Notch1 Mutations Are Drivers of Oral Tumorigenesis

Abstract

Disruption of NOTCH1 signaling was recently discovered in head and neck cancer. This study aims to evaluate NOTCH1 alterations in the progression of oral squamous cell carcinoma (OSCC) and compare the occurrence of these mutations in Chinese and Caucasian populations. We used a high-throughput-PCR-based enrichment technology and next generation sequencing (NGS) to sequence NOTCH1 in 144 samples collected in China. Forty nine samples were normal oral mucosa from patients undergoing oral surgery, 45 were oral leukoplakia biopsies and 50 were chemoradiation naïve OSCC samples with 22 paired-normal tissues from the adjacent unaffected areas. NOTCH1 mutations were found in 54% of primary OSCC and 60% of pre-malignant lesions. Importantly, almost 60% of leukoplakia patients with mutated NOTCH1 carried mutations that were also identified in OSCC, indicating an important role of these clonal events in the progression of early neoplasms. We then compared all known NOTCH1 mutations identified in Chinese OSCC patients with those reported in Caucasians to date. Although we found obvious overlaps in critical regulatory NOTCH1 domains alterations and identified specific mutations shared by both groups, possible gain-of-function mutations were predominantly seen in Chinese population. Our findings demonstrate that pre-malignant lesions display NOTCH1 mutations at an early stage and are thus bona fide drivers of OSCC progression. Moreover, our results reveal that NOTCH1 promotes distinct tumorigenic mechanisms in patients from different ethnical populations.

NOTCH Mutations: Multiple Faces in Human Malignancies

“…Nevertheless, the impact of this lack of matched controls is likely small, because the NOTCH1 mutations were observed in 50% of the 22 OSCC tumors with matched controls, which is comparable with 57% of the 28 tumors without matched controls in this study (22). The mutation frequency is also similar to our previously reported data where 90% of the OSCC patients had matched DNA controls and the NOTCH1 mutation rate was 43% (21).…”

“…The most interesting observation by Izumchenko and colleagues (22) is the high rate of NOTCH1 mutation in oral leukoplakia lesions from a Chinese cohort. Based on the calling criteria by the investigators, 60% of the 45 lesions carried at least one NOTCH1 mutation (22), representing the most common genetic alterations in a single gene ever observed in such lesions.…”

“…In this issue, Izumchenko and colleagues (22) studied an independent Han Chinese OSCC cohort (50 patients) and found that NOTCH1 mutations in 54% of the tumors with approximately 40% of the mutations are potentially gain-of-functions. The results are consistent with our findings in the Han Chinese, which provide further support for the considerable differences in NOTCH1 mutation rate and mutation spectrum between Caucasian and Chinese OSCC.…”

“…Based on the calling criteria by the investigators, 60% of the 45 lesions carried at least one NOTCH1 mutation (22), representing the most common genetic alterations in a single gene ever observed in such lesions. It should be noted, however, the data are derived from a relatively small patient cohort with no matched DNA controls and are not validated in independent cohorts.…”

Expression and influence of Notch signaling in oral squamous cell carcinoma

“…On the other hand, Notch may also attenuate development of oral cancer. Although this hypothesis was supported by evidence that demonstrated the presence of NOTCH1 mutation in OSCC patients (17,18); the role of Notch signaling in OSCC is yet to be clarified. The Gene Expression Omnibus (GEO) database has grown tremendously in recent years (19).…”