Correlation of alterations in the 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 somatic mutations in genes associated with radiation resistance, particularly in genes associated with the 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 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 pathway was observed in RR vs RS tumors ( < .05). In an analysis of only ES-LSCC patients (RR, n = 3 and RS, n = 3), RR tumors had increased NFE2L2 somatic pathway mutations ( = .014) and increased mRNA expression ( = .05).

CONCLUSION

Increased TMB and pathway alterations were associated with radiation resistance in LSCC. mRNA expression may serve as a biomarker for RT response in ES-LSCC.Level of Evidence: II1.