Use of DNA repair pathway analysis to predict overall survival in head and neck cancer patients treated with TFHX chemoradiotherapy

6033 Background: Concurrent chemoradiotherapy is a standard-of-care for head and neck cancer. Radiotherapy and chemotherapeutic agents damage DNA; lack of adequate repair induces tumor cell death. The network of DNA repair pathways was examined to predict TFHX chemoradiotherapy outcomes. Methods: Biopsy specimens (paraffin) from 60 HNC patients were evaluated from tissue microarrays. Samples originated from patient groups from phase I/II studies: 1) poor-prognosis radiation-naïve, 2) re-irradiation. All were treated with TFHX-based chemoradiotherapy. DNA repair biomarkers XPF, pMK2, PAR, pH2AX, FANCD2, ATM, BRCA1, RAD51, ERCC1 (clone 8F1), and p53 were explored using IHC, automated image processing, and machine reading (>500 cells/read), for nuclear and cytoplasmic quantity, area, and intensity, and correlated with clinical outcome. Results: There was low inter-core variability per tumor with median patient ranking signal to noise ratio of 15.0 across all markers. Patients were stratified into short and long survival groups by determination of critical marker thresholds. Five DNA repair biomarkers (RAD51, ATM, BRCA1, XPF, FANCD2) exhibited univariate significance for overall survival (p = 2.65e-3, 1.53e-2, 4.77e-4, 8.57e-5, 1.32e-3)(additional clinical parameters multivariate analysis was not feasible due to sample size). ERCC1 was not statistically significant (p = 1.0). Pairwise biomarker combinations improved survival group discrimination. Combination of 4 DNA repair biomarkers (FANCD2, BRCA1, ATM, XPF) was also significant (p = 1.31e-4). Discriminant analysis demonstrated higher fractions of correctly identified patients in good/poor survival groups from four-marker tests. Conclusions: Five DNA repair biomarkers predicted overall survival following TFHX-based chemoradiotherapy. By contrast ERCC1 (8F1) was not significant. Combination of markers improved predictive ability in this study. The analysis of DNA repair pathways, particularly in homologous recombination, DNA damage response, and nucleotide excision repair, may be clinically useful. Validation in a larger, homogeneous patient population, and using platinum-based chemoradiotherapy, is indicated and currently ongoing. [Table: see text]

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Use of systematic analysis of DNA repair pathways in head and neck cancer (HNC) to identify XPF as a novel predictor of induction response, and pMK2 relationship to chemoradiotherapy

Journal of Clinical Oncology ◽

10.1200/jco.2008.26.15_suppl.6003 ◽

2008 ◽

Vol 26 (15_suppl) ◽

pp. 6003-6003 ◽

Cited By ~ 2

Author(s):

T. Y. Seiwert ◽

E. E. Cohen ◽

X. Wang ◽

M. Kocherginsky ◽

M. Bhayani ◽

...

Keyword(s):

Dna Repair ◽

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Systematic Analysis ◽

Repair Pathways

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DNA repair pathways to regulate response to chemoradiotherapy in patients with locally advanced head and neck cancer

Tumor Biology ◽

10.1007/s13277-016-5149-0 ◽

2016 ◽

Vol 37 (10) ◽

pp. 13435-13443 ◽

Cited By ~ 7

Author(s):

B. Cirauqui ◽

M. Margelí ◽

V. Quiroga ◽

A. Quer ◽

N. Karachaliou ◽

...

Keyword(s):

Dna Repair ◽

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Locally Advanced ◽

Advanced Head ◽

Repair Pathways

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Downregulation of the DNA Repair Gene DDB2 by Arecoline Is through p53’s DNA-Binding Domain and Is Correlated with Poor Outcome of Head and Neck Cancer Patients with Betel Quid Consumption

Cancers ◽

10.3390/cancers12082053 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2053

Author(s):

Yu-Chu Wang ◽

Jau-Ling Huang ◽

Ka-Wo Lee ◽

Hsing-Han Lu ◽

Yuan-Jen Lin ◽

...

