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NOTCH1 and PIK3CA mutation are related to HPV-associated vulvar squamous cell carcinoma
M Choschzick1, C Stergiou1, A Gut1
1Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
Abstract:
NOTCH1 and PIK3CA are members of important cell signalling pathways that are deregulated in squamous cell carcinomas of various organs. Vulvar squamous cell carcinomas (vulvSCC) are classically divided into two pathways, HPV-associated or HPV-independent, but the effect of NOTCH1 and PIK3CA mutations in both groups is unclear. We analysed two different cohorts of vulvSCC using Hybrid Capture-based Comprehensive Genomic Profiling and identified NOTCH1 and PIK3CA mutations in 35% and 31% of 48 primary vulvSCC. In this first cohort, PIK3CA and NOTCH1 mutations were significantly correlated with HPV infection (p < 0.01). Furthermore, mutations in both genes were associated with an advanced tumor stage and poorly differentiated status (p < 0.05). PIK3CA and NOTCH1 mutations were also associated with shorter patient survival which did not reach significance. In the second cohort of 735 advanced vulvSCC from metastatic site biopsies or from sites of unresectable loco-regional disease, NOTCH1 and PIK3CA mutations were reported in 14% and 20.3%, respectively. 4 of 48 (8%) and 22 of 735 vulvSCC (3.0%) featured genomic alterations (short variants and/or copy number changes and/or rearrangements) in both NOTCH1 and PIK3CA. NOTCH1 mutations were mostly located in the extracellular EGF-like domains, were inactivating and indicated that NOTCH1 functions predominantly as a tumor suppressor gene in vulvSCC. In contrast, PIK3CA mutations favored hotspot codons 1624 and 1633 of the gene, indicating that PIK3CA acts as an oncogene in vulvar carcinogenesis. In conclusion, NOTCH1 and PIK3CA mutations are detectable in a substantial proportion of vulvSCC and are related to HPV infection and more aggressive tumor behaviour.
Insights
Mutations in NOTCH1 and PIK3CA genes are common in vulvar squamous cell carcinomas (vulvSCC) and linked to HPV infection and aggressive tumor behavior. These genetic alterations suggest distinct roles for NOTCH1 as a tumor suppressor and PIK3CA as an oncogene in vulvar cancer development.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Squamous cell carcinomas of the vulva (vulvSCC) are classified by HPV association, but the roles of NOTCH1 and PIK3CA mutations remain unclear.
- NOTCH1 and PIK3CA are key players in cell signaling pathways frequently dysregulated in various squamous cell carcinomas.
Purpose of the Study:
- To investigate the prevalence and clinical significance of NOTCH1 and PIK3CA mutations in different vulvSCC cohorts.
- To determine the association of these mutations with HPV status, tumor characteristics, and patient survival.
Main Methods:
- Comprehensive genomic profiling using Hybrid Capture was performed on two cohorts of vulvSCC.
- Analysis included identification of short variants, copy number changes, and rearrangements in NOTCH1 and PIK3CA.
- Statistical methods were used to correlate mutations with HPV infection, tumor stage, differentiation, and survival.
Main Results:
- NOTCH1 and PIK3CA mutations were identified in 35% and 31% of primary vulvSCC, respectively, and correlated significantly with HPV infection.
- Mutations in these genes were associated with advanced tumor stage and poor differentiation.
- NOTCH1 mutations were predominantly inactivating, suggesting a tumor suppressor role, while PIK3CA mutations favored oncogenic hotspots.
Conclusions:
- NOTCH1 and PIK3CA mutations are frequent in vulvSCC and linked to HPV status and aggressive tumor behavior.
- NOTCH1 acts as a tumor suppressor, whereas PIK3CA functions as an oncogene in vulvar carcinogenesis.
- These findings highlight the importance of these genetic alterations in understanding vulvSCC pathogenesis and potential therapeutic targets.
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