Novel molecular typing reveals the risk of recurrence in patients with early-stage papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is an indolent disease with a favorable prognosis but characterized by a high recurrence rate. We aimed to improve precise stratification of recurrence risk in PTC patients with early stage using multi-gene signatures. PATIENTS AND METHODS: The present study was performed using data from The Cancer Genome Atlas (TCGA) and multi-center datasets. Unsupervised consensus clustering was used to obtain the optimal molecular subtypes and least absolute shrinkage and selection operator (LASSO) analysis was performed to identify potential genes for the construction of recurrence signature. Kaplan-Meier survival analysis and the log-rank test was used to detect survival differences. Harrells concordance index (C-index) was used to assess the performance of the DNA damage repair (DDR) recurrence signature. RESULTS: Through screening 8 candidate gene sets, the entire cohort was successfully stratified into two recurrence-related molecular subtypes based on DDR genes: DDR-high subtype and DDR-low subtype. The recurrence rate of DDR-high subtype was significantly lower than DDR-low subtype [HR = 0.288 (95%CI, 0.084-0.986), P = 0.047]. Further, a two-gene DDR recurrence signature was constructed, including PER1 and EME2. The high-risk group showed a significantly worse recurrence-free survival (RFS) than the low-risk group [HR = 10.647 (95%CI, 1.363-83.197), P = 0.024]. The multi-center data demonstrated that proportion of patients with low expression of PER1 and EME2 was higher in the recurrence group than those in the non-recurrence group. CONCLUSIONS: These findings could help accurately and reliably identify PTC patients with high risk of recurrence so that they could receive more radical and aggressive treatment strategies and more rigorous surveillance practices.

LINC01234 promoted malignant behaviors of breast cancer cells via hsa-miR-30c-2-3p/CCT4/mTOR signaling pathway.

OBJECTIVE: Despite continuous progress in treatment, recurrence and metastasis limit further improvement in the prognosis of breast cancer (BC) patients. Our aim was to search for a crucial prognostic biomarker of BC. MATERIALS AND METHODS: Patient data were selected from The Cancer Genome Atlas (TCGA) and GTEx databases. Several online public databases, including Gene Expression Profiling Interactive Analysis (GEPIA), miRWalk, miRDB, and LncBase Predicted v.2, were used to identify potential upstream miRNAs and lncRNAs. These findings were validated through in vitro experiments. RESULTS: A total of 1, 097 invasive BC samples and 572 normal breast tissues (including 113 samples from TCGA and 459 samples from GTEx) were collected for the study. CCT4 was not only significantly overexpressed in BC compared with normal breast tissues but also had important prognostic significance (P < 0.001). By intersecting miRWalk and miRDB and conducting correlation analysis, hsa-miR-30c-2-3p was identified as the most probable upstream miRNA of CCT4. Following an extensive assessment that included survival analysis, correlation analysis, and common binding-site prediction, LINC01234 was chosen as the most likely upstream lncRNA. In vitro experiments showed that LINC01234-siRNA inhibited the proliferation, invasion, and migration abilities of BC cells. Western blot analysis further confirmed that LINC01234 promoted malignant behaviors of BC cells via the CCT4/mTOR signaling pathway. CONCLUSION: The LINC01234/hsa-miR-30c-2-3p/CCT4/mTOR axis was identified as a potential ceRNA regulatory mechanism in BC. These findings established the foundation for systematically unveiling the pathological mechanisms of BC and provided new insights for targeted therapy of BC patients.

IL-6/IL-10 mRNA expression ratio in tumor tissues predicts prognosis in gastric cancer patients without distant metastasis.

There was growing evidence that inflammatory responses played significant roles in malignancies. However, the impact of pro-inflammatory-to-anti-inflammatory factor ratio in tumor tissues has not been investigated in gastric cancer (GC) yet. We collected patient data from The Cancer Genome Atlas (TCGA) database. A total of 270 stomach adenocarcinoma (STAD) patients without distant metastasis were included in the study. After screening 12 candidate pro-inflammatory-to-anti-inflammatory pairs, only the IL-6/IL-10 mRNA expression ratio in tumor tissues had a significant effect on overall survival (OS) of STAD patients (P = 0.014). X-tile analysis showed that the greatest survival differences were obtained when the cutoff value of IL-6/IL-10 mRNA expression ratio was set at 1.3 and 5.5. With the low-ratio group (IL-6/IL-10 mRNA expression ratio: < 1.3) as reference, OS time for both the medium-ratio group (IL-6/IL-10 mRNA expression ratio: 1.3-5.5) and the high-ratio group (IL-6/IL-10 mRNA expression ratio: > 5.5) was significantly shorter (P < 0.05). Multivariate Cox regression analyses indicated that IL-6/IL-10 mRNA expression ratio was an independent prognostic factor for OS and disease-specific survival (DSS). These findings provided a novel and powerful tool for a more rational management of GC patients.

