HAMP as a Prognostic Biomarker for Colorectal Cancer Based on Tumor Microenvironment Analysis.

Colorectal cancer (CRC) is the most common digestive tumor in the world and has a high mortality rate. The development and treatment of CRC are related to the immune microenvironment, but immune response-related prognostic biomarkers are lacking. In this study, we used The Cancer Genome Atlas (TCGA) to explore the tumor microenvironment (TME) and weighted gene coexpression network analysis (WGCNA) to identify significant prognostic genes. We also identified differentially expressed genes in the TCGA data and explored immune-related genes and transcription factors (TFs). Then, we built a TF regulatory network and performed a comprehensive prognostic analysis of an lncRNA-associated competitive endogenous RNA network (ceRNA network) to build a prognostic model. CCR8 and HAMP were identified both in the WGCNA key module and as immune-related genes. HAMP had good prognostic value for CRC and was highly expressed in CRC tissues and had a negative correlation with CD4+ T cells and M0 macrophages based on immunohistochemistry and immunofluorescence staining of clinical specimens.We found that HAMP had high prognostic and therapeutic target value for CRC and was associated with liver metastasis. These analysis results revealed that HAMP may be a candidate immune-related prognostic biomarker for CRC.

Development and Validation of a Nomogram and a Comprehensive Prognostic Analysis of an LncRNA-Associated Competitive Endogenous RNA Network Based on Immune-Related Genes for Locally Advanced Rectal Cancer With Neoadjuvant Therapy.

Colorectal cancer (CRC) is a common digestive tract tumor worldwide. In recent years, neoadjuvant chemoradiotherapy (CRT) has been the most comprehensive treatment for locally advanced rectal cancer (LARC). In this study, we explored immune infiltration in rectal cancer (RC) and identified immune-related differentially expressed genes (IRDEGs). Then, we identified response markers in datasets in GEO databases by principal component analysis (PCA). We also utilized three GEO datasets to identify the up- and downregulated response-related genes simultaneously and then identified genes shared between the PCA markers and three GEO datasets. Based on the hub IRDEGs, we identified target mRNAs and constructed a ceRNA network. Based on the ceRNA network, we explored prognostic biomarkers to develop a prognostic model for RC through Cox regression. We utilized the specimen to validate the expression of the two biomarkers. We also utilized LASSO regression to screen hub IRDEGs and built a nomogram to predict the response of LARC patients to CRT. All of the results show that the nomogram and prognostic model offer good prognostic value and that the ceRNA network can effectively highlight the regulatory relationship. hsa-mir-107 and WDFY3-AS2 may be prognostic biomarkers for RC.

Differential analysis revealing APOC1 to be a diagnostic and prognostic marker for liver metastases of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the most malignant gastrointestinal cancers worldwide. The liver is the most important metastatic target organ, and liver metastasis is the leading cause of death in patients with CRC. Owing to the lack of sensitive biomarkers and unclear molecular mechanism, the occurrence of liver metastases cannot be predicted and the clinical outcomes are bad for liver metastases. Therefore, it is very important to identify the diagnostic or prognostic markers for liver metastases of CRC. AIM: To investigate the highly differentially expressed genes (HDEGs) and prognostic marker for liver metastases of CRC. METHODS: Data from three NCBI Gene Expression Omnibus (GEO) datasets were used to show HDEGs between liver metastases of CRC and tumour or normal samples. These significantly HDEGs of the three GEO datasets take the interactions. And these genes were screened through an online tool to explore the prognostic value. Then, TIMER and R package were utilized to investigate the immunity functions of the HDEGs and gene set enrichment analysis was used to explore their potential functions. RESULTS: Based on the selection criteria, three CRC datasets for exploration (GSE14297, GSE41258, and GSE49355) were chosen. Venn diagrams were used to show HDEGs common to the six groups and 47 HDEGs were obtained. The HDEGs were shown by using STRING and Cytoscape software. Based on the TCGA database, APOC1 showed significantly different expression between N2 and N0, and N2 and N1. And there was also a significant difference in expression between T2 and T4, and between T2 and T3. In 20 paired CRC and normal tissues, quantitative real-time polymerase chain reaction illustrated that the APOC1 mRNA was strongly upregulated in CRC tissues (P = 0.014). PrognoScan and GEPIA2 revealed the prognostic value of APOC1 for overall survival and disease-free survival in CRC (P < 0.05). TIMER showed that APOC1 has a close relationship with immune infiltration (P < 0.05). CONCLUSION: APOC1 is a biomarker that is associated with both the diagnosis and prognosis of liver metastases of CRC.

