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Molecular marker identification for relapse prediction in 5-FU-based adjuvant chemotherapy in gastric and colorectal cancers.

ABSTRACT: To confirm the clinical significance of NF-?B and JNK protein expression from experimentally identified candidates for predicting prognosis for patients with 5-FU treatment, we evaluated the protein expression of surgically removed specimens. A total of 79 specimens were obtained from 30 gastric and 49 colorectal cancer patients who underwent R0 resection followed by postoperative 5-FU based adjuvant chemotherapy. Immunohistochemical examinations of NF-?B and JNK on tissue microarrays (TMAs) revealed that significantly shorter time-to-relapse (TTR) in both NF-?B(+) and JNK(-) subgroups in both gastric (NF-?B(+), p = 0.0002, HR11.7. 95%CI3 3.2-43.4; JNK(-), p = 0.0302, HR4.4, 95%CI 1.2-16.6) and colon (NF-?B(+), p = 0.0038, HR36.9, 95%CI 3.2-426.0; JNK(-), p = 0.0098, HR3.2, 95%CI 1.3-7.7) cancers. These protein expression patterns also show strong discriminately power in gastric cancer patients for overall survival rate, suggesting a potential utility as prognostic or chemosensitivity markers. Baseline expression of these proteins using gastric cancer cell lines demonstrated the reciprocal patterns between NF-?B and JNK, while 5-FU exposure of these cell lines only induced NF-?B, suggesting that NF-?B plays a dominant role in the response to 5-FU. Subsequent siRNA experiments confirmed that gene knockdown of NF-?B increased 5-FU-specific sensitivity, whereas that of JNK did not affect the chemosensitivity. These results suggest that the expression of these proteins may aid in the decisions involved with adjuvant chemotherapy for gastrointestinal tract cancers.

SUBMITTER: Ishida K

PROVIDER: S-EPMC3419205 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Molecular marker identification for relapse prediction in 5-FU-based adjuvant chemotherapy in gastric and colorectal cancers.

Ishida Kazushige K Nishizuka Satoshi S SS Chiba Takehiro T Ikeda Miyuki M Kume Kohei K Endo Fumitaka F Katagiri Hirokatsu H Matsuo Teppei T Noda Hironobu H Iwaya Takeshi T Yamada Noriyuki N Fujiwara Hisataka H Takahashi Masanori M Itabashi Tetsuya T Uesugi Noriyuki N Maesawa Chihaya C Tamura Gen G Sugai Tamotsu T Otsuka Koki K Koeda Keisuke K Wakabayashi Go G

PloS one 20120814 8

To confirm the clinical significance of NF-κB and JNK protein expression from experimentally identified candidates for predicting prognosis for patients with 5-FU treatment, we evaluated the protein expression of surgically removed specimens. A total of 79 specimens were obtained from 30 gastric and 49 colorectal cancer patients who underwent R0 resection followed by postoperative 5-FU based adjuvant chemotherapy. Immunohistochemical examinations of NF-κB and JNK on tissue microarrays (TMAs) rev ...[more]

PMID: 22905237

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Project description:BACKGROUND:Liver fibrosis, resulted from several liver diseases, are increasing up to 25% in population in global. It remains undetermined how much impact liver fibrosis have on the development of hepatic metastasis and relapse in colorectal cancer (CRC). Hence the aim of this study was to clarify the role of liver fibrosis on hepatic metastasis and relapse in CRC undergoing curative therapy. METHODS:We enrolled consecutive 1652 patients with radical colorectal surgery as the discovery cohort, and the validation set enrolled 432 CRC patients with hepatic metastasis. To determine liver fibrosis, the NFS, FIB4 and APRI scores were applied. The influence of liver fibrosis on hepatic metastasis and relapse was assessed by survival analyses. Nomograms with fibrosis score incorporated were established to identify the incremental value for individualized relapse estimation, which was then assessed with respect to calibration, discrimination, and clinical usefulness. RESULTS:The high liver fibrosis score patients had significantly worse outcomes than low score in 5-year hepatic metastasis (22.6 vs. 8.7%) in discovery cohort, and relapse (58.2 vs. 44.1%) in validation cohort. Multivariate analysis also revealed liver fibrosis as an independent prognostic factor. The distribution analysis also demonstrated higher liver fibrosis score a powerful prognostic factor for hepatic metastasis and relapse. The nomogram incorporated with liver fibrosis score resulted in better performance than TNM staging system and clinicopathologic nomograms. Importantly, the discriminatory capacity of the fibrosis score was superior to that of the CRS score in predicting hepatic specific disease-free survival (DFS) and relapse-free survival (RFS), as demonstrated by the C-index and AUC. The concordance study showed well agreement among NFS, FIB4 and APRI in predicting DFS and RFS. Among these three noninvasive liver fibrosis scores, NFS score performed the best in predicting hepatic specific DFS and RFS. CONCLUSION:The liver fibrosis was a powerful predictor of hepatic specific DFS and RFS in CRC. Fibrosis niche may be a favorable microenvironment for metastatic formation in the liver.

Dataset Information

Molecular marker identification for relapse prediction in 5-FU-based adjuvant chemotherapy in gastric and colorectal cancers.

Publications

Molecular marker identification for relapse prediction in 5-FU-based adjuvant chemotherapy in gastric and colorectal cancers.

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