Inclusion of the Number of Metastatic Lymph Nodes in the Staging System for Medullary Thyroid Cancer: Validating a Modified American Joint Committee on Cancer Tumor-Node-Metastasis Staging System.

Background: The current American Joint Committee on Cancer (AJCC) staging system (8th edition) for medullary thyroid cancer (MTC) was originally extrapolated from the staging system for differentiated thyroid cancer. However, the current staging system does not accurately predict the prognosis of patients with MTC. Patients and Methods: The present study was based on data from the Surveillance, Epidemiology, and End Results (SEER) database and validated by multicenter data from the Shanghai Tenth People's Hospital, Tongji University School of Medicine, Xuzhou City Central Hospital, and Suzhou Ninth People's Hospital. Hazard ratio with its 95% confidence interval [CI] was estimated by Cox proportional hazards regression analysis. The concordance index (C-index) was used to evaluate the discrimination accuracy of the current AJCC tumor-node-metastasis (TNM) staging system and the modified AJCC (mAJCC) TNM staging system. Results: A total of 1175 MTC patients were selected from the SEER database and 312 from the three hospitals in China. We redefined the N category according to the number of metastatic lymph nodes (LNs) as follows: N'0 category (0 metastatic LNs), N'1 category (1-9 metastatic LNs), and N'2 category (≥10 metastatic LNs). The four distinct tumor stages were reclassified in the mAJCC staging system as follows: stage I (T1-4N'0M0, T1N'1M0), stage II (T2-3N'1M0, T1N'2M0), stage III (T4N'1M0, T2-4N'2M0), and stage IV (TanyN'anyM1). The C-index of the current AJCC staging system and the mAJCC staging system was 0.72 [CI, 0.67-0.78] and 0.78 [CI, 0.73-0.84], respectively. Similar results were observed in the survival analysis of the multicenter data set. Conclusions: The mAJCC staging system could discriminate the prognosis of MTC patients more effectively than the current AJCC staging system, indicating that it is feasible and appropriate to modify the current AJCC staging system by introducing the number of metastatic LNs instead of the location of LNs. These findings might be adopted in the next edition of the AJCC staging system and be used to guide clinical practice.

MicroRNA-4521 targets hepatoma up-regulated protein (HURP) to inhibit the malignant progression of breast cancer.

Breast cancer (BC) is a common malignancy among women, and microRNAs (miRNAs) play a role in its progression. Reportedly, microRNA-4521 (miR-4521) participates in regulating the progression of some carcinomas. In the present work, miR-4521 and hepatoma up-regulated protein (HURP) mRNA expressions in BC tissues and cell lines were examined by qRT-PCR. After miR-4521 was overexpressed or knocked down in BC cells, CCK-8 experiment and EdU experiment were employed to detect BC cell growth. Moreover, the Transwell assay was adopted to detect the migration and invasion. Subsequently, flow cytometry was executed to evaluate the changes in cell cycle progression. KEGG analysis was utilized to predict the signaling pathways related with the target genes of miR-524-5p. The binding relationship between miR-4521 and HURP 3'UTR was validated by dual-luciferase reporter gene experiment. HURP and NF-kB p65 protein expression in BC cells was detected by Western blot. It was revealed that, miR-4521 was lowly expressed in BC tissues, and its expression was associated with tumor grade, lymph node metastasis and clinical stage of the patients. Overexpression of miR-4521 suppressed the growth, migration, invasion and cell cycle progression of BC cells and restrained p65 expression; downregulation of miR-4521 in BC cells showed opposite biological effects. Additionally, HURP was a downstream target gene of miR-4521, and overexpression of HURP reversed the above effects of miR-4521 overexpression. In short, miR-4521 can inhibit BC progression by modulating the HURP/NF-κB pathway.

Comprehensive analysis of suppressor of cytokine signaling proteins in human breast Cancer.

