Acute normal tissue reactions in head-and-neck cancer patients treated with IMRT: influence of dose and association with genetic polymorphisms in DNA DSB repair genes.
OBJECTIVE
To investigate the association between dose-related parameters and polymorphisms in DNA DSB repair genes XRCC3 (c.-1843A>G, c.562-14A>G, c.722C>T), Rad51 (c.-3429G>C, c.-3392G>T), Lig4 (c.26C>T, c.1704T>C), Ku70 (c.-1310C>G), and Ku80 (c.2110-2408G>A) and the occurrence of acute reactions after radiotherapy.


METHODS
The study population consisted of 88 intensity-modulated radiation therapy (IMRT)-treated head-and-neck cancer patients. Mucositis, dermatitis, and dysphagia were scored using the Common Terminology Criteria (CTC) for Adverse Events v.3.0 scale. The population was divided into a CTC0-2 and CTC3+ group for the analysis of each acute effect. The influence of the dose on critical structures was analyzed using dose-volume histograms. Genotypes were determined by polymerase chain reaction (PCR) combined with restriction fragment length polymorphism or PCR-single base extension assays.


RESULTS
The mean dose (D(mean)) to the oral cavity and constrictor pharyngeus (PC) muscles was significantly associated with the development of mucositis and dysphagia, respectively. These parameters were considered confounding factors in the radiogenomics analyses. The XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes were significantly associated with the development of severe dysphagia (CTC3+). No association was found between the investigated polymorphisms and the development of mucositis or dermatitis. A risk analysis model for severe dysphagia, which was developed based on the XRCC3c.722CT/TT and Ku70c.-1310CG/GG genotypes and the PC dose, showed a sensitivity of 78.6% and a specificity of 77.6%.


CONCLUSIONS
The XRCC3c.722C>T and Ku70c.-1310C>G polymorphisms as well as the D(mean) to the PC muscles were highly associated with the development of severe dysphagia after IMRT. The prediction model developed using these parameters showed a high sensitivity and specificity.
Werbrouck
Joke
J
Department of Basic Medical Sciences, Ghent University, Ghent, Belgium. joke.werbrouck@ugent.be
De Ruyck
Kim
K
Duprez
Fréderic
F
Veldeman
Liv
L
Claes
Kathleen
K
Van Eijkeren
Marc
M
Boterberg
Tom
T
Willems
Petra
P
Vral
Anne
A
De Neve
Wilfried
W
Thierens
Hubert
H
D000230:Adenocarcinoma / Q000235:genetics / Q000532:radiotherapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D034961:Antigens, Nuclear / Q000235:genetics; D029681:Arabidopsis Proteins / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000532:radiotherapy; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D003680:Deglutition Disorders / Q000235:genetics*; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D006801:Humans; D000072200:Ku Autoantigen; D008297:Male; D008875:Middle Aged; D009055:Mouth / Q000528:radiation effects; D009061:Mouth Mucosa / Q000528:radiation effects; D010609:Pharyngeal Muscles / Q000528:radiation effects; D011110:Polymorphism, Genetic / Q000235:genetics*; D051135:Rad51 Recombinase / Q000235:genetics; D011855:Radiodermatitis / Q000235:genetics; D011879:Radiotherapy Dosage; D050397:Radiotherapy, Intensity-Modulated / Q000009:adverse effects*; D012044:Regression Analysis
D034961:Antigens, Nuclear; D029681:Arabidopsis Proteins; D004268:DNA-Binding Proteins; C000607893:LIG4 protein, human; C110901:X-ray repair cross complementing protein 3; C495146:ATRAD51 protein, Arabidopsis; D051135:Rad51 Recombinase; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen; D011088:DNA Ligases; D000072481:DNA Ligase ATP