Keyword(s):

Dna Repair ◽

Head And Neck Cancer ◽

Dna Binding ◽

Head And Neck ◽

Neck Cancer ◽

Excision Repair ◽

Ectopic Expression ◽

Transactivation Domain ◽

Poor Outcome ◽

Dna Repair Gene

Arecoline is the principal alkaloid in the areca nut, a component of betel quids (BQs), which are carcinogenic to humans. Epidemiological studies indicate that BQ-chewing contributes to the occurrence of head and neck cancer (HNC). Previously, we have reported that arecoline (0.3 mM) is able to inhibit DNA repair in a p53-dependent pathway, but the underlying mechanism is unclear. Here we demonstrated that arecoline suppressed the expression of DDB2, which is transcriptionally regulated by p53 and is required for nucleotide excision repair (NER). Ectopic expression of DDB2 restored NER activity in arecoline-treated cells, suggesting that DDB2 downregulation was critical for arecoline-mediated NER inhibition. Mechanistically, arecoline inhibited p53-induced DDB2 promoter activity through the DNA-binding but not the transactivation domain of p53. Both NER and DDB2 promoter activities declined in the chronic arecoline-exposed cells, which were consistent with the downregulated DDB2 mRNA in BQ-associated HNC specimens, but not in those of The Cancer Genome Atlas (TCGA) cohort (no BQ exposure). Lower DDB2 mRNA expression was correlated with a poor outcome in HNC patients. These data uncover one of mechanisms underlying arecoline-mediated carcinogenicity through inhibiting p53-regulated DDB2 expression and DNA repair.

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Which is the most suitable lymph node predictor for overall survival after primary surgery of head and neck cancer: pN, the number or the ratio of positive lymph nodes, or log odds?

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-015-2104-1 ◽

2015 ◽

Vol 142 (4) ◽

pp. 885-893 ◽

Cited By ~ 18

Author(s):

Mehmet Metin Yildiz ◽

Iver Petersen ◽

Ekkehard Eigendorff ◽

Peter Schlattmann ◽

Orlando Guntinas-Lichius

Keyword(s):

Overall Survival ◽

Head And Neck Cancer ◽

Lymph Node ◽

Lymph Nodes ◽

Head And Neck ◽

Neck Cancer ◽

Primary Surgery ◽

Log Odds ◽

Positive Lymph Nodes

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Association of genetic variability in enzymes metabolizing chemotherapeutic agents with treatment response in head and neck cancer cases

Asia-Pacific Journal of Clinical Oncology ◽

10.1111/ajco.12446 ◽

2016 ◽

Vol 13 (2) ◽

pp. e11-e20 ◽

Cited By ~ 1

Author(s):

Ankur Dhawan ◽

Munindra Ruwali ◽

Mohan C Pant ◽

Qamar Rahman ◽

Devendra Parmar

Keyword(s):

Head And Neck Cancer ◽

Genetic Variability ◽

Head And Neck ◽

Treatment Response ◽

Neck Cancer ◽

Chemotherapeutic Agents

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Bioelectrical impedance phase angle as a prognostic indicator of survival in head-and-neck cancer

Current Oncology ◽

10.3747/co.23.3181 ◽

2016 ◽

Vol 23 (5) ◽

pp. 481 ◽

Cited By ~ 14

Author(s):

M.S. Wladysiuk ◽

R. Mlak ◽

K. Morshed ◽

W. Surtel ◽

A. Brzozowska ◽

...

Keyword(s):

Overall Survival ◽

Head And Neck Cancer ◽

Head And Neck ◽

Phase Angle ◽

Neck Cancer ◽

Bioelectrical Impedance ◽

Impedance Analysis ◽

Neck Surgery ◽

Department Head ◽

Nutrition Status

Background Phase angle could be an alternative to subjective global assessment for the assessment of nutrition status in patients with head-and-neck cancer.Methods We prospectively evaluated a cohort of 75 stage iiib and iv head-and-neck patients treated at the Otolaryngology Department, Head and Neck Surgery, Medical University of Lublin, Poland. Bioelectrical impedance analysis was performed in all patients using an analyzer that operated at 50 kHz. The phase angle was calculated as reactance divided by resistance (Xc/R) and expressed in degrees. The Kaplan–Meier method was used to calculate survival.Results Median overall survival in the cohort was 32.0 months. At the time of analysis, 47 deaths had been recorded in the cohort (62.7%). The risk of shortened overall survival was significantly higher in patients whose phase angle was less than 4.733 degrees than in the remaining patients (19.6 months vs. 45 months, p = 0.0489; chi-square: 3.88; hazard ratio: 1.8856; 95% confidence interval: 1.0031 to 3.5446).Conclusions Phase angle might be prognostic of survival in patients with advanced head-and-neck cancer. Further investigation in a larger population is required to confirm our results.

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