Weixing Dai

A robust gene signature for the prediction of early relapse in stage I–III colon cancer

Colon cancer patients experiencing early relapse consistently exhibited poor survival. The aim of our study was to develop an mRNA signature that can help to detect early relapse cases in stage I–III colon cancer. Public microarray datasets of stage I–III colon cancer samples were extracted from the Gene Expression Omnibus database. Propensity score matching analysis was performed between patients in the early relapse group and the long‐term survival group from GSE39582 discovery series (N = 386), and patients were 1 : 1 matched. Global mRNA expression changes were then analyzed between the paired groups to identify the differentially expressed genes. Lasso Cox regression modeling analysis was conducted for the selection of prognostic mRNA. Fifteen mRNA were finally identified to build an early relapse classifier. With specific risk score formula, patients were classified into a high‐risk group and a low‐risk group. Relapse‐free survival was significantly different between the two groups in every series, including discovery [hazard ratio (HR): 2.547, 95% confidence interval (CI): 1.708–3.797, P < 0.001)], internal validation (HR: 5.146, 95% CI: 1.968–13.457, P < 0.001), and external validation (HR: 1.977, 95% CI: 1.295–3.021, P < 0.001) sets of patients. Time‐dependent receiver‐operating characteristic at 1 year suggested more prognostic accuracy of the classifier [area under curve (AUC = 0.703)] than the American Joint Commission on Cancer tumor–node–metastasis staging system (AUC = 0.659) in all 951 patients. In conclusion, we developed a robust mRNA signature that can effectively classify colon cancer patients into groups with low and high risks of early relapse. This mRNA signature may help select high‐risk colon cancer patients who require more aggressive therapeutic intervention.

Adjuvant radiotherapy improves cause specific survival in stage II, not stage III mucinous carcinoma of the rectum

BackgroundThe effect of adjuvant radiotherapy on the survival outcomes of patients with mucinous rectal cancer remains unclear. This study evaluated the 5-year cause specific survival (CSS) of patients with mucinous rectal cancer after surgery to determine whether adjuvant radiotherapy conferred a survival benefit.MethodsAn analysis of the Surveillance, Epidemiology, and End Results (SEER)-registered database was conducted of patients presenting with mucinous rectal cancer between 2004 and 2011. The primary endpoint was 5-year CSS; univariate and multivariate analyses were performed using Cox proportional hazards regression models.ResultsA total of 574 patients were included for analysis with 248 patients in postoperative radiotherapy group and 326 patients in surgery alone group. Preliminary analysis demonstrated that adjuvant radiotherapy was not associated with CSS (χ2 = 0.560, P = 0.454). Subgroup analysis indicated that postoperative radiotherapy group had survival advantage in stage II rectal cancer (93.3% vs. 76.6%, χ2 = 4.654, P = 0.031), but not in stage III rectal cancer (67.5% vs. 64.7%, χ2 = 0.186, P = 0.666). Multivariate analysis demonstrated that postoperative radiotherapy group had a reduced risk of death on survival (HR 0.346; 95%CI 0.129-0.927, P = 0.035)ConclusionPostoperative radiotherapy is an independent factor for improvement in CSS in patients with stage II rectal mucinous adenocarcinoma, and it should be routinely recommended in these patients. But for stage III patients, considering the losing of CSS advantage and potential radiotherapy toxicity, postoperative radiotherapy should be recommended with great caution.

