PhD Defense: Genetic dissection of the 11q13 amplicon in squamous cell carcinoma

Head and neck cancer is a morbid and lethal disease with limited treatment options. These cancers develop from a cell type called keratinocytes that line the cavities of the mouth, nose, and throat. Accumulation of specific alterations to the DNA of these cells can result in uncontrolled cell proliferation and eventually cancer.

A better understanding of the mechanisms through which these alterations contribute to cancer development can help identify better treatment options. 25% of all head and neck cancers have gained extra copies of a particular part of the DNA that is located on chromosome 11, called the 11q13 amplicon. The 11q13 amplicon contains 10 genes and it is unclear which of these genes contribute to cancer development. Here, we describe a systematic approach in which we test the role of all these genes in cancer development. We use a combination of techniques and models, including a novel workflow that we developed to efficiently deliver so-called CRISPR-Cas machinery to keratinocytes, which allows us to make very precise edits to the DNA of these cells.

We identify three genes on the 11q13 amplicon (CCND1, MIR548K, and ORAOV1) that contribute to tumor formation. Particularly for CCND1 and ORAOV1, we find that increased activity of either gene is sufficient to induce tumor growth in mice. In subsequent analyses we find novel mechanisms through which these genes contribute to head and neck cancer progression and we identify ways to target these activities, thus suggesting novel therapeutic approaches for patients with 11q13-amplified head and neck cancer.