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GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer.

ABSTRACT: GADD45B acts as a member of the growth arrest DNA damage-inducible gene family, which has demonstrated to play critical roles in DNA damage repair, cell growth, and apoptosis. This study aimed to explore the potential relationship between GADD45B expression and tumor progression and evaluate the clinical value of GADD45B in stage II colorectal cancer (CRC). The expression patterns and prognostic value of GADD45B in CRC were analyzed based on The Cancer Genomic Atlas (TCGA). GADD45B expression features of 306 patients with stage II CRC and 201 patients with liver metastasis of CRC were investigated using immunochemical staining on tissue microarrays. Afterward, survival analysis and stratification analysis were performed in stage II to explore the prognostic and predictive significance of GADD45B. Overexpressed GADD45B is associated with poorer prognosis for CRC patients both in overall survival (OS) (p < 0.001) and disease-free survival (DFS) (p = 0.001) based on the TCGA database. Analysis results according to the stage II CRC cohort and the liver metastatic CRC cohort revealed that GADD45B was gradually upregulated in normal mucosa including primary colorectal cancer (PCC). Colorectal liver metastases (CLM) tissues were arranged in order (normal tissue vs. PCC p = 0.005 and PCC vs. CLM p = 0.001). The low GADD45B group had a significantly longer five-year OS (p = 0.001) and progression-free survival (PFS) (p < 0.001) than the high GADD45B group for the stage II patients. The multivariate Cox regression analysis results proved that the expression level of GADD45B was an independent prognostic factor for stage II after radical surgery (OS: Hazard Ratio (HR) 0.479, [95% confidence interval (CI) 0.305?0.753] and PFS:HR 0.490, [95% CI 0.336?0.714]). In high GADD45B expression subgroup of stage II cohort, the patients who underwent adjuvant chemotherapy had longer PFS than those who did not (p = 0.008). High expression levels of GADD45B is an independent prognostic factor of decreased OS and PFS in stage II CRC patients. The stage II CRC patients with high GADD45B expression might benefit from adjuvant chemotherapy.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC6071283 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer.

Zhao Zhixun Z Gao Yibo Y Guan Xu X Liu Zheng Z Jiang Zheng Z Liu Xiuyun X Lin Huixin H Yang Ming M Li Chunxiang C Yang Runkun R Zou Shuangmei S Wang Xishan X

Genes 20180719 7

GADD45B acts as a member of the growth arrest DNA damage-inducible gene family, which has demonstrated to play critical roles in DNA damage repair, cell growth, and apoptosis. This study aimed to explore the potential relationship between GADD45B expression and tumor progression and evaluate the clinical value of GADD45B in stage II colorectal cancer (CRC). The expression patterns and prognostic value of GADD45B in CRC were analyzed based on The Cancer Genomic Atlas ( ...[more]

