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Rare driver mutations in head and neck squamous cell carcinomas converge on NOTCH signaling
Sampath K Loganathan1, Krista Schleicher1,2, Ahmad Malik1,2
1Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Abstract:
In most human cancers, only a few genes are mutated at high frequencies; most are mutated at low frequencies. The functional consequences of these recurrent but infrequent "long tail" mutations are often unknown. We focused on 484 long tail genes in head and neck squamous cell carcinoma (HNSCC) and used in vivo CRISPR to screen for genes that, upon mutation, trigger tumor development in mice. Of the 15 tumor-suppressor genes identified, ADAM10 and AJUBA suppressed HNSCC in a haploinsufficient manner by promoting NOTCH receptor signaling. ADAM10 and AJUBA mutations or monoallelic loss occur in 28% of human HNSCC cases and are mutually exclusive with NOTCH receptor mutations. Our results show that oncogenic mutations in 67% of human HNSCC cases converge onto the NOTCH signaling pathway, making NOTCH inactivation a hallmark of HNSCC.
Insights
Researchers identified 15 tumor-suppressor genes, including ADAM10 and AJUBA, that suppress head and neck squamous cell carcinoma (HNSCC). These genes promote NOTCH receptor signaling, and their inactivation is a hallmark of HNSCC.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Most human cancers exhibit a few high-frequency mutations and many low-frequency "long tail" mutations with unknown functional roles.
- The significance of low-frequency genetic alterations in cancer development remains largely unexplored.
Purpose of the Study:
- To investigate the functional consequences of "long tail" mutations in head and neck squamous cell carcinoma (HNSCC).
- To identify genes that, when mutated, drive tumor development in HNSCC.
Main Methods:
- Utilized in vivo CRISPR screening in mice to assess the impact of mutations in 484 "long tail" genes in HNSCC.
- Analyzed gene mutations, monoallelic loss, and their association with NOTCH receptor signaling and mutations in human HNSCC samples.
Main Results:
- Identified 15 tumor-suppressor genes that suppress HNSCC development in mice.
- Discovered that ADAM10 and AJUBA act as haploinsufficient tumor suppressors by enhancing NOTCH receptor signaling.
- Found that ADAM10 and AJUBA mutations or monoallelic loss occur in 28% of HNSCC cases and are mutually exclusive with NOTCH receptor mutations.
Conclusions:
- Inactivation of the NOTCH signaling pathway is a key event in 67% of human HNSCC cases.
- ADAM10 and AJUBA are critical tumor suppressors in HNSCC, highlighting the importance of the NOTCH pathway in this cancer type.
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