BACKGROUND: Abnormal expression of suppressor of cytokine signaling (SOCS) proteins regulates tumor angiogenesis and development in cancers. In this study, we aimed to perform a comprehensive bioinformatic analysis of SOCS proteins in breast invasive carcinoma (BRCA). METHODS: The gene expression, methylation level, copy number, protein expression and patient survival data related to SOCS family members in BRCA patients were obtained from the following databases: Oncomine, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), PCViz, cBioPortal and Kaplan-Meier plotter. Correlation analyses, identification of interacting genes and construction of regulatory networks were performed by functional and pathway enrichment analyses, weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA). RESULTS: Data related to 1109 BRCA tissues and 113 normal breast tissue samples were extracted from the TCGA database. SOCS2 and SOCS3 exhibited significantly lower mRNA expression levels in BRCA tissues than in normal tissues. BRCA patients with high mRNA levels of SOCS3 (p < 0.01) and SOCS4 (p < 0.05) were predicted to have significantly longer overall survival (OS) times. Multivariate analysis showed that SOCS3 was an independent prognostic factor for OS. High mRNA expression levels of SOCS2 (p < 0.001), SOCS3 (p < 0.001), and SOCS4 (p < 0.01), and a low expression level of SOCS5 (p < 0.001) were predicted to be significantly associated with better recurrence-free survival (RFS). Multivariate analysis showed that SOCS2 was an independent prognostic factor for RFS. Lower expression levels of SOCS2 and SOCS3 were observed in patients with tumors of more advanced clinical stage (p < 0.05). Functional and pathway enrichment analyses, together with WGCNA and GSEA, showed that SOCS3 and its interacting genes were significantly involved in the JAK-STAT signaling pathway, suggesting that JAK-STAT signaling might play a critical role in BRCA angiogenesis and development. Western blot results showed that overexpression of SOCS3 inhibited the activity of the JAK-STAT signaling pathway in vitro. CONCLUSIONS: SOCS family proteins play a very important role in BRCA. SOCS3 may be a prognostic factor and SOCS2 may be a potential therapeutic target in breast cancer.

Lymph Node Ratio-Based Staging System for Gallbladder Cancer With Fewer Than Six Lymph Nodes Examined.

PURPOSE: The 8th edition of the American Joint Committee on Cancer (AJCC) tumor-lymph node-metastasis (TNM) staging system for gallbladder cancer (GBC) recommended that at least six lymph nodes (LNs) should be examined. But most patients with GBC had fewer than six LNs resected. This study aimed to establish an alternative index for assessing the LN status during the staging system for GBC patients with fewer than six LNs retrieved. PATIENTS AND METHODS: Patient data was extracted from the Surveillance, Epidemiology, and End Results (SEER) database (cases between 2004 and 2013). X-tile software was used to determine the optimal cutoff value for lymph node ratio (LNR) and a concordance index (C-index) was used to evaluate the discriminatory powers of the two staging systems. RESULTS: The majority of GBC patients in our cohort (1353, 78.5%) had fewer than six LNs examined. Among patients with inadequate LN examination, the higher number of LNs examined correlated with a lower proportion of patients. Using the TNM staging system, the C-index for patients with fewer than six LNs and patients with six or more LNs screened were 0.636 and 0.704, respectively. Using the staging system based on LNR (TNrM), the C-index for patients with fewer than six LNs retrieved and patients with six or more LNs retrieved were 0.649 and 0.694, respectively. Similar results were observed in patients with gallbladder adenocarcinoma (GBA). CONCLUSION: TNrM might be superior to the 8th AJCC TNM staging system for stratifying GBC patients with fewer than six LNs examined, and it can complement TNM for more accurate risk stratification. Future prospective studies are needed to validate our findings.

Incidence, prevalence, and outcomes of systemic malignancy with bone metastases.

PURPOSE: Evidence on the incidence, prevalence, and outcomes of bone metastases among patients with systemic malignancy is limited. This study aimed to evaluate it using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: We collected patients diagnosed with solid malignant tumors deriving outside of the bone, hematologic malignancies, Kaposi sarcoma, lymphoma, and myeloma from the SEER database (from 2010 to 2013). The incidence, prevalence, and outcomes of these systemic malignancies with bone metastases were then analyzed. RESULTS: A total of 67,605 patients with bone metastases at cancer diagnosis were included. The highest rate of bone metastases was observed in patients with small-cell lung cancer at the time of alternative primary site cancer diagnosis. Among 226,816 cases with metastatic disease, cases with breast cancer (65.58%), and prostate cancer (89.60%) had a high incidence proportion (>10%) of identified bone metastases. Patients with additional bone metastases resulting from prostate cancer, breast cancer, and testis cancer presented the best survival time. CONCLUSIONS: Incidence and prognosis differ considerably among bone metastases with different primary malignancy sites. These results may encourage appropriate application of bone imaging.

Redefining the T1 category of the 8th American Joint Committee on Cancer Staging System for intrahepatic cholangiocarcinoma: A SEER database analysis.

