The Ala134Thr variant in TMEM176B exerts a beneficial role in colorectal cancer prognosis by increasing NLRP3 inflammasome activation.

PURPOSE: TMEM176B was recently described as a negative modulator of Nlrp3 inflammasome activation in mice. In the mouse model, the inhibition of TMEM176B leads to an increased anti-tumoral activity which is dependent on Nlrp3. Since we have recently shown that single nucleotide variants (SNPs) in inflammasome genes, including NLRP3, significantly affect colorectal cancer (CRC) prognosis, we proposed to investigate here the association between genetic variants in TMEM176B and CRC prognosis. METHODS: Considering that, up to now, no genetic study analyzing this gene in humans exists, we selected possible functional SNPs and genotyped them in a cohort of CRC patients submitted to surgery and followed up for more than 10 years. Genotype-guided assays were realized to evaluate the effect of the variant on NLRP3 inflammasome activation. Gene expression from The Cancer Genome Atlas (TCGA) cohort was analyzed to valid possible prognostic and predictive features. RESULTS: We identified the Ala134Thr variant (rs2072443) in TMEM176B as a protective factor for CRC prognosis. This SNP is associated with decreased gene expression and with an increased activation of NLRP3 inflammasome, at least in monocytes and dendritic cells. Furthermore, low TMEM176B expression is associated with higher overall survival. CONCLUSION: Altogether, these findings supported the role of TMEM176B in NLRP3 inflammasome biology and for the first time demonstrated the genetic association between rs2072443 and CRC in humans.

Brazilian society of surgical oncology: Guidelines for the surgical treatment of mid-low rectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the third leading cause of cancer in North America, Western Europe, and Brazil, and represents an important public health problem. It is estimated that approximately 30% of all the CRC cases correspond to tumors located in the rectum, requiring complex multidisciplinary treatment. In an effort to provide surgeons who treat rectal cancer with the most current information based on the best evidence in the literature, the Brazilian Society of Surgical Oncology (SBCO) has produced the present guidelines for rectal cancer treatment that is focused on the main topics related to daily clinical practice. OBJECTIVES: The SBCO developed the present guidelines to provide recommendations on the main topics related to the treatment of mid-low rectal cancer based on current scientific evidence. METHODS: Between May and June 2021, 11 experts in CRC surgery met to develop the guidelines for the treatment of mid-low rectal cancer. A total of 22 relevant topics were disseminated among the participants. The methodological quality of a final list with 221 sources was evaluated, all the evidence was examined and revised, and the treatment guideline was formulated by the 11-expert committee. To reach a final consensus, all the topics were reviewed via a videoconference meeting that was attended by all 11 of the experts. RESULTS: The prepared guidelines contained 22 topics considered to be highly relevant in the treatment of mid-low rectal cancer, covering subjects related to the tests required for staging, surgical technique-related aspects, recommended measures to reduce surgical complications, neoadjuvant strategies, and nonoperative treatments. In addition, a checklist was proposed to summarize the important information and offer an updated tool to assist surgeons who treat rectal cancer provide the best care to their patients. CONCLUSION: These guidelines summarize concisely the recommendations based on the most current scientific evidence on the most relevant aspects of the treatment of mid-low rectal cancer and are a practical guide that can help surgeons who treat rectal cancer make the best therapeutic decision.

Double-edged sword of inflammasome genetics in colorectal cancer prognosis.

Inflammation is a colorectal cancer (CRC) hallmark. Inflammasome-dependent cytokines IL-1ß and IL-18 can play a beneficial or detrimental role in tumorigenesis depending on cancer type. Variants in inflammasome genes were associated with tumor development and/or outcome, and have been proposed as potential biomarkers for population screening. In this study, 215 CRC patients followed-up for 10 years were examined for 9 polymorphisms in selected inflammasome genes. Multivariate association analysis and survival analysis were performed to evaluate the association between the polymorphisms and CRC prognosis. Variants associated with lower levels of IL-18 (rs1834481, rs5744256), or with increased activation of inflammasome receptors NLRP1 (rs12150220) and NLRP3 (rs35829419) resulted detrimental to CRC prognosis and may be used as prognostic markers.

Prognostic significance of vascular endothelial growth factor polymorphisms in colorectal cancer patients.

AIM: To investigate the associations of the genetic polymorphisms of vascular endothelial growth factor A (VEGF-A) -1498C>T and -634G>C, with the survival of patients with colorectal cancer (CRC). METHODS: A prospective cohort consisting of 131 Brazilians patients consecutively operated on with a curative intention as a result of sporadic colorectal carcinoma was studied. DNA was extracted from peripheral blood and its amplification and allelic discrimination for each genetic polymorphism was performed using the technique of polymerase chain reaction (PCR) in real-time. The real-time PCR technique was used to identify the VEGF-A -1498C>T (rs833031) and -634G>C (rs2010963) polymorphisms. Genotyping was validated for VEGF-A -1498C>T polymorphism in 129 patients and for VEGF-A -634G>C polymorphism in 118 patients. The analysis of association between categorical variables was performed using logistic regression, survival by Kaplan-Meier method and multivariate analysis by the Cox regression method. RESULTS: In the univariate analysis there was a significant association (OR = 0.32; P = 0.048) between genotype CC of the VEGF-A -1498C>T polymorphism and the presence of CRC liver metastasis. There was no association between VEGF-A -1498C>T polymorphism and VEGF-A -634G>C polymorphism with further clinical or anatomopathologic variables. The genotype CC of the VEGF-A -1498C>T polymorphism was significantly correlated with the 5-year survival (P = 0.032), but not significant difference (P = 0.27) was obtained with the VEGF-A -634G>C polymorphism with the 5-year survival in the univariate analysis. The genotype CT (HR = 2.79) and CC (HR = 4.67) of the polymorphism VEGF-A -1498C>T and the genotype CC (HR = 3.76) of the polymorphism VEGF-A -634C>G acted as an independent prognostic factor for the risk of death in CRC patients. CONCLUSION: The CT and CC genotypes of the VEGF-A -1498C>T and the CC genotype of the VEGF-A -634C>G polymorphisms are prognostic factors of survival in Brazilians patients with sporadic colorectal carcinoma.

Study of the Annexin A1 and Its Associations with Carcinoembryonic Antigen and Mismatch Repair Proteins in Colorectal Cancer.

PURPOSE: Annexin-A1 (ANXA1) has been implicated in various tumor types, but few studies have investigated its involvement in colorectal cancer. The study aimed to analyze ANXA1 expression in the normal margin and colorectal tumor tissues of 104 patients who underwent surgery for colorectal cancer and to associate the ANXA1 expression with predictive clinicopathological variables. METHODS: Hematoxylin-eosin and immunohistochemical staining were used for the analysis. RESULTS: ANXA1 expression was higher in colorectal cancer than in normal margin tissue (p = 0.0001). However, no differences were observed when we analyzed the ANXA1 expression in colon and rectal tumors (p = 0.830). Also, this protein positivity was associated with increased carcinoembryonic antigen levels (p = 0.004). Our data in the DNA-mismatch repair proteins expression was in accordance to the literature. And their positivity was not associated with ANXA1 presence in colorectal cancer. CONCLUSION: The high incidence of ANXA1 positive expression in colorectal cancer and its association with carcinoembryonic antigen levels might indicate the importance of this protein in the colorectal cancer biology.