Genomic profile predicts the efficacy of neoadjuvant chemotherapy for cervical cancer patients.
BACKGROUND
Neoadjuvant chemotherapy (NAC) using platinum and irinotecan (CPT-11) followed by radical excision has been shown to be a valid treatment for locally advanced squamous cervical cancer (SCC) patients. However, in NAC-resistant or NAC-toxic cases, surgical treatment or radiotherapy might be delayed and the prognosis may be adversely affected. Therefore, it is important to establish a method to predict the efficacy of NAC.


METHODS
Gene expression microarrays of SCC tissue samples (n = 12) and UGT1A1 genotyping of blood samples (n = 23) were investigated in terms of their association with NAC sensitivity. Gene expression and drug sensitivity of SCC cell lines were analyzed for validation.


RESULTS
Microarray analysis revealed that the glutathione metabolic pathway (GMP) was significantly up-regulated in NAC-resistant patients (p < 0.01), and there was a positive correlation between 50 % growth inhibitory concentrations of CPT-11 and predictive scores of GMP activation in SCC cells (r = 0.32, p < 0.05). The intracellular glutathione (GSH) concentration showed a highly positive correlation with GMP scores among 4 SCC cell lines (r = 0.72). UGT1A1 genotyping revealed that patients with UGT1A1 polymorphisms exhibited significantly higher response rates to NAC than those with the wild-type (79.5 vs. 49.5 %, respectively, p < 0.05).


CONCLUSIONS
These results indicate that GMP scores of cancerous tissue combined with UGT1A1 genotyping of blood samples may serve as highly potent markers for predicting the efficacy of NAC for individual SCC patients.
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan. gorizou@kuhp.kyoto-u.ac.jp.
Naoki
N
Horikawa
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan. babatsu@kuhp.kyoto-u.ac.jp.
Tsukasa
T
Baba
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan. noriomi@kuhp.kyoto-u.ac.jp.
Noriomi
N
Matsumura
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan. ryusukem@kuhp.kyoto-u.ac.jp.
Ryusuke
R
Murakami
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan. kaoruvc@kuhp.kyoto-u.ac.jp.
Kaoru
K
Abiko
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan. jnkhmns@kuhp.kyoto-u.ac.jp.
Junzo
J
Hamanishi
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan. soulken@kuhp.kyoto-u.ac.jp.
Ken
K
Yamaguchi
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan. koshiya@kuhp.kyoto-u.ac.jp.
Masafumi
M
Koshiyama
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan. yyumivn@kuhp.kyoto-u.ac.jp.
Yumiko
Y
Yoshioka
Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Kyoto, Sakyo-ku, 606-8507, Japan. konishi@kuhp.kyoto-u.ac.jp.
Ikuo
I
Konishi
D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics / Q000379:methods*; D005838:Genotype; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012334:RNA, Neoplasm / Q000235:genetics*; D012189:Retrospective Studies; D002583:Uterine Cervical Neoplasms / Q000235:genetics* / Q000628:therapy; D000099148:UGT1A1 Enzyme
D014453:Glucuronosyltransferase; D012334:RNA, Neoplasm; D000099148:UGT1A1 Enzyme