Correlation of alterations in the KEAP1/CUL3/NFE2L2 pathway with radiation failure in larynx squamous cell carcinoma

Objectives Patients with laryngeal squamous cell carcinoma (LSCC) often fail radiation therapy (RT), when received as monotherapy or in combination with other treatment modalities. Mechanisms for RT failure are poorly understood. We hypothesized that tumors failing RT would have increased rates of s...

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Published in:Laryngoscope investigative otolaryngology 2021-08, Vol.6 (4), p.699-707
Main Authors: Sheth, Siddharth, Farquhar, Douglas R., Schrank, Travis P., Stepp, Wesley, Mazul, Angela, Hayward, Michele, Lenze, Nicholas, Little, Paul, Jo, Heejoon, Major, M. Ben, Chera, Bhishamjit S., Zevallos, Jose P., Hayes, D. Neil
Format: Article
Language:English
Subjects:
Automation
Bioinformatics
Cancer therapies
Chemotherapy
Enzymes
Gene expression
Genomes
HEAD AND NECK, AND TUMOR BIOLOGY
Homeostasis
Human papillomavirus
Laryngeal cancer
laryngeal squamous cell carcinoma
Mutation
Original Research
Oxidative stress
Patients
radiation resistance
Radiation therapy
Squamous cell carcinoma
Tumors
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Summary:Objectives Patients with laryngeal squamous cell carcinoma (LSCC) often fail radiation therapy (RT), when received as monotherapy or in combination with other treatment modalities. Mechanisms for RT failure are poorly understood. We hypothesized that tumors failing RT would have increased rates of somatic mutations in genes associated with radiation resistance, particularly in genes associated with the NFE2L2 oxidative stress pathway. Using targeted exome sequencing on pretreated LSCC tumors, we retrospectively compared somatic mutation profile with clinical data and response to treatment. Methods Tumors were classified as either radiation‐resistant (RR) or radiation‐sensitive (RS). RR was defined as persistent or recurrent disease within 2 years of receiving full‐dose RT. Early stage (ES) LSCC was defined as Stage I or II tumors without lymph node involvement. Eight genes associated with radiation resistance were prioritized for analysis. RT‐qPCR was performed on five NFE2L2 pathway genes. Results Twenty LSCC tumors were included and classified as either RR (n = 8) or RS (n = 12). No differences in individual rates of somatic mutations by genes associated with radiation resistance were identified. Higher rates of total mutational burden (TMB) and increased alterations associated with the NFE2L2 pathway was observed in RR vs RS tumors (P 
ISSN:2378-8038
2378-8038
DOI:10.1002/lio2.588