Survival Contradiction Between Stage IIA and Stage IIIA Rectal Cancer: A Retrospective Study

Background: When compared with patients harboring stage IIB and stage IIC disease, those with stage IIIA colorectal cancer have a better prognosis. We aimed to compare the cause-specific survival (CSS) of the patients with stage IIA rectal cancer with that of the patients with stage IIIA rectal cancer. Methods: Data analyzed about patients with stage IIA and stage IIIA rectal cancer was from the US Surveillance, Epidemiology, and End Results (SEER) database. We then validated the results using data derived from Fudan University Shanghai Cancer Center (FUSCC). Results: A total of 16,788 patients (13,551 staged IIA and 3,237 staged IIIA) were identified in SEER database. A multivariate analysis manifested that patients with stage IIIA disease were more likely to have a better CSS (HR 0.894, 95% CI 0.816-0.979, p=0.016) compared with patients with stage IIA rectal cancer. In the subgroup of patients whose number of lymph nodes harvested (LNH) <12, multivariate analysis signified that patients with stage IIIA disease were more prone to have favorable CSS (HR 0.805, 95% CI 0.719-0.901, p<0.001) compared with patients with stage IIA rectal cancer. In LNH≥12 subgroup, the Kaplan-Meier analysis revealed no significant difference between patients experiencing stage IIA and IIIA rectal cancer (p=0.618). Validation of data from FUSCC proved that patients with stage IIIA rectal cancer were more inclined to have better CSS (HR 0.407, 95% CI 0.187-0.885, p=0.019) in comparison to those with stage IIA rectal cancer. Specifically, in LNH<12 subgroup, the survival outcomes of stage IIIA patients were significantly better than that of the stage IIA patients (p=0.019), while there was no statistical significance between these two stages in the subgroup of patients with LNH≥12 (p=0.180). Conclusions: Patients with stage IIA rectal cancer have poorer CSS than patients with stage IIIA rectal cancer, particularly when inadequate lymph nodes are harvested.

Predictive factors of synchronous colorectal peritoneal metastases: Development of a nomogram and study of its utilities using decision curve analysis

BACKGROUND The objective of this study was to summarize the clinicopathological and molecular features of synchronous colorectal peritoneal metastases (CPM). We then combined clinical and pathological variables associated with synchronous CPM into a nomogram and confirmed its utilities using decision curve analysis. MATERIALS AND METHODS Synchronous metastatic colorectal cancer (mCRC) patients who received primary tumor resection and underwent KRAS, NRAS, and BRAF gene mutation detection at our center from January 2014 to September 2015 were included in this retrospective study. An analysis was performed to investigate the clinicopathological and molecular features for independent risk factors of synchronous CPM and to subsequently develop a nomogram for synchronous CPM based on multivariate logistic regression. Model performance was quantified in terms of calibration and discrimination. We studied the utility of the nomogram using decision curve analysis. RESULTS In total, 226 patients were diagnosed with synchronous mCRC, of whom 50 patients (22.1%) presented with CPM. After uni- and multivariate analysis, a nomogram was built based on tumor site, histological type, age, and T4 status. The model had good discrimination with an area under the curve (AUC) at 0.777 (95% CI 0.703-0.850) and adequate calibration. By decision curve analysis, the model was shown to be relevant between thresholds of 0.10 and 0.66. CONCLUSION Synchronous CPM is more likely to happen to patients with age ≤60, right-sided primary lesions, signet ring cell cancer or T4 stage. This is the first nomogram to predict synchronous CPM. To ensure generalizability, this model needs to be externally validated.

The effect of marital status by age on patients with colorectal cancer over the past decades: a SEER-based analysis

ObjectiveMarital status has been found as an independent prognostic factor for survival in colorectal cancer (CRC). However, it is unclear whether patients with different marital status have benefited the same from the treatment improvement.MethodsWe queried the Surveillance, Epidemiology, and End Results (SEER) 9 database for patients diagnosed with CRC from 1975 to 2009. Yearly survival data was presented with overlying loess smoothing lines, stratifying by marital status. We further referred to the SEER 18 database for patients diagnosed with CRC from 1973 to 2014. We also performed yearly data for stage proportion, surgery-performed rate, cancer-specific survival (CSS), and multivariate hazard ratio with overlying loess smoothing lines across all marital status.ResultsFive-year CSS of married, single, and separated/divorced patients showed remarkable increase since 1975; however, survival of widowed patients remained low and no survival gains were observed since 1990. The same trends persisted after stratifying patients by stage and gender. Married and widowed patients tended to have more localized disease and less distant disease compared with the other two groups, and married patients were more likely to receive surgery. Multivariate analysis revealed the hazard ratio of widowed patients dropped dramatically when including age at diagnosis.ConclusionsWidowed patients have not benefited substantially from the remarkable treatment improvement over the past four decades, which may be the result of the older age of this particular group. This study is a wake-up call to the medical community for additional care for the widowed patients.