Nomograms and risk score models for predicting survival in rectal cancer patients with neoadjuvant therapy.

BACKGROUND: Colorectal cancer is a common digestive cancer worldwide. As a comprehensive treatment for locally advanced rectal cancer (LARC), neoadjuvant therapy (NT) has been increasingly used as the standard treatment for clinical stage II/III rectal cancer. However, few patients achieve a complete pathological response, and most patients require surgical resection and adjuvant therapy. Therefore, identifying risk factors and developing accurate models to predict the prognosis of LARC patients are of great clinical significance. AIM: To establish effective prognostic nomograms and risk score prediction models to predict overall survival (OS) and disease-free survival (DFS) for LARC treated with NT. METHODS: Nomograms and risk factor score prediction models were based on patients who received NT at the Cancer Hospital from 2015 to 2017. The least absolute shrinkage and selection operator regression model were utilized to screen for prognostic risk factors, which were validated by the Cox regression method. Assessment of the performance of the two prediction models was conducted using receiver operating characteristic curves, and that of the two nomograms was conducted by calculating the concordance index (C-index) and calibration curves. The results were validated in a cohort of 65 patients from 2015 to 2017. RESULTS: Seven features were significantly associated with OS and were included in the OS prediction nomogram and prediction model: Vascular_tumors_bolt, cancer nodules, yN, body mass index, matchmouth distance from the edge, nerve aggression and postoperative carcinoembryonic antigen. The nomogram showed good predictive value for OS, with a C-index of 0.91 (95%CI: 0.85, 0.97) and good calibration. In the validation cohort, the C-index was 0.69 (95%CI: 0.53, 0.84). The risk factor prediction model showed good predictive value. The areas under the curve for 3- and 5-year survival were 0.811 and 0.782. The nomogram for predicting DFS included ypTNM and nerve aggression and showed good calibration and a C-index of 0.77 (95%CI: 0.69, 0.85). In the validation cohort, the C-index was 0.71 (95%CI: 0.61, 0.81). The prediction model for DFS also had good predictive value, with an AUC for 3-year survival of 0.784 and an AUC for 5-year survival of 0.754. CONCLUSION: We established accurate nomograms and prediction models for predicting OS and DFS in patients with LARC after undergoing NT.

Differential Expression Analysis Revealing CLCA1 to Be a Prognostic and Diagnostic Biomarker for Colorectal Cancer.

Colorectal cancer (CRC) is a common malignant tumor of the digestive tract and lacks specific diagnostic markers. In this study, we utilized 10 public datasets from the NCBI Gene Expression Omnibus (NCBI-GEO) database to identify a set of significantly differentially expressed genes (DEGs) between tumor and control samples and WGCNA (Weighted Gene Co-Expression Network Analysis) to construct gene co-expression networks incorporating the DEGs from The Cancer Genome Atlas (TCGA) and then identify genes shared between the GEO datasets and key modules. Then, these genes were screened via MCC to identify 20 hub genes. We utilized regression analyses to develop a prognostic model and utilized the random forest method to validate. All hub genes had good diagnostic value for CRC, but only CLCA1 was related to prognosis. Thus, we explored the potential biological value of CLCA1. The results of gene set enrichment analysis (GSEA) and immune infiltration analysis showed that CLCA1 was closely related to tumor metabolism and immune invasion of CRC. These analysis results revealed that CLCA1 may be a candidate diagnostic and prognostic biomarker for CRC.

Impact of interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer patients.

