Primary Colorectal Cancer Research Articles

The structure of synchronous multiple primary colorectal cancer

One of the problems of modern oncology is the lack of timely diagnosis of synchronous forms of colorectal cancer. Therefore, the aim of this study was to evaluate the structure of synchronous primary multiple forms of colorectal cancer. Methods: We analyzed the results of colorectal cancer diagnostics (n = 583) in the period 2010–2019. We did not include patients with metachronous colorectal cancer in the study. The average age of all patients was 71.6 ± 7.4 years. There were 1.5 times more men than women. Results: Synchronous colorectal cancer was detected in 171 (29.3%) patients. With synchronous primary multiple forms of colorectal cancer, 2 tumors were diagnosed in every second patient. In synchronous colorectal cancer, tumors were localized twice as often in the colon (n = 118) than in the rectum (n = 53). Conclusions: In patients with colorectal cancer, synchronous tumors occur in every third case. Synchronous colorectal cancer is more common in men. In the majority of patients (59.1%), synchronous colorectal cancer was detected within 6 months after imaging of the primary tumor.

Proof-of-Concept Pilot Study on Comprehensive Spatiotemporal Intra-Patient Heterogeneity for Colorectal Cancer With Liver Metastasis.

IntroductionThe mechanisms underlying high drug resistance and relapse rates after multi-modal treatment in patients with colorectal cancer (CRC) and liver metastasis (LM) remain poorly understood.ObjectiveWe evaluate the potential translational implications of intra-patient heterogeneity (IPH) comprising primary and matched metastatic intratumor heterogeneity (ITH) coupled with circulating tumor DNA (ctDNA) variability.MethodsA total of 122 multi-regional tumor and perioperative liquid biopsies from 18 patients were analyzed via targeted next-generation sequencing (NGS).ResultsThe proportion of patients with ITH were 53% and 56% in primary CRC and LM respectively, while 35% of patients harbored de novo mutations in LM indicating spatiotemporal tumor evolution and the necessity of multiregional analysis. Among the 56% of patients with alterations in liquid biopsies, de novo mutations in cfDNA were identified in 25% of patients, which were undetectable in both CRC and LM. All 17 patients with driver alterations harbored mutations targetable by molecularly targeted drugs, either approved or currently under evaluation.ConclusionOur proof-of-concept prospective study provides initial evidence on potential clinical superiority of IPH and warrants the conduction of precision oncology trials to evaluate the clinical utility of I PH-driven matched therapy.

Association of tumor size in pathological T4 colorectal cancer with desmoplastic reaction and prognosis.

BackgroundTumor size in pathological T4 (pT4) colorectal cancer (CRC) is associated with oncological prognosis; however, its relation to epithelial‐mesenchymal transition (EMT)‐associated histology is unclear. We aimed to investigate the association of tumor size with oncological prognosis and EMT.MethodsWe performed a retrospective analysis of 95 patients with primary CRC who underwent radical surgery and were consecutively diagnosed with pT4.ResultsBoth 3‐y disease‐free survival (DFS) and cancer‐specific survival (CSS) were significantly higher in patients with tumor size ≥50 mm than in those with tumor size <50 mm (P = .009 and P = .011, respectively). The independent factors identified in the multivariate analysis for DFS were pathological lymph node metastasis (hazard ratio [HR], 2.551; 95% confidence interval [CI], 1.031–6.315; P = .043), distant metastasis (HR, 2.511; 95% CI, 1.140–5.532; P = .022), tumor size (HR, 0.462; 95% CI, 0.234–0.913; P = .026), and adjuvant chemotherapy (HR, 0.357; 95% CI, 0.166–0.766; P = .008). The independent factors identified in multivariate analysis for CSS were tumor location (HR, 10.867; 95% CI, 2.539–45.518; P = .001) and tumor size (HR, 0.067; 95% CI, 0.014–0.321; P < .001). In pT4 CRC, smaller tumor size was associated with nonmature desmoplastic reaction and EMT‐related histology.ConclusionsTumor size ≥50 mm was associated with a better DFS and CSS than that of <50 mm, in patients with pT4 CRC. Smaller tumor size with advanced invasion likely reflects a more biologically aggressive phenotype in pT4 CRC.

