Rare driver mutations disrupt NOTCH signalling to promote squamous cell carcinoma

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Head and neck squamous cell carcinoma (HNSCC) – a group of cancers that affect the the mouth, nose and throat – is a disease driven by mutations in the NOTCH tumour suppressor signalling pathway, according to a new study.

It reveals the identity of rare driver mutations in tumour-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 tumour 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 characterised by a few genes mutated at high frequency in many patients (including the NOTCH tumour 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 tumour evolution and perhaps lead to novel treatment strategies.

Sampath Loganathan and colleagues developed a reverse genetic CRISPR screen that allowed them to identify genes that, upon mutation, predispose mice to developing MNSCC.

The research is published in the journal Science.

Through their analysis, Loganathan et al. identified 15 potent tumour 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 signalling.

These results show that HNSCC-associated mutations converge on inactivation of the NOTCH tumour suppressor signalling pathway.

Source: American Association for the Advancement of Science


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The ONA Editor curates oncology news, views and reviews from Australia and around the world for our readers. In aggregated content, original sources will be acknowledged in the article footer.

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