Abstract G-protein coupled receptors (GPCRs) and G-proteins are critical signal transduction molecules that regulate cell survival, proliferation, motility and differentiation. However, mutations and disruptions in the expression or function of these molecules have been linked to growth, progression and metastasis of various cancers. Recently, major efforts in the area of genome-wide sequencing of tumors have unveiled numerous previously uncharacterized mutations in G-proteins and GPCRs, which could have significant implications to cancer initiation and progression. In particular, mutations in the gene encoding the G-protein G13 (GNA13) and/or its downstream effector, RhoA, have been identified in B cell lymphomas (particularly Burkitt's lymphoma and Diffuse Large B cell Lymphoma), T cell lymphomas, and Head and Neck Squamous Cell Carcinomas (HNSCCs). Our analyses indicate that these mutations are highly statistically significant over background cancer gene mutation rate, and mutations in GNA13 alone occur in ∼10-15% of patients with Burkitt's lymphoma and Diffuse Large B cell Lymphoma. Surprisingly, although G13 and RhoA have previously been linked to cellular transformation and metastatic potential of epithelial cancers, our data suggests that the mutations in GNA13 and/or RHOA in these B cell lymphomas and HNSCC are inhibitory in nature. Furthermore, our results indicate a tumor suppressive function for wild-type GNA13 and RHOA in in vivo cancer models. Overall, our data suggest a novel function tumor suppressive function for the G13/RhoA axis in multiple human malignancies. Citation Format: Morgan O'hayre, Asuka Inoue, Katiuchia Sales, Irina Kufareva, Juan Luis Callejas Valera, Fukun Guo, Constantinos Mikelis, Giovanni DiPasquale, Kira Finkel, Junken Aoki, Yi Zheng, Thomas H. Bugge, J. Silvio Gutkind. Novel roles for GNA13 and RHOA as tumor suppressor genes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2059. doi:10.1158/1538-7445.AM2015-2059