The radiation-induced cell-death signaling pathway is activated by concurrent use of cisplatin in sequential biopsy specimens from patients with cervical cancer.
OBJECTIVE
To identify changes in gene expression related to the concurrent use of platinum compounds with radiotherapy, in the treatment of cervical cancer.


METHODS
Biopsy specimens were obtained from 39 patients with squamous cell carcinoma of the uterine cervix, before and during fractionated radiotherapy. Twenty patients were treated with radiotherapy (RT) alone, while 19 received the same radiotherapy plus concomitant chemotherapy with cisplatin (CRT). Changes in gene expression induced by treatment were investigated using single-color oligo-microarrays consisting of 44K human sequences. Paraffin-embedded samples were used to examine apoptosis and the expression of protein by treatment-responsive genes. Changes in mRNA expression were assessed for these genes by real-time reverse transcriptase-polymerase chain reaction. Aberrant genomic change (detected using microarray-based comparative genomic hybridization), human papillomavirus infection, and p53 status were also evaluated.


RESULTS
The expression of CDKN1A, BAX, TNFSF8, and RRM2B was consistently upregulated by CRT (9 Gy with a single administration of cisplatin). Similar expression changes were induced by RT (9 Gy) alone, although the variability between tumors was greater. Apoptotic cells were significantly increased in both groups. CRT significantly increased the numbers of cases with diffusely distributed CDKN1A-positive cells. Genetic losses at 2q33-ter and gains of 3q26-ter were detected in the samples with high frequency; 60% were positive for human papillomavirus DNA; and three tumors had deletions/mutations of the p53 gene. There was no difference in the incidence of these genomic changes between the groups, and no association was found with the changes in expression of CDKN1A, BAX, TNFSF8 or RRM2B.


CONCLUSIONS
Using biopsy samples from pretreatment and midtreatment cervical tumors, we identified therapy-induced genes related to the cell death signaling pathway. CRT produced a homogenous pattern of changes in expression of known radiation-responsive genes.
Iwakawa
Mayumi
M
RadGenomics Research Group, Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan. mayumii@nirs.go.jp
Ohno
Tatsuya
T
Imadome
Kaori
K
Nakawatari
Miyako
M
Ishikawa
Ken-ichi
K
Sakai
Minako
M
Katoh
Shingo
S
Ishikawa
Hitoshi
H
Tsujii
Hirohiko
H
Imai
Takashi
T
D000970:Antineoplastic Agents / Q000494:pharmacology; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D016923:Cell Death; D002945:Cisplatin / Q000494:pharmacology*; D003131:Combined Modality Therapy; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020411:Oligonucleotide Array Sequence Analysis; D018807:Polymorphism, Single-Stranded Conformational; D015398:Signal Transduction; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*
D000970:Antineoplastic Agents; D002945:Cisplatin