FBW7 suppresses metastasis of colorectal cancer by inhibiting HIF1α/CEACAM5 functional axis

F-box and WD repeat domain-containing 7 (FBW7) functions as a major tumor suppressor by targeting oncoproteins for degradations. FBW7 has been reported to be one of the most frequently mutated genes in colorectal cancer (CRC). However, its roles and possible mechanisms in the development of CRC are still unclear. In the present study, we adopted immunohistochemistry staining in tissue microarray (TMA), consisting of 276 samples from stage I-IV CRC patients, and analyzed the correlation between FBW7 expression and clinicopathological parameters, as well as overall survival (OS) and disease-free survival (DFS). The impact of FBW7 on migration was further validated in vitro. Whole-genome expression microarray (GEO,accession numbers GSE76443), was then analyzed to find the possible target of FBW7. The results were verified by functional experiments in vitro and IHC staining of TMA. Finally, luciferase and chromatin immunoprecipitation (ChIP) assays were carried out to identify the possible mechanisms. The expression level of FBW7 in TMA was negatively correlated with serum CEA level, venous invasion, N stage and M stage, and positively associated with the survival of CRC patients(P<0.05). Ectopic FBW7 expression significantly suppressed migration of colon cancer cells in vitro. GEO analysis revealed that decreased FBW7 significantly correlated with increased level of CEACAM5, which encoded CEA. The correlation was verified by IHC of TMA and silencing CEACAM5 inhibited migration in vitro. Mechanistically, we demonstrated that CEACAM5 was a HIF1α target gene and that FBW7 regulated CEACAM5 in a HIF1α-dependent manner. In conclusion, our results revealed that FBW7 suppressed migration through regulation of the HIF1α/CEACAM5 axis in colorectal cancer. Therefore, our study sheds novel lights on the impact of FBW7 on HIF1α/CEACAM5 signaling axis and constitutes potential prognostic predictors and therapeutic targets for CRC.

The Prognostic Effect of Tumor Sidedness in Colorectal Cancer: A SEER-based Analysis

Background: The prognostic value of tumor sidedness in metastatic colorectal cancer (CRC) has been established, but its impact on nonmetastatic disease remains unclear. Our study aimed to explore the prognostic effect of tumor sidedness by subgroup survival analyses, according to histology and tumor grade in stage I‐IV CRCs. Methods: A retrospective population‐based study was conducted based on Surveillance, Epidemiology and End Results (SEER) data. Population data in the SEER 9 registry (1975‐2014) were used to determine survival trends of CRCs, and associated population data in the SEER 18 registry (2000 to 2014) were used to assess the prognostic impact of tumor sidedness on CRCs. Results: The 5‐year cause‐specific survival for all subgroups of CRCs improved from 1975 to 2014. Of 238,826 patients, 44.2% had right‐sided cancer. Patients with right‐sided cancer were more likely to be older, to be women, to have disease of mucinous or signet‐ring cell histology, to have more poorly differentiated tumors, and to be diagnosed with a more advanced disease stage. Multivariate Cox regression showed stage I‐II right‐sided cancers had better cause‐specific survival than the left‐sided cancers (left colon: hazard ratio [HR] = 1.091, 95% confidence interval [CI], 1.052‐1.132; rectum: HR = 1.363; 95% CI, 1.304‐1.425; P < .001), while stage III and IV right‐sided cancers had worse cause‐specific survival. In subgroup analyses by histology and tumor grade within stage III CRCs, right‐sided poorly differentiated mucinous adenocarcinoma showed significantly better survival (left colon: HR = 1.352; 95% CI, 1.145‐1.596; rectum: HR = 1.125; 95% CI, 0.916‐1.381; P = .002). Conclusion: The relationship between sidedness and prognosis in CRCs depends on stage and histopathologic characteristics, especially for stage III disease. Micro‐Abstract A retrospective population‐based study was conducted based on the SEER database stratified by colorectal cancer (CRC) histologic subtype and differentiation. Unlike adenocarcinoma (AC), stage III right‐sided poorly differentiated mucinous and signet‐ring cell AC showed significantly better survival than left‐sided disease. Combining histologic subtype and sidedness may help to more precisely predict prognosis and help guide personalized treatment for patients with CRC.

