Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma

Abstract

Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ∼75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.cancer genetics | genomic | cellular signaling

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

“…Most of the NOTCH1 alterations (8 in 17) were truncating mutations, likely causing loss of function 88. Similarly, an analysis of publicly available lung SCC exome‐sequencing data revealed mutations of NOTCH1 and NOTCH2 at a combined frequency of 12.5% 5.…”

“…Whole‐exome or NOTCH1 / NOTCH2 exons sequencing of primary CSCC or CSCC cell lines identified NOTCH1 or NOTCH2 mutations in ~75% of samples tested 5. The missense mutations were found to be localized to NECD EGF‐like repeats, NECD HD domain, and the intracellular RAM domain.…”

“…Gene alteration data are obtained from COSMIC (B) NOTCH 1 mutations identified in CSCC 5. (C‐F) NOTCH 1 mutations identified in HNSCC , esophageal SCC , lung SCC , and cervical SCC , respectively.…”

“…To our knowledge, only three mutations identified from CSCC have been characterized 5. To gain more insights into these mutations, we resorted to the accumulating structural knowledge of Notch signaling.…”

“…However, Notch signaling activation can be tumor suppressive or oncogenic, depending on cellular context 4. Recently, considerable NOTCH gene mutations were identified in different types of squamous cell carcinoma 5, 6, 7, 8, 9, questioning the general role of Notch pathway in SCCs.…”