Diagnostic and Prognostic Roles of CDX2 Immunohistochemical Expression in Colorectal Cancers.

The study is aimed to evaluate the diagnostic and prognostic role of the immunohistochemical expression of the Caudal-type homeobox transcription factor 2 (CDX2) in colorectal cancers (CRCs) through a meta-analysis. By searching relevant databases, 38 articles were eligible to be included in this study. We extracted the information for CDX2 expression rates and the correlation between CDX2 expression and clinicopathological characteristics. The estimated rates of CDX2 expression were 0.882 [95% confidence interval (CI) 0.774–0.861] and 0.893 (95% CI 0.820–0.938) in primary and metastatic CRCs, respectively. Furthermore, based on their histologic subtype, CDX2 expression rates of adenocarcinoma and medullary carcinoma were 0.886 (95% CI 0.837–0.923) and 0.436 (95% CI 0.269–0.618), respectively. There was a significant difference in CDX2 expression rates between adenocarcinoma and medullary carcinoma in the meta-regression test (p < 0.001). In addition, CDX2 expression was significantly lower in CRCs with the BRAFV600E mutation than in CRCs without mutation. Patients with CDX2 expression had better overall and cancer-specific survival rates than those without CDX2 expression. Thus, CDX2 is a useful diagnostic and prognostic marker CRCs.

Tumour grade and stage are associated with specific body composition phenotypes with visceral obesity predisposing the host to a less aggressive tumour in colorectal cancer

BackgroundSarcopenia, myosteatosis and visceral obesity (VO) are known to negatively impact on outcomes from colorectal cancer (CRC). Little is known about tumour factors associated with these body composition (BC) phenotypes. We aimed to identify whether histopathological tumour characteristics were associated with various BC phenotypes. MethodsA prospectively collected database of patients undergoing surgery for primary CRC at a tertiary referral unit in the United Kingdom was analysed. Sarcopenia, myosteatosis and VO were identified on preoperative CT. Binary logistic regression modelling was performed to determine significant associations between tumour stage, grade and BC phenotype. ResultsFinal analysis included 795 patients; median age 69, 56% male, 65% were sarcopenic, 72% myosteatotic, 52% VO and 20% had sarcopenic obesity (SO). VO patients were significantly less likely to have advanced T Stage (T3-4) OR0.62(95%CI 0.44–0.86, p = 0.005); nodal metastases OR0.60(95%CI 0.44–0.82, p = 0.001); vascular invasion OR0.63(95%CI 0.46–0.88, p = 0.006) and poor tumour differentiation OR0.49(95%CI 0.28–0.86, p = 0.012). Myosteatotic patients were more likely to have metastatic disease OR2.31(95%CI 1.15–4.63, p = 0.018) but less likely to have poorly differentiated tumours OR0.48(95%CI 0.27–0.86, p = 0.013). SO patients were significantly more likely to have poorly differentiated tumours OR2.01(95%CI 1.04–3.87, p = 0.037). ConclusionVO predisposes to earlier stage tumours with a less aggressive tumour phenotype. The SO group have adverse tumour characteristics which may be explained by differences in fat distribution. Myosteatosis relates to increased likelihood of distant metastasis that may be related to a systemic inflammatory response, despite the association with better differentiated tumours.

