Double mutation in ARID1A and PIK3CA in luminal breast cancer is associated with inflammation-driven tumorigenesis
2Institute of Oncology, Tel Aviv Sourasky Medical Center, Israel
3Sackler Faculty of Medicine, Tel Aviv University, Israel
4Adelson School of Medicine, Ariel University, Israel
Tumorigenesis is promoted by the co-occurrence of certain mutations in cancer risk genes. Co-occurrence of PIK3CA and ARID1A mutations in luminal breast cancer leads to a more aggressive, basal-like phenotype. However, uncertainty remains about how these mutations work together to promote tumor cell growth.
The main goal of this project is to reveal the effect of ARID1A loss separately and in combination with PIK3CA mutations on important cellular and signaling pathways in luminal breast tumors.
We utilized gene set and pathway enrichment analyses of primary breast cancer tumors from TCGA and METABRIC datasets.
Our results show enrichment of ARID1A and PIK3CA double mutations in luminal tumors. Supervised and unsupervised gene expression analyses revealed an association of immune-system-related pathways in tumors harboring the double mutations compared to tumors having mutation only in ARID1A or PIK3CA genes.
Assessment of Tumor-Infiltrating Lymphocytes (TILs) into the tumor microenvironment using gene expression profiles showed a unique composition of TILs in tumors harboring the double mutation, which includes an increase in Tregs and reduction in Eosinophils. These results indicate an impaired immune system function that may contribute to tumor survival.
The high rate of Tumor Mutational Burden (TMB) and upregulation of CTLA-4 expression identified in tumors containing double mutations may suggest that these tumors are good candidates for immunotherapy treatments such as CTLA-4 inhibitors.
Overall, by examining gene expression profiles, we were able to understand better the immune system-related mechanisms underlying the proliferation of cancer cells in tumors with both ARID1A and PIK3CA mutations.