PMID: 30029519

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Project description:BackgroundFor stage II colorectal cancer (CRC), the efficacy of adjuvant chemotherapy remains controversial. Consensus molecular subtype (CMS) has been validated to be a prognostic tool for CRCs. In this study, CMS status was investigated as a prognostic biomarker for the efficacy of adjuvant chemotherapy for stage II colorectal cancer.Materials and methodsThe tissue microarray was retrospectively constructed of 165 nonconsecutive, primary, and sporadic stage II CRCs. CMS status was determined by immunohistochemistry staining of CDX2, HTR2B, FRMD6, and ZEB1, combining with microsatellite instability testing. The prognostic for adjuvant chemotherapy efficacy of CMS status was calculated by Kaplan-Meier curves and Cox regression analysis. Subgroup analyses were conducted according to tumor location.ResultsKaplan-Meier curves indicated that CMS was associated with overall survival (OS) and disease-free survival for stage II CRCs. Cox regression analysis showed that CMS was an independent risk factor for OS. Among high-risk clinicopathological factors, patients with CMS2/3 (hazard ratio [HR]: 0.445, 95% confidence interval [CI]: 0.227-0.875), left-sided tumors (HR: 0.488, 95% CI: 0.247-0.968), or fewer than 12 lymph nodes examined (HR: 0.307, 95% CI: 0.097-0.974) had survival benefit from adjuvant chemotherapy. Subgroup analysis showed that adjuvant chemotherapy only improved OS for patients with left-sided tumors of CMS2/3 subtype. Regardless of CMS, right-sided tumors had no benefit from adjuvant chemotherapy.ConclusionCMS is a better prognostic factor for adjuvant chemotherapy for stage II CRCs. Together with tumor location, CMS classification will aid in personalized treatment for stage II CRCs.Implications for practiceFor stage II colorectal cancer (CRC), the efficacy of adjuvant chemotherapy remains controversial, in that its minimal benefit (no more than 5% on average) is considered not worth the toxic effects of the drugs. There are still no effective prognostic and predictive biomarkers. This study showed that consensus molecular subtype (CMS) status is a predictive marker for adjuvant chemotherapy efficacy. Patients with left-sided tumors of CMS2/3 subtype have survival benefit by receiving adjuvant chemotherapy, which will aid in personalized treatment for stage II CRCs. Moreover, this test of CMS based on immunohistochemistry is cheap, not time consuming, and easily conducted in the laboratories of most hospitals.

Project description:Background The identification of high-risk stage II colon cancers is key to the selection of patients who require adjuvant treatment after surgery. Microarray-based multigene-expression signatures derived from stem cells and progenitor cells hold promise, but they are difficult to use in clinical practice. Methods We used a new bioinformatics approach to search for biomarkers of colon epithelial differentiation across gene-expression arrays and then ranked candidate genes according to the availability of clinical-grade diagnostic assays. With the use of subgroup analysis involving independent and retrospective cohorts of patients with stage II or stage III colon cancer, the top candidate gene was tested for its association with disease-free survival and a benefit from adjuvant chemotherapy. Results The transcription factor CDX2 ranked first in our screening test. A group of 87 of 2115 tumor samples (4.1%) lacked CDX2 expression. In the discovery data set, which included 466 patients, the rate of 5-year disease-free survival was lower among the 32 patients (6.9%) with CDX2-negative colon cancers than among the 434 (93.1%) with CDX2-positive colon cancers (hazard ratio for disease recurrence, 3.44; 95% confidence interval [CI], 1.60 to 7.38; P=0.002). In the validation data set, which included 314 patients, the rate of 5-year disease-free survival was lower among the 38 patients (12.1%) with CDX2 protein-negative colon cancers than among the 276 (87.9%) with CDX2 protein-positive colon cancers (hazard ratio, 2.42; 95% CI, 1.36 to 4.29; P=0.003). In both these groups, these findings were independent of the patient's age, sex, and tumor stage and grade. Among patients with stage II cancer, the difference in 5-year disease-free survival was significant both in the discovery data set (49% among 15 patients with CDX2-negative tumors vs. 87% among 191 patients with CDX2-positive tumors, P=0.003) and in the validation data set (51% among 15 patients with CDX2-negative tumors vs. 80% among 106 patients with CDX2-positive tumors, P=0.004). In a pooled database of all patient cohorts, the rate of 5-year disease-free survival was higher among 23 patients with stage II CDX2-negative tumors who were treated with adjuvant chemotherapy than among 25 who were not treated with adjuvant chemotherapy (91% vs. 56%, P=0.006). Conclusions Lack of CDX2 expression identified a subgroup of patients with high-risk stage II colon cancer who appeared to benefit from adjuvant chemotherapy. (Funded by the National Comprehensive Cancer Network, the National Institutes of Health, and others.).

Dataset Information

GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer.

Publications

GADD45B as a Prognostic and Predictive Biomarker in Stage II Colorectal Cancer.

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