The Complete Loss of p53 Expression Uniquely Predicts Worse Prognosis in Colorectal Cancer.

p53 immunohistochemistry is considered an accurate surrogate marker reflecting the underlying TP53 mutation status and has utility in tumor diagnostics. In the present study, 269 primary CRCs were immunohistochemically evaluated for p53 expression to assess its utility in diagnostic pathology and prognostication. p53 expression was wild-type in 59 cases (23%), overexpressed in 143 cases (55%), completely lost in 50 cases (19%), and cytoplasmic in 10 cases (4%). p53 immunoreactivity was associated with tumor size (p = 0.0056), mucus production (p = 0.0015), and mismatch repair (MMR) system status (p < 0.0001). Furthermore, among CRCs with wild-type p53 expression, a significantly higher number of cases had decreased CDX2 than those with p53 overexpression (p = 0.012) or complete p53 loss (p = 0.043). In contrast, among CRCs with p53 overexpression, there were significantly fewer ALCAM-positive cases than p53 wild-type cases (p = 0.0045). However, no significant association was detected between p53 immunoreactivity and the “stem-like” immunophenotype defined by CDX2 downregulation and ALCAM-positivity. Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.17, p < 0.0001), younger age (HR = 0.52, p = 0.021), and female sex (HR = 0.55, p = 0.046) as potential favorable factors. The analysis also revealed complete p53 loss (HR = 2.16, p = 0.0087), incomplete resection (HR = 2.65, p = 0.0068), and peritoneal metastasis (HR = 5.32, p < 0.0001) as potential independent risk factors for patients with CRC. The sub-cohort survival analyses classified according to chemotherapy after surgery revealed that CRC patients with wild-type p53 expression tended to have better survival than those with overexpression or complete loss after chemotherapy. Thus, immunohistochemistry for p53 could be used for the prognostication and chemotherapy target selection of patients with CRC.

Fibroblast activation protein identifies Consensus Molecular Subtype 4 in colorectal cancer and allows its detection by 68Ga-FAPI-PET imaging

BackgroundIn colorectal cancer (CRC), the consensus molecular subtype 4 (CMS4) is associated with therapy resistance and poor prognosis. Clinical diagnosis of CMS4 is hampered by locoregional and temporal variables influencing CMS classification. Diagnostic tools that comprehensively detect CMS4 are therefore urgently needed.MethodsTo identify targets for molecular CMS4 imaging, RNA sequencing data of 3232 primary CRC patients were explored. Heterogeneity of marker expression in relation to CMS4 status was assessed by analysing 3–5 tumour regions and 91.103 single-tumour cells (7 and 29 tumours, respectively). Candidate marker expression was validated in CMS4 peritoneal metastases (PM; n = 59). Molecular imaging was performed using the 68Ga-DOTA-FAPI-46 PET tracer.ResultsFibroblast activation protein (FAP) mRNA identified CMS4 with very high sensitivity and specificity (AUROC > 0.91), and was associated with significantly shorter relapse-free survival (P = 0.0038). Heterogeneous expression of FAP among and within tumour lesions correlated with CMS4 heterogeneity (AUROC = 1.00). FAP expression was homogeneously high in PM, a near-homogeneous CMS4 entity. FAPI-PET identified focal and diffuse PM that were missed using conventional imaging. Extra-peritoneal metastases displayed extensive heterogeneity of tracer uptake.ConclusionFAP expression identifies CMS4 CRC. FAPI-PET may have value in the comprehensive detection of CMS4 tumours in CRC. This is especially relevant in patients with PM, for whom effective imaging tools are currently lacking.

Combined Estrogen Alpha and Beta Receptor Expression Has a Prognostic Significance for Colorectal Cancer Patients.

We reported that high estrogen receptor beta (ERβ) expression is independently associated with better prognosis in female colorectal cancer (CRC) patients. However, estrogen receptor alpha (ERα) is expressed at very low levels in normal colon mucosa, and its prognostic role in CRC has not been explored. Herein, we investigated the combined role of ERα and ERβ expression in the prognosis of female patients with CRC, which, to the best of our knowledge, is the first study to investigate this topic. A total number of 306 primary CRCs were immunostained for ERα and ERβ expression. A Cox regression model was used to evaluate overall survival (OS) and disease-free survival (DFS). The combined expression of high ERβ + negative ERα correlates with longer OS (HR = 0.23; 95% CI: 0.11–0.45, P <0.0001) and DFS (HR = 0.10; 95% CI: 0.03–0.26, P < 0.0001) and a more favorable tumor outcome, as well as significantly higher expression of antitumorigenic proteins than combined expression of low ERβ + positive ERα. Importantly, we found that low ERβ expression was associated with local recurrence of CRC, whereas ERα expression was correlated with liver metastasis. Overall, our results show that the combined high ERβ + negative ERα expression correlated with a better prognosis for CRC patients. Our results suggest that the combined expression of ERα and ERβ could be used as a predictive combination marker for CRC patients, especially for predicting DFS.

Clinicopathologic characteristics and prognosis of synchronous colorectal cancer: a retrospective study

BackgroundThe clinical characteristics of synchronous colorectal cancer (SCRC) reported in previous studies differ significantly. Furthermore, little is known about the characteristics of early-onset synchronous colorectal cancer (EO-SCRC). The aim of this retrospective study was to identify the clinicopathological characteristics of SCRC and EO-SCRC and define their relevant prognostic factors.MethodsPatients who underwent surgery for SCRC and primary unifocal colorectal cancer (PCRC) between January 2007 and December 2020 were included in this study. The clinical, histological, and molecular characteristics of the patient’s tumours were analysed. The primary endpoint was overall survival (OS). Univariate and multivariate Cox regression analyses were used to assess the association between clinicopathological factors and patient survival.ResultsA total of 1554 patients were included in the analysis. Of these, 1132 (72.84%) had PCRC and 422 (27.16%) had SCRC. SCRC occurred more frequently in the elderly (P < 0.001) and in male patients (P = 0.002). The 5-year OS rate was 73.7% ± 2.0% for PCRC and 61.9% ± 3.9% for SCRC (P < 0.05). However, the Cox regression analysis showed that SCRC was not an independent prognostic factor for the prediction of OS. A total of 64 patients (15.17%) in the SCRC group had early-onset colorectal cancer (EOCRC), whereas 257 (22.70%) in the PCRC group had EOCRC (P = 0.001). The proportion of patients with deficient mismatch repair proteins (dMMR) in EO-SCRC subgroup was significantly higher than that in late-onset synchronous colorectal cancer (LO-SCRC) subgroup (23.44% vs. 10.34%, P = 0.006). Patients with EO-SCRC had more TNM stage IV (P < 0.001) and fewer opportunities for radical surgery (79.69% vs. 92.22%, P = 0.007) than those with early-onset primary unifocal colorectal cancer (EO-PCRC). There was no significant difference in 5-year OS between the EO-SCRC and LO-SCRC subgroups (P = 0.091) and between the EO-SCRC and EO-PCRC subgroups (P = 0.094). Multivariate analysis revealed that EOCRC was an independent good prognostic parameter for colorectal cancer (CRC) and SCRC.ConclusionFor patients with operative treatment, EO-SCRC is different from LO-SCRC and EO-PCRC. Patients with SCRC show a poorer survival rate than those with PCRC. However, SCRC is not an independent prognostic factor for CRC, whereas EOCRC is a good prognostic factor for CRC and SCRC.

Clinicopathologic characteristics of early-onset colorectal cancer

The aim of this study was to analysis of the clinicopathological characteristics and prognosis of colorectal cancer (CRC) under the age of 50 years. Between January 2009 and December 2018, 1,126 primary CRC patients were included from National Health Insurance Service Ilsan Hospital. The patients were divided into group 1 (n=111, ≤50 years) and group 2 (n=1,015, >50 years). The clinicopathologic features and prognostic outcomes were compared. In addition, to analyze whether there were any differences of those characteristics in 3 groups, patients aged under 50 years were divided into their 20s, 30s, and 40s. Group 1 had a slightly higher distribution in the left colon and rectum, lower T stage I and higher T stage IV rate, and a significantly higher distribution in stage N2 than group 2 (30.6%:16.3%, P<0.001). Poor histological differentiation of tumors was significantly high in group 1 (P=0.003). The 5-year survival rate for those in their 30s (69.2%) and 40s (91.6%) was higher than those in their 20s who died immediately after surgery (P<0.001). The 5-year disease-free survival rate was also confirmed to be meaningful for each age group, with 0% in their 20s, 53.8% in their 30s, 79.2% in their 40s (P<0.001). Although the age was not an independent prognostic factor for overall survival in this study, the early onset group of CRCs is more advanced at the time of diagnosis and has a more aggressive histologic type.

Modeling colorectal cancer: A bio-resource of 50 patient-derived organoid lines.

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. To improve outcomes for these patients, we need to develop new treatment strategies. Personalized cancer medicine, where patients are treated based on the characteristics of their own tumor, has gained significant interest for its promise to improve outcomes and reduce unnecessary side effects. The purpose of this study was to examine the potential utility of patient-derived colorectal cancer organoids (PDCOs) in a personalized cancer medicine setting. Patient-derived colorectal cancer organoids were derived from tissue obtained from treatment-naïve patients undergoing surgical resection for the treatment of CRC. We examined the recapitulation of key histopathological, molecular, and phenotypic characteristics of the primary tumor. We created a bio-resource of PDCOs from primary and metastatic CRCs. Key histopathological features were retained in PDCOs when compared with the primary tumor. Additionally, a cohort of 12 PDCOs, and their corresponding primary tumors and normal sample, were characterized through whole exome sequencing and somatic variant calling. These PDCOs exhibited a high level of concordance in key driver mutations when compared with the primary tumor. Patient-derived colorectal cancer organoids recapitulate characteristics of the tissue from which they are derived and are a powerful tool for cancer research. Further research will determine their utility for predicting patient outcomes in a personalized cancer medicine setting.

An integrative gene expression signature analysis identifies CMS4 KRAS-mutated colorectal cancers sensitive to combined MEK and SRC targeted therapy

BackgroundOver half of colorectal cancers (CRCs) are hard-wired to RAS/RAF/MEK/ERK pathway oncogenic signaling. However, the promise of targeted therapeutic inhibitors, has been tempered by disappointing clinical activity, likely due to complex resistance mechanisms that are not well understood. This study aims to investigate MEK inhibitor-associated resistance signaling and identify subpopulation(s) of CRC patients who may be sensitive to biomarker-driven drug combination(s).MethodsWe classified 2250 primary and metastatic human CRC tumors by consensus molecular subtypes (CMS). For each tumor, we generated multiple gene expression signature scores measuring MEK pathway activation, MEKi “bypass” resistance, SRC activation, dasatinib sensitivity, EMT, PC1, Hu-Lgr5-ISC, Hu-EphB2-ISC, Hu-Late TA, Hu-Proliferation, and WNT activity. We carried out correlation, survival and other bioinformatic analyses. Validation analyses were performed in two independent publicly available CRC tumor datasets (n = 585 and n = 677) and a CRC cell line dataset (n = 154).ResultsHere we report a central role of SRC in mediating “bypass”-resistance to MEK inhibition (MEKi), primarily in cancer stem cells (CSCs). Our integrated and comprehensive gene expression signature analyses in 2250 CRC tumors reveal that MEKi-resistance is strikingly-correlated with SRC activation (Spearman P < 10–320), which is similarly associated with EMT (epithelial to mesenchymal transition), regional metastasis and disease recurrence with poor prognosis. Deeper analysis shows that both MEKi-resistance and SRC activation are preferentially associated with a mesenchymal CSC phenotype. This association is validated in additional independent CRC tumor and cell lines datasets. The CMS classification analysis demonstrates the strikingly-distinct associations of CMS1-4 subtypes with the MEKi-resistance and SRC activation. Importantly, MEKi + SRCi sensitivities are predicted to occur predominantly in the KRAS mutant, mesenchymal CSC-like CMS4 CRCs.ConclusionsLarge human tumor gene expression datasets representing CRC heterogeneity can provide deep biological insights heretofore not possible with cell line models, suggesting novel repurposed drug combinations. We identified SRC as a common targetable node–-an Achilles’ heel–-in MEKi-targeted therapy-associated resistance in mesenchymal stem-like CRCs, which may help development of a biomarker-driven drug combination (MEKi + SRCi) to treat problematic subpopulations of CRC.

Yin Yang 1 regulates ITGAV and ITGB1, contributing to improved prognosis of colorectal cancer.

Yin Yang 1 (YY1) is a multifunctional transcription factor with critical roles in carcinogenesis and metastasis. However, its biological role and clinical impact in colorectal cancer (CRC) remain unclear. In the present study, the function and underlying molecular mechanisms of YY1 in CRC progression were investigated. The immunohistochemistry (IHC) of 143 CRC tissues revealed a significant correlation of low YY1 expression with aggressive clinicopathological features, increased metastasis and recurrence and poor patient survival. Multivariate analysis identified low YY1 expression as an independent poor prognostic factor. Subsequently, the IHC of 66 paired CRC primary tumor and liver metastasis tissues revealed that low YY1 expression in the primary CRC was significantly associated with multiple liver metastases, major hepatectomy, extrahepatic metastasis and poor prognosis. In vitro experiments revealed that YY1 knockdown promoted the migration and invasion of CRC cells. To examine the downstream genes of YY1, a cDNA microarray assay was conducted and the differentially expressed genes between the YY1-knockdown and control cells were compared. Integrin alpha V (ITGAV) and integrin beta 1 (ITGB1) were identified as upregulated hub genes using gene enrichment analysis and protein-protein interaction analyses. Western blotting and IHC confirmed YY1 expression to be negatively correlated with ITGAV and ITGB1 expression. In summary, it was revealed that YY1, as a tumor-suppressor in CRC, contributes to the survival of patients with CRC. Low YY1 expression was associated with the poor prognosis of the patients with primary CRC and liver metastases. YY1 suppressed the expression of ITGAV and ITGB1, and this transcriptional regulation may lead to the suppression of CRC cell migration and invasion.

Histological growth patterns of colorectal cancer liver metastases: a strong prognostic marker associated with invasive patterns of the primary tumor and p53 alteration

The histological growth pattern of liver metastases (desmoplastic, pushing, and replacement patterns) at the tumor-liver parenchymal interface is a prognostic factor in patients with colorectal cancer. However, data regarding its association with the primary tumor characteristics and molecular alterations are limited. This study evaluated the histological growth pattern in 136 cases of colorectal cancer liver metastases without preoperative treatment, comparing it with the clinicopathological features of the primary tumor. Liver metastasis exhibiting predominantly non-desmoplastic pattern (<50%), observed in 74 cases (54%), was associated with hepatic vein invasion (P=0.025), worse recurrence-free survival (P<0.001) and overall survival (P=0.008). In multivariate analyses, multiple tumors (P<0.001) and non-desmoplastic patterns (P=0.009) were associated with worse recurrence-free survival, and tumor size (P=0.025) and non-desmoplastic pattern (P=0.025) were associated with worse overall survival. In 88 patients with available primary tumor tissue slides, non-desmoplastic pattern in the liver metastasis was associated with high-grade tumor budding (P=0.002), high-grade poorly differentiated cluster (P=0.021), absence of mucinous histology (P=0.016), and aberrant p53 expression (complete loss or overexpression; P0.001) of the primary colorectal cancer. In conclusion, the histological growth pattern in liver metastasis was a strong and independent prognostic factor for colorectal cancer. Our observations highlight the significant associations between histological growth patterns in liver metastases and histopathological features of the primary tumor, especially invasive front morphology and p53 aberration.

Pairwise association of key lifestyle factors and risk of colorectal cancer: a prospective pooled multicohort study.

Several lifestyle factors are associated with an increased risk of colorectal cancer (CRC). Although lifestyle factors co-occur, in most previous studies these factors have been studied focusing upon a single risk factor or assuming independent effects between risk factors. To examine the pairwise effects and interactions of smoking, alcohol consumption, physical inactivity, and body mass index (BMI) with risk of subsequent colorectal cancer (CRC). We used METCA cohort data (pooled data from seven population-based Finnish health behavior survey studies during years 1972-2015) consisting of 171 063 women and men. Participants' smoking, alcohol consumption, physical inactivity and BMI measures were gathered, and participants were categorized into those exposed and those not exposed. The incidence of CRC was modeled by Poisson regression with main and interaction effects of key lifestyle factors. The cohort members were followed-up through register linkage to the Finnish Cancer Registry for first primary CRC case until the end of 2015. Follow-up time was 1715, 690 person years. The highest pairwise CRC risk was among male smokers who had overweight (BMI ≥ 25 kg/m2 ) (HR 1.75, 95% CI 1.36-2.26) and women who had overweight and consumed alcohol (HR 1.45, 95% CI 1.14-1.85). Overall, among men the association of lifestyle factors and CRC risk was stronger than among women. In men, both having overweight and being a smoker combined with any other adverse lifestyle factor increased CRC risk. Among women, elevated CRC risks were observed for those who were physically inactive and who consumed alcohol or had overweight. No statistically significant interactions were detected between pairs of lifestyle factors. This study strengthens the evidence of overweight, smoking, and alcohol consumption as CRC risk factors. Substantial protective benefits in CRC risk can be achieved by preventing smoking, maintaining BMI to <25 kg/m2 and not consuming alcohol.

SPATA18 Expression Predicts Favorable Clinical Outcome in Colorectal Cancer.

Dysregulation of mitochondrial quality control has been reported to be associated with cancer and degenerative diseases. SPATA18 (spermatogenesis-associated 18, also known as Mieap) encodes a p53-inducible protein that can induce lysosome-like organelles within mitochondria that eliminate oxidized mitochondrial proteins and has tumor suppressor functions in mitochondrial quality control. In the present study, 268 primary colorectal cancers (CRCs) were evaluated immunohistochemically for SPATA18 expression to assess its predictive utility and its association with cellular proliferation activity. Furthermore, the association with p53 immunoreactivity, a surrogate marker for TP53 mutation, was analyzed. Non-neoplastic colonic mucosa showed cytoplasmic SPATA18 expression. Seventy-two percent of the lesions (193/268) displayed high SPATA18 expression in the cytoplasm of CRC cells. Univariate analyses revealed significant associations between SPATA18 expression and tumor size (p < 0.0001), histological differentiation (p = 0.0017), and lymph node metastasis (p = 0.00039). The log-rank test revealed that patients with SPATA18-high CRCs had significantly better survival than SPATA18-low patients (p < 0.0001). Multivariate Cox hazards regression analysis identified tubular-forming histology (hazard ratio [HR] = 0.25), age < 70 years (HR = 0.50), and SPATA18-high (HR = 0.55) as potential favorable factors. Lymph node metastasis (HR = 1.98) and peritoneal metastasis (HR = 5.45) were cited as potential independent risk factors. Cellular proliferation activity was significantly higher in SPATA18-high tumors. However, no significant correlation was detected between SPATA18 expression and p53 immunoreactivity or KRAS/BRAF mutation status. On the basis of our observations, SPATA18 immunohistochemistry can be used in the prognostication of CRC patients.

Assessment of Primary Colorectal Cancer CT Radiomics to Predict Metachronous Liver Metastasis.

