Elucidating the Consequences of Chromosome 3 Arm Aneuploidies in Squamous Cell Carcinoma

PROJECT SUMMARY Aneuploidy, the gain or loss of whole chromosomes or chromosome arms, is a near-universal feature of cancer. However, the role of aneuploidy in tumor pathogenesis remains an unanswered question in cancer biology. Squamous cell carcinomas (SCCs), whether in the lung, esophagus or head and neck, are characterized by

specific patterns of aneuploidy. In many SCCs, unlike other cancer types, there are fewer oncogenic mutations identified resulting in few targeted therapies available for patients. However, SCCs are characterized by a distinct aneuploidy profile. In particular, chromosome arm 3p is lost in almost 80% of lung SCCs, with gain of

chromosome arm 3q the next most frequent event in this cancer type. Our preliminary data suggest that these two aneuploidy events play an important role in oncogenesis in this tumor type and may be a useful disease target. The goal of this proposal is to understand the phenotypic consequences of chromosome 3 arm aneuploidies.

We have previously developed a genome engineering approach to delete chromosome arm 3p in human lung epithelial cells. With this approach, we also isolated isogenic cell lines with chromosome 3q gain. Using this model system, here we will explore three pathways affected by these aneuploidy events: (1) lipid and PI3K

signaling in cells with chromosome 3q gain, (2) hypoxia response and VHL haploinsufficiency in cells with chromosome 3p deletion, and (3) squamous differentiation and tumorigenesis. By determining the effect of chromosome 3p deletion and chromosome 3q gain in lung cells, we will gain insights into how a patient-specific

aneuploidy contributes to tumor development. These studies may also identify novel therapeutic targets for treatment of SCCs.