Genetic variants of NPAT-ATM and AURKA are associated with an early adverse reaction in the gastrointestinal tract of patients with cervical cancer treated with pelvic radiation therapy.
OBJECTIVE
This study sought to associate polymorphisms in genes related to cell cycle regulation or genome maintenance with radiotherapy (RT)-induced an early adverse reaction (EAR) in patients with cervical cancer.


METHODS
This study enrolled 243 cervical cancer patients who were treated with pelvic RT. An early gastrointestinal reaction was graded using the National Cancer Institute Common Toxicity Criteria, version 2. Clinical factors of the enrolled patients were analyzed, and 208 patients were grouped for genetic analysis according to their EAR (Grade ≤1, n = 150; Grade ≥2, n = 58). Genomic DNA was genotyped, and association with the risk of EAR for 44 functional single-nucleotide polymorphisms (SNPs) of 19 candidate genes was assessed by single-locus, haplotype, and multilocus analyses.


RESULTS
Our analysis revealed two haplotypes to be associated with an increased risk of EAR. The first, comprising rs625120C, rs189037T, rs228589A, and rs183460G, is located between the 5' ends of NPAT and ATM (OR = 1.86; 95% CI, 1.21-2.87), whereas the second is located in the AURKA gene and comprises rs2273535A and rs1047972G (OR = 1.75; 95% CI, 1.10-2.78). A third haplotype, rs2273535T and rs1047972A in AURKA, was associated with a reduced EAR risk (OR = 0.42; 95% CI, 0.20-0.89). The risk of EAR was significantly higher among patients with both risk diplotypes than in those possessing the other diplotypes (OR = 3.24; 95% CI, 1.52-6.92).


CONCLUSIONS
Individual radiosensitivity of intestine may be determined by haplotypes in the NPAT-ATM and AURKA genes. These variants should be explored in larger association studies in cervical cancer patients.
RadGenomics Project, National Institute of Radiological Sciences, Chiba, Japan.
Atsuko
A
Ishikawa
Tomo
T
Suga
Yoshimi
Y
Shoji
Shingo
S
Kato
Tatsuya
T
Ohno
Hitoshi
H
Ishikawa
Shinji
S
Yoshinaga
Kiyoshi
K
Ohara
Hisanori
H
Ariga
Kuninori
K
Nomura
Yuta
Y
Shibamoto
Ken-ichi
K
Ishikawa
Takashi
T
Moritake
Yuichi
Y
Michikawa
Mayumi
M
Iwakawa
Takashi
T
Imai
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins; D064096:Aurora Kinase A; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D041981:Gastrointestinal Tract / Q000528:radiation effects*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007564:Japan; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011832:Radiation Injuries / Q000235:genetics / Q000473:pathology; D011836:Radiation Tolerance / Q000235:genetics*; D018709:Statistics, Nonparametric; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C101693:NPAT protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576917:AURKA protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases