The association of tumor-expressed REG4, SPINK4 and alpha-1 antitrypsin with cancer-associated thrombosis in colorectal cancer.

Novel biomarkers are needed to improve current imperfect risk prediction models for cancer-associated thrombosis (CAT). We recently identified an RNA-sequencing profile that associates with CAT in colorectal cancer (CRC) patients, with REG4, SPINK4, and SERPINA1 as the top-3 upregulated genes at mRNA level. In the current study, we investigated whether protein expression of REG4, SPINK4 and alpha-1 antitrypsin (A1AT, encoded by SERPINA1) in the tumor associated with CAT in an independent cohort of CRC patients. From 418 patients with resected CRC, 18 patients who developed CAT were age, sex, and tumor stage-matched to 18 CRC patients without CAT. Protein expression was detected by immunohistochemical staining and scored blindly by assessing the H-score (percentage positive cells*scoring intensity). The association with CAT was assessed by means of logistic regression, using patients with an H-score below 33 as reference group. The odds ratios (ORs) for developing CAT for patients with A1AThigh, REG4high, SPINK4high tumors were 3.5 (95%CI 0.8-14.5), 2.0 (95%CI 0.5-7.6) and 2.0 (95%CI 0.5-7.4) when compared to A1ATlow, REG4low, SPINK4low, respectively. The OR was increased to 24.0 (95%CI 1.1-505.1) when two proteins were combined (A1AThigh/REG4high). This nested case-control study shows that combined protein expression of A1AT and REG4 associate with CAT in patients with colorectal cancer. Therefore, REG4/A1AT are potential biomarkers to improve the identification of patients with CRC who may benefit from thromboprophylaxis.

MicroRNAs as prognostic biomarkers for (cancer-associated) venous thromboembolism.

MicroRNAs (miRNAs) are small noncoding RNAs with gene regulatory functions and are commonly dysregulated in disease states. As miRNAs are relatively stable, easily measured, and accessible from plasma or other body fluids, they are promising biomarkers for the diagnosis and prediction of cancer and cardiovascular diseases. Venous thromboembolism (VTE) is the third most common cardiovascular disease worldwide with high morbidity and mortality. The suggested roles of miRNAs in regulating the pathophysiology of VTE and as VTE biomarkers are nowadays more evidenced. Patients with cancer are at increased risk of developing VTE compared to the general population. However, current risk prediction models for cancer-associated thrombosis (CAT) perform suboptimally, and novel biomarkers are therefore urgently needed to identify which patients may benefit the most from thromboprophylaxis. This review will first discuss how miRNAs mechanistically contribute to the pathophysiology of VTE. Next, the potential use of miRNAs as predictive biomarkers for VTE in subjects without cancer is reviewed, followed by an in-depth focus on CAT. Several of the identified miRNAs in CAT were found to be differentially regulated in VTE as well, giving clues on the pathophysiology of CAT. We propose that subsequent studies should be adequately sized to determine which panel of miRNAs best predicts VTE and CAT. Thereafter, validation studies using comparable patient populations are required to ultimately unveil whether miRNAs-as standalone or incorporated into existing risk models-are promising valuable VTE and CAT biomarkers.

Survival after cancer-related venous thrombosis: the Scandinavian Thrombosis and Cancer Study.

Patients with cancer have an increased risk of developing venous thromboembolism (VTE), and this combination is reported to result in poorer survival compared with cancer alone. This study aimed to investigate the impact of VTE on the survival of patients with cancer in a general population. The Scandinavian Thrombosis and Cancer (STAC) cohort, a population-based cohort including 144 952 participants without previous VTE or cancer, was used. During follow-up, cancer and VTE incidences were registered. "Cancer-related VTE" was defined as VTE diagnosed in patients with overt or occult cancer. The survival of participants without cancer and/or VTE ("disease-free") was compared with the survival of participants with cancer and cancer-related VTE. Cox regression models with cancer and VTE as time-varying exposures were performed to calculate hazard ratios for death. Subanalyses were performed across cancer types and stages and VTE type (deep vein thrombosis or pulmonary embolism). During follow-up (mean, 11.7 years), 14 621 participants developed cancer, and 2444 developed VTE, of which 1241 were cancer-related. The mortality rates (per 100 person years) for disease-free participants, VTE only, cancer only, and cancer-related VTE were 0.63, 5.0, 9.2, and 45.3, respectively. Compared with patients with cancer only, the risk of death for patients with cancer-related VTE was increased 3.4-fold. Within all cancer types, the occurrence of VTE increased the mortality risk 2.8- to 14.7-fold. In a general population, patients with cancer with VTE had a 3.4-fold higher mortality risk than patients with cancer without VTE, independent of cancer type.

Tumor-expressed microRNAs associated with venous thromboembolism in colorectal cancer.

Background: Colorectal cancer patients have an increased risk of developing venous thromboembolism (VTE), resulting in increased morbidity and mortality. Because the exact mechanism is yet unknown, risk prediction is still challenging; therefore, new biomarkers are needed. MicroRNAs (miRNAs) are small, relatively stable RNAs, that regulate a variety of cellular processes, and are easily measured in body fluids. Objective: The aim of this study was to identify novel tumor-expressed miRNAs associated with VTE. Methods: In a cohort of 418 colorectal cancer patients diagnosed between 2001 and 2015 at the Leiden University Medical Center, 23 patients (5.5%) developed VTE 1 year before or after cancer diagnosis. Based on availability of frozen tumor material, tumor cells of 17 patients with VTE and 18 patients without VTE were isolated using laser capture microdissection and subsequently analyzed on the Illumina sequencing platform NovaSeq600 using 150-bp paired-end sequencing. Cases and controls were matched on age, sex, tumor stage, and grade. Differential miRNA expression was analyzed using edgeR. Results: A total of 547 miRNAs were detected. Applying a 1.5-fold difference and false discovery rate of <0.1, 19 tumor-miRNAs were differentially regulated in VTE cases versus controls, with hsa-miR-3652, hsa-miR-92b-5p, and hsa-miR-10,394-5p as most significantly downregulated. Seven of the 19 identified miRNAs were predicted to regulate the gonadotropin-releasing hormone receptor pathway. Conclusion: We identified 19 differentially regulated tumor-expressed miRNAs in colorectal cancer-associated VTE, which may provide insights into the biological mechanism and in the future might have potential to serve as novel, predictive biomarkers.