PMID- 34401494
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240404
IS  - 2378-8038 (Print)
IS  - 2378-8038 (Electronic)
IS  - 2378-8038 (Linking)
VI  - 6
IP  - 4
DP  - 2021 Aug
TI  - Correlation of alterations in the KEAP1/CUL3/NFE2L2 pathway with radiation 
      failure in larynx squamous cell carcinoma.
PG  - 699-707
LID - 10.1002/lio2.588 [doi]
AB  - 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.
CI  - (c) 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley 
      Periodicals LLC on behalf of The Triological Society.
FAU - Sheth, Siddharth
AU  - Sheth S
AUID- ORCID: 0000-0002-1923-2309
AD  - Division of Hematology and Oncology, Department of Medicine The University of 
      North Carolina at Chapel Hill Chapel Hill North Carolina USA.
FAU - Farquhar, Douglas R
AU  - Farquhar DR
AD  - Department of Otolaryngology-Head and Neck Surgery The University of North 
      Carolina at Chapel Hill Chapel Hill North Carolina USA.
FAU - Schrank, Travis P
AU  - Schrank TP
AUID- ORCID: 0000-0002-8297-3329
AD  - Department of Otolaryngology-Head and Neck Surgery The University of North 
      Carolina at Chapel Hill Chapel Hill North Carolina USA.
AD  - Department of Cell Biology and Physiology The University of North Carolina at 
      Chapel Hill Chapel Hill North Carolina USA.
FAU - Stepp, Wesley
AU  - Stepp W
AD  - Department of Otolaryngology-Head and Neck Surgery The University of North 
      Carolina at Chapel Hill Chapel Hill North Carolina USA.
FAU - Mazul, Angela
AU  - Mazul A
AD  - Department of Otolaryngology Washington University in Saint Louis, School of 
      Medicine St. Louis Missouri USA.
FAU - Hayward, Michele
AU  - Hayward M
AD  - Division of Hematology and Oncology, Department of Medicine The University of 
      North Carolina at Chapel Hill Chapel Hill North Carolina USA.
FAU - Lenze, Nicholas
AU  - Lenze N
AUID- ORCID: 0000-0002-2126-6663
AD  - Department of Otolaryngology-Head and Neck Surgery The University of North 
      Carolina at Chapel Hill Chapel Hill North Carolina USA.
FAU - Little, Paul
AU  - Little P
AD  - Division of Hematology and Oncology, Department of Medicine The University of 
      North Carolina at Chapel Hill Chapel Hill North Carolina USA.
FAU - Jo, Heejoon
AU  - Jo H
AD  - Division of Hematology-Oncology, Department of Medicine University of Tennessee 
      Health Science Center Memphis Tennessee USA.
FAU - Major, M Ben
AU  - Major MB
AD  - Department of Cell Biology and Physiology The University of North Carolina at 
      Chapel Hill Chapel Hill North Carolina USA.
FAU - Chera, Bhishamjit S
AU  - Chera BS
AD  - Department of Radiation Oncology The University of North Carolina at Chapel Hill 
      Chapel Hill North Carolina USA.
FAU - Zevallos, Jose P
AU  - Zevallos JP
AUID- ORCID: 0000-0002-9111-6767
AD  - Department of Otolaryngology Washington University in Saint Louis, School of 
      Medicine St. Louis Missouri USA.
FAU - Hayes, D Neil
AU  - Hayes DN
AD  - Division of Hematology-Oncology, Department of Medicine University of Tennessee 
      Health Science Center Memphis Tennessee USA.
LA  - eng
GR  - R01 CA211939/CA/NCI NIH HHS/United States
GR  - R01 CA216051/CA/NCI NIH HHS/United States
GR  - U10 CA181009/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20210603
PL  - United States
TA  - Laryngoscope Investig Otolaryngol
JT  - Laryngoscope investigative otolaryngology
JID - 101684963
PMC - PMC8356873
OTO - NOTNLM
OT  - laryngeal squamous cell carcinoma
OT  - oxidative stress
OT  - radiation resistance
COIS- The authors declare no potential conflict of interest.
EDAT- 2021/08/18 06:00
MHDA- 2021/08/18 06:01
PMCR- 2021/06/03
CRDT- 2021/08/17 07:33
PHST- 2021/03/15 00:00 [received]
PHST- 2021/04/27 00:00 [accepted]
PHST- 2021/08/17 07:33 [entrez]
PHST- 2021/08/18 06:00 [pubmed]
PHST- 2021/08/18 06:01 [medline]
PHST- 2021/06/03 00:00 [pmc-release]
AID - LIO2588 [pii]
AID - 10.1002/lio2.588 [doi]
PST - epublish
SO  - Laryngoscope Investig Otolaryngol. 2021 Jun 3;6(4):699-707. doi: 
      10.1002/lio2.588. eCollection 2021 Aug.