Haplotype-based analysis of genes associated with risk of adverse skin reactions after radiotherapy in breast cancer patients.
OBJECTIVE
To identify haplotypes of single nucleotide polymorphism markers associated with the risk of early adverse skin reactions (EASRs) after radiotherapy in breast cancer patients.


METHODS
DNA was sampled from 399 Japanese breast cancer patients who qualified for breast-conserving radiotherapy. Using the National Cancer Institute-Common Toxicity Criteria scoring system, version 2, the patients were grouped according to EASRs, defined as those occurring within 3 months of starting radiotherapy (Grade 1 or less, n = 290; Grade 2 or greater, n = 109). A total of 999 single nucleotide polymorphisms from 137 candidate genes for radiation susceptibility were genotyped, and the haplotype associations between groups were assessed.


RESULTS
The global haplotype association analysis (p < 0.05 and false discovery rate < 0.05) indicated that estimated haplotypes in six loci were associated with EASR risk. A comparison of the risk haplotype with the most frequent haplotype in each locus showed haplotype GGTT in CD44 (odds ratio [OR] = 2.17; 95% confidence interval [CI], 1.07-4.43) resulted in a significantly greater EASR risk. Five haplotypes, CG in MAD2L2 (OR = 0.55; 95% CI, 0.35-0.87), GTTG in PTTG1 (OR = 0.48; 95% CI, 0.24-0.96), TCC (OR = 0.48; 95% CI, 0.26-0.89) and CCG (OR = 0.50; 95% CI, 0.27-0.92) in RAD9A, and GCT in LIG3 (OR = 0.46; 95% CI, 0.22-0.93) were associated with a reduced EASR risk. No significant risk haplotype was observed in REV3L.


CONCLUSIONS
Individual radiosensitivity can be partly determined by these haplotypes in multiple loci. Our findings may lead to a better understanding of the mechanisms underlying the genetic variation in radiation sensitivity and resistance among breast cancer patients.
Suga
Tomo
T
RadGenomics Project, National Institute of Radiological Sciences, Chiba, Japan.
Ishikawa
Atsuko
A
Kohda
Masakazu
M
Otsuka
Yoshimi
Y
Yamada
Shigeru
S
Yamamoto
Naohito
N
Shibamoto
Yuta
Y
Ogawa
Yoshihiro
Y
Nomura
Kuninori
K
Sho
Keizen
K
Omura
Motoko
M
Sekiguchi
Kenji
K
Kikuchi
Yuzo
Y
Michikawa
Yuichi
Y
Noda
Shuhei
S
Sagara
Masashi
M
Ohashi
Jun
J
Yoshinaga
Shinji
S
Mizoe
Junetsu
J
Tsujii
Hirohiko
H
Iwakawa
Mayumi
M
Imai
Takashi
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics* / Q000532:radiotherapy; D016009:Chi-Square Distribution; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011832:Radiation Injuries / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D012867:Skin / Q000528:radiation effects*
D005819:Genetic Markers