BACKGROUND: Epidemiologically, in China, locally advanced rectal cancer is a more common form of rectal cancer. Preoperative neoadjuvant concurrent chemoradiotherapy can effectively reduce the size of locally invasive tumors and improve disease-free survival (DFS) and pathologic response after surgery. At present, this modality has become the standard protocol for the treatment of locally advanced rectal cancer in many centers, but the optimal time for surgery after neoadjuvant therapy is still controversial. AIM: To investigate the impact of time interval between neoadjuvant therapy and surgery on DFS and pathologic response in patients with locally advanced rectal cancer. METHODS: A total of 231 patients who were classified as having clinical stage II or III advanced rectal cancer and underwent neoadjuvant chemoradiation followed by surgery at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from November 2014 to August 2017 were involved in this retrospective cohort study. The patients were divided into two groups based on the different time intervals between neoadjuvant therapy and surgery: 139 (60.2%) patients were in group A (≤ 9 wk), and 92 (39.2%) patients were in group B (> 9 wk). DFS and pathologic response were analyzed as the primary endpoints. The secondary endpoints were postoperative complications and sphincter preservation. RESULTS: For the 231 patients included, surgery was performed at ≤ 9 wk in 139 (60.2%) patients and at > 9 wk in 92 (39.8%). The patients' clinical characteristics, surgical results, and tumor outcomes were analyzed through univariate analysis combined with multivariate regression analysis. The overall pathologic complete response (pCR) rate was 27.2% (n = 25) in the longer time interval group (> 9 wk) and 10.8% (n = 15) in the shorter time interval group (≤ 9 wk, P = 0.001). The postoperative complications did not differ between the groups (group A, 5% vs group B, 5.4%; P = 0.894). Surgical procedures for sphincter preservation were performed in 113 (48.9%) patients, which were not significantly different between the groups (group A, 52.5% vs group B, 43.5%; P = 0.179). The pCR rate was an independent factor affected by time interval (P = 0.009; odds ratio [OR] = 2.668; 95%CI: 1.276-5.578). Kaplan-Meier analysis and Cox regression analysis showed that the longer time interval (> 9 wk) was a significant independent prognostic factor for DFS (P = 0.032; OR = 2.295; 95%CI: 1.074-4.905), but the time interval was not an independent prognostic factor for overall survival (P > 0.05). CONCLUSION: A longer time interval to surgery after neoadjuvant therapy may improve the pCR rate and DFS but has little impact on postoperative complications and sphincter preservation.

Low ligation has a lower anastomotic leakage rate after rectal cancer surgery.

BACKGROUND: For laparoscopic rectal cancer surgery, the inferior mesenteric artery (IMA) can be ligated at its origin from the aorta [high ligation (HL)] or distally to the origin of the left colic artery [low ligation (LL)]. Whether different ligation levels are related to different postoperative complications, operation time, and lymph node yield remains controversial. Therefore, we designed this study to determine the effects of different ligation levels in rectal cancer surgery. AIM: To investigate the operative results following HL and LL of the IMA in rectal cancer patients. METHODS: From January 2017 to July 2019, this retrospective cohort study collected information from 462 consecutive rectal cancer patients. According to the ligation level, 235 patients were assigned to the HL group while 227 patients were assigned to the LL group. Data regarding the clinical characteristics, surgical characteristics and complications, pathological outcomes and postoperative recovery were obtained and compared between the two groups. A multivariate logistic regression analysis was performed to evaluate the possible risk factors for anastomotic leakage (AL). RESULTS: Compared to the HL group, the LL group had a significantly lower AL rate, with 6 (2.8%) cases in the LL group and 24 (11.0%) cases in the HL group (P = 0.001). The HL group also had a higher diverting stoma rate (16.5% vs 7.5%, P = 0.003). A multivariate logistic regression analysis was subsequently performed to adjust for the confounding factors and confirmed that HL (OR = 3.599; 95%CI: 1.374-9.425; P = 0.009), tumor located below the peritoneal reflection (OR = 2.751; 95%CI: 0.772-3.985; P = 0.031) and age (≥ 65 years) (OR = 2.494; 95%CI: 1.080-5.760; P = 0.032) were risk factors for AL. There were no differences in terms of patient demographics, pathological outcomes, lymph nodes harvested, blood loss, hospital stay and urinary function (P > 0.05). CONCLUSION: In rectal cancer surgery, LL should be the preferred method, as it has a lower AL and diverting stoma rate.

Corrigendum: Differential Expression Analysis Revealing CLCA1 to Be a Prognostic and Diagnostic Biomarker for Colorectal Cancer.

[This corrects the article DOI: 10.3389/fonc.2020.573295.].

