ancestry [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A009.