The T1 tumor category is further divided into T1a (≤5 cm) and T1b (>5 cm) by tumor size in the 8th edition of the American Joint Committee on Cancer (AJCC) staging system for intrahepatic cholangiocarcinoma (ICC). The aim of the present study was to investigate the association between tumor size and prognosis in patients with T1 ICC. The data regarding patients with ICC was downloaded from the Surveillance, Epidemiology, and End Results database between January 2004 and December 2013, at the time of first diagnosis and entered into the database. Demographic and pathological characteristics of patients were analyzed using an independent t-test and χ2 test. Overall survival was evaluated using Kaplan-Meier analysis; the cut-off point for tumor size was determined using the X-tile software. A total of 407 patients with ICC were selected from the analysis, including 199 cases with stage IA and 208 cases with stage IB tumors. The independent prognostic factors for patients with stage IA ICC were age and surgery. Independent prognostic factors for patients with stage IB ICC included age, surgery (yes vs. no) and tumor size (5-7 vs. ≥7 cm). The optimal cut-off value for tumor size was determined to be ~7 cm using X-tile software. Tumor size with a cut-off value of 7 cm could stratify patients by risk better than a value of 5 cm [hazard ratio (HR), 1.775; 95% confidence interval (CI), 1.356-2.323 and; HR, 1.402; 95% CI, 1.078-1.824, respectively]. This suggests that the T1 tumor category should be subclassified into T1a and T1b with a cut-off of 7 cm rather than 5 cm. The next edition of the AJCC staging system may take the present evidence into consideration for improvement regarding the accurate staging of ICC.

Lymph node status have a prognostic impact in breast cancer patients with distant metastasis.

BACKGROUND: The objective of this retrospective study was to determine whether lymph node metastasis has a prognostic impact on patients with stage IV breast cancer. PATIENTS AND METHODS: Seven thousand three hundred and seventy-nine patients with de novo stage IV breast cancer diagnosed from 2004 to 2013 were identified. Kaplan-Meier estimate method was fitted to measure overall survival and breast cancer-specific survival (BCSS). Cox proportional hazard analysis was used to evaluate the association between N stage and BCSS after controlling variables such as other patient/tumor characteristics. RESULTS: The primary site of M1 tumors was mainly upper-outer quadrant and overlapping lesion of the breast. Patients with N1 disease had better overall survival and BCSS than did those without lymph node metastasis. The overall survival and BCSS of M1 patients with N3 disease were significantly lower than that of those with N0, N1 and N2 disease, whereas patients with N2 and N0/N1 involvement showed no significant difference with survival. Multivariate analysis showed that lymph node metastasis was an important prognostic factor for M1 patients (N1 versus N0, hazard ratio [HR] = 0.902, 95% confidence interval [CI]: 0.825-0.986, p = 0.023; N3 versus N0, HR = 1.161, 95% CI: 1.055-1.276, p = 0.002). For M1 patients, age, race, marital status, primary site, ER, PR and HER2 were the independent prognostic factors. CONCLUSIONS: The cohort study provides an insight into de novo stage IV breast cancer with lymph node metastasis. Our results indicated that accurate lymph node evaluation for stage IV patients is still necessary to obtain important prognostic information.

Outcomes and prognostic factors of patients with stage IB and IIA pancreatic cancer according to the 8th edition American Joint Committee on Cancer criteria.

AIM: To evaluate the changes in the 8th edition American Joint Committee on Cancer (AJCC) for defining stage IB and IIA pancreatic cancer and identify their prognostic factors. METHODS: Pancreatic cancer patients were selected from the Surveillance Epidemiology and End Results database (1973-2013). The enrolled patients were divided into IB and IIA groups based on tumor size according to the 8th edition AJCC criteria. Clinical characteristics, including age, gender, race, tumor size, primary site, and grade were summarized. Univariate and multivariate analyses were performed to explore the prognostic factors of the IB and IIA stages of pancreatic cancer under new criteria. RESULTS: A total of 1349 pancreatic cancer patients were included. More patients had stage IB rather than stage IIA. Stage IB tumors (54.85%) were mainly located in the head of the pancreas, while stage IIA tumors were more often located in the tail and head of the pancreas (35.21% and 31.75%, respectively). The survival time of stage IB and IIA patients had no significant difference. Univariate and multivariate analyses indicated that the prognostic factors of survival for stage IB and IIA patients were different. For stage IB patients, age and primary site were the independent prognostic factors; for stage IIA patients, age and grade were the independent prognostic factors. The risk of death was lower among patients aged ≤ 65 years than those aged > 65 years. CONCLUSION: The prognostic factors for stage IB and IIA patients are different, but age is the independent prognostic factor for all patients. The survival time of stage IB and IIA patients has no significant difference.