Impact factors of lymph node retrieval on survival in locally advanced rectal cancer with neoadjuvant therapy.

BACKGROUND: Conventional clinical guidelines recommend that at least 12 lymph nodes should be removed during radical rectal cancer surgery to achieve accurate staging. The current application of neoadjuvant therapy has changed the number of lymph node dissection. AIM: To investigate factors affecting the number of lymph nodes dissected after neoadjuvant chemoradiotherapy in locally advanced rectal cancer and to evaluate the relationship of the total number of retrieved lymph nodes (TLN) with disease-free survival (DFS) and overall survival (OS). METHODS: A total of 231 patients with locally advanced rectal cancer from 2015 to 2017 were included in this study. According to the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) classification system and the NCCN guidelines for rectal cancer, the patients were divided into two groups: group A (TLN ≥ 12, n = 177) and group B (TLN < 12, n = 54). Factors influencing lymph node retrieval were analyzed by univariate and binary logistic regression analysis. DFS and OS were evaluated by Kaplan-Meier curves and Cox regression models. RESULTS: The median number of lymph nodes dissected was 18 (range, 12-45) in group A and 8 (range, 2-11) in group B. The lymph node ratio (number of positive lymph nodes/total number of lymph nodes) (P = 0.039) and the interval between neoadjuvant therapy and radical surgery (P = 0.002) were independent factors of the TLN. However,TLN was not associated with sex, age, ASA score, clinical T or N stage, pathological T stage, tumor response grade (Dworak), downstaging, pathological complete response, radiotherapy dose, preoperative concurrent chemotherapy regimen, tumor distance from anal verge, multivisceral resection, preoperative carcinoembryonic antigen level, perineural invasion, intravascular tumor embolus or degree of differentiation. The pathological T stage (P < 0.001) and TLN (P < 0.001) were independent factors of DFS, and pathological T stage (P = 0.011) and perineural invasion (P = 0.002) were independent factors of OS. In addition, the risk of distant recurrence was greater for TLN < 12 (P = 0.009). CONCLUSION: A shorter interval to surgery after neoadjuvant chemoradiotherapy for rectal cancer under indications may cause increased number of lymph nodes harvested. Tumor shrinkage and more extensive lymph node retrieval may lead to a more favorable prognosis.

Analysis of 72 patients with colorectal high-grade neuroendocrine neoplasms from three Chinese hospitals.

BACKGROUND: Colorectal high-grade neuroendocrine neoplasms (HGNENs) are rare and constitute less than 1% of all colorectal malignancies. Based on their morphological differentiation and proliferation identity, these neoplasms present heterogeneous clinicopathologic features. Opinions regarding treatment strategies for and improvement of the clinical outcomes of these patients remain controversial. AIM: To delineate the clinicopathologic features of and explore the prognostic factors for this rare malignancy. METHODS: This observational study reviewed the data of 72 consecutive patients with colorectal HGNENs from three Chinese hospitals between 2000 and 2019. The clinicopathologic characteristics and follow-up data were carefully collected from their medical records, outpatient reexaminations, and telephone interviews. A survival analysis was conducted to evaluate their outcomes and to identify the prognostic factors for this disease. RESULTS: According to the latest recommendations for the classification and nomenclature of colorectal HGNENs, 61 (84.7%) patients in our cohort had poorly differentiated neoplasms, which were categorized as high-grade neuroendocrine carcinomas (HGNECs), and the remaining 11 (15.3%) patients had well differentiated neoplasms, which were categorized as high-grade neuroendocrine tumors (HGNETs). Most of the neoplasms (63.9%) were located at the rectum. More than half of the patients (51.4%) presented with distant metastasis at the date of diagnosis. All patients were followed for a median duration of 15.5 mo. In the entire cohort, the median survival time was 31 mo, and the 3-year and 5-year survival rates were 44.3% and 36.3%, respectively. Both the univariate and multivariate analyses demonstrated that increasing age, HGNEC type, and distant metastasis were risk factors for poor clinical outcomes. CONCLUSION: Colorectal HGNENs are rare and aggressive malignancies with poor clinical outcomes. However, patients with younger age, good morphological differentiation, and without metastatic disease can have a relatively favorable prognosis.