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Correlation of alterations in the KEAP1/CUL3/NFE2L2 pathway with radiation failure in larynx squamous cell carcinoma.
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.
Afiliação
  • Sheth S; Division of Hematology and Oncology, Department of Medicine The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  • Farquhar DR; Department of Otolaryngology-Head and Neck Surgery The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  • Schrank TP; Department of Otolaryngology-Head and Neck Surgery The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  • Stepp W; Department of Cell Biology and Physiology The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  • Mazul A; Department of Otolaryngology-Head and Neck Surgery The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  • Hayward M; Department of Otolaryngology Washington University in Saint Louis, School of Medicine St. Louis Missouri USA.
  • Lenze N; Division of Hematology and Oncology, Department of Medicine The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  • Little P; Department of Otolaryngology-Head and Neck Surgery The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  • Jo H; Division of Hematology and Oncology, Department of Medicine The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  • Major MB; Division of Hematology-Oncology, Department of Medicine University of Tennessee Health Science Center Memphis Tennessee USA.
  • Chera BS; Department of Cell Biology and Physiology The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  • Zevallos JP; Department of Radiation Oncology The University of North Carolina at Chapel Hill Chapel Hill North Carolina USA.
  • Hayes DN; Department of Otolaryngology Washington University in Saint Louis, School of Medicine St. Louis Missouri USA.
Laryngoscope Investig Otolaryngol ; 6(4): 699-707, 2021 Aug.
Article em En | MEDLINE | ID: mdl-34401494
ABSTRACT

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 < .05). In an analysis of only ES-LSCC patients (RR, n = 3 and RS, n = 3), RR tumors had increased NFE2L2 somatic pathway mutations (P = .014) and increased NQO1 mRNA expression (P = .05).

CONCLUSION:

Increased TMB and NFE2L2 pathway alterations were associated with radiation resistance in LSCC. NQO1 mRNA expression may serve as a biomarker for RT response in ES-LSCC.Level of Evidence II1.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Laryngoscope Investig Otolaryngol Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Laryngoscope Investig Otolaryngol Ano de publicação: 2021 Tipo de documento: Article