Transcriptome profiling reveals an integrated mRNA–lncRNA signature with predictive value of early relapse in colon cancer

The purpose of our study was to develop a multigene signature based on transcriptome profiles of both mRNAs and lncRNAs to identify a group of patients who are at high risk of early relapse in stages II-III colon cancer. Firstly, propensity score matching was conducted between patients in early relapse group and long-term survival group from GSE39582 training series (N = 359) and patients were matched 1:1. Global transcriptome analysis was then performed between the paired groups to identify tumor specific mRNAs and lncRNAs. Finally, using LASSO Cox regression model, we built a multigene early relapse classifier incorporating 15 mRNAs and three lncRNAs. The prognostic and predictive accuracy of the signature was internally validated in 102 colon cancer patients and externally validated in other 241 patients. In the training set, patients with high risk score were more likely to suffer from relapse than those with low risk score (HR: 2.67, 95% CI: 2.07-3.46, P < 0.001). The results were validated in the internal validation set (HR: 2.23, 95% CI: 1.23-3.78, P = 0.003) and external validation (HR 1.88, 95% CI 1.42-2.48; P < 0.001) set. Time-dependent receiver operating curve at 1 year showed that the integrated mRNA-lncRNA signature [area under curve (AUC) = 0.742] had better prognostic accuracy than AJCC TNM stage (AUC = 0.615) in the entire 702 patients. In addition, survival decision curve analyses at 12 months revealed a good clinical usefulness of the integrated mRNA-lncRNA signature. In conclusion, we successfully developed an integrated mRNA-lncRNA signature that can accurately predict early relapse.

Nomograms for predicting the prognostic value of serological tumor biomarkers in colorectal cancer patients after radical resection

A wide range of serum tumor biomarkers, including CA19-9, CA242, CA72-4, CA50, and CA125, has been studied in association with colorectal cancer (CRC). However, few previous studies have comprehensively considered the above tumor biomarkers to assess their clinical significance in predicting prognosis. Data from Fudan University Shanghai Cancer Center (FUSCC) between January 1, 2007 and December 30, 2012 was retrospectively analyzed. Univariate and multivariate analyses were performed to assess the association between prognostic factors and survival outcomes. Nomograms were established based on multivariate Cox regression model analysis for overall survival (OS) and disease free survival (DFS), and c-indexes were 0.772 (95% CI: 0.724-0.820) and 0.715 (95% CI: 0.678–0.752), respectively. Subgroup analyses according to CEA status (high/normal) suggested that CA724 was the only independent prognostic factor for OS (P = 0.001) and DFS (P < 0.001) in the CEA-high group, while, in the CEA-normal group, the only independent prognostic factor for OS (P = 0.031) and DFS (P = 0.043) was CA50. CA50 and CA724 could supplement CEA in monitoring recurrence and metastasis. Accordingly, nomograms based on CEA, CA50, CA724 and other clinical-pathological factors could improve prognosis prediction for colorectal cancer patients.