Head and neck squamous cell carcinoma (HNSCC) - a group of cancers that affect the mouth, nose and throat - is a disease driven by mutations in the NOTCH tumor suppressor signaling pathway, according to a new study.
It reveals the identity of rare driver mutations in tumor-suppressing genes using a mouse-based in vivo CRISPR screen to evaluate the function of so-called "long tail" mutations. In humans, these mutations are present in 67% of HNSCC patients and converge on NOTCH inactivation, thus promoting tumor development.
HNSCC is the 6th most common human cancer and, while curable, has a poor survival rate and claims the lives of roughly 350,000 people worldwide each year. Like other cancers, HNSCC is characterized by a few genes mutated at high frequency in many patients (including the NOTCH tumor suppressor gene), followed by a "long-tail" of hundreds of other individually rare mutations observed in only a few patients.
The functional consequences and biological significance of recurrent but rare mutations are generally unknown, but these mutations could potentially shed light on cancer biology and tumor evolution and perhaps lead to novel treatment strategies.
The researchers developed a reverse genetic CRISPR screen that allowed them to identify genes that, upon mutation, predispose mice to developing MNSCC. Through their analysis, the authors identified 15 potent tumor suppressor genes that, when mutated, triggered rapid growth of HNSCC in the mice. These genes included ADAM10 and AJUBA, which are also mutated in human HNSCC.
The wild type versions of ADAM10 and AJUBA promote NOTCH signaling. DAM10 and AJUBA mutations or monoallelic loss occur in 28% of human HNSCC cases and are mutually exclusive with NOTCH receptor mutations. The results show that oncogenic mutations in 67% of human HNSCC cases converge onto the NOTCH signaling pathway, making NOTCH inactivation a hallmark of HNSCC.
Rare driver mutations disrupt NOTCH signaling to promote squamous cell carcinoma
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