ObjectivesTo establish and validate a machine learning-based CT radiomics model to predict metachronous liver metastasis (MLM) in patients with colorectal cancer.MethodsIn total, 323 patients were retrospectively recruited from two independent institutions to develop and evaluate the CT radiomics model. Then, 1288 radiomics features were extracted to decode the imaging phenotypes of colorectal cancer on CT images. The optimal radiomics features were selected using a recursive feature elimination selector configured by a support vector machine. To reduce the bias caused by an unbalanced dataset, the synthetic minority oversampling technique was applied to resample the minority samples in the datasets. Then, both radiomics and clinical features were used to train the multilayer perceptron classifier to develop two classification models. Finally, a score-level fusion model was developed to further improve the model performance.ResultsThe area under the curve (AUC) was 0.78 ± 0.07 for the tumour feature model and 0.79 ± 0.08 for the clinical feature model. The fusion model achieved the best performance, with AUCs of 0.79 ± 0.08 and 0.72 ± 0.07 in the internal and external validation cohorts.ConclusionsRadiomics models based on baseline colorectal contrast-enhanced CT have high potential for MLM prediction. The fusion model combining radiomics and clinical features can provide valuable biomarkers to identify patients with a high risk of colorectal liver metastases.

Spatial expression of IKK-alpha is associated with a differential mutational landscape and survival in primary colorectal cancer

BackgroundTo understand the relationship between key non-canonical NF-κB kinase IKK-alpha(α), tumour mutational profile and survival in primary colorectal cancer.MethodsImmunohistochemical expression of IKKα was assessed in a cohort of 1030 patients who had undergone surgery for colorectal cancer using immunohistochemistry. Mutational tumour profile was examined using a customised gene panel. Immunofluorescence was used to identify the cellular location of punctate IKKα expression.ResultsTwo patterns of IKKα expression were observed; firstly, in the tumour cell cytoplasm and secondly as discrete ‘punctate’ areas in a juxtanuclear position. Although cytoplasmic expression of IKKα was not associated with survival, high ‘punctate’ IKKα expression was associated with significantly reduced cancer-specific survival on multivariate analysis. High punctate expression of IKKα was associated with mutations in KRAS and PDGFRA. Dual immunofluorescence suggested punctate IKKα expression was co-located with the Golgi apparatus.ConclusionsThese results suggest the spatial expression of IKKα is a potential biomarker in colorectal cancer. This is associated with a differential mutational profile highlighting possible distinct signalling roles for IKKα in the context of colorectal cancer as well as potential implications for future treatment strategies using IKKα inhibitors.

Expression of TMED3 is independently associated with colorectal cancer prognosis.

Colorectal cancer (CRC) is the third most common cancer type and one of the deadliest cancers worldwide. Transmembrane p24 trafficking protein 3 (TMED3) has previously been indicated to suppress CRC metastasis, but its clinical significance has remained undetermined. In the present study, the expression of TMED3 was indicated to be elevated at the mRNA and protein levels in CRC tumor samples relative to that in para-cancerous healthy tissue samples (P<0.05). Furthermore, Kaplan-Meier survival analysis revealed a significant negative association between elevated TMED3 protein levels and overall survival of patients with CRC (P<0.001, log-rank test). Multivariate Cox regression analysis additionally determined that elevated TMED3 expression in primary CRC tumors was an independent predictor of poor prognosis (P<0.05). These results revealed that elevated TMED3 expression in CRC was associated with patient survival outcomes, suggesting that TMED3 may be a potential prognostic biomarker for this cancer type.

Colorectal cancer on a dish: exploring the 3D-sphere culture of primary colorectal cancer cells from an Indonesian perspective

Background : Colorectal Cancer (CRC) is one of the deadliest types of cancer and has emerged as one of Indonesia's most devastating diseases. The growing number of colorectal cancer cases is frequently undiagnosed until the disease has progressed to a metastatic stage. This issue has lasted for years, limiting therapy options and resulting in a bad prognosis for the majority of patients. Thus, the purpose of this work is to develop a CRC detection method for Indonesia and other low-middle income nations that integrates in vitro 3D culture, molecular analysis, and in silico analysis. Methods : Colorectal cancer biopsies were transported to the lab and underwent mechanical disaggregation and centrifuged at 300 x g for five minutes. Approximately 10,000 cells were seeded in each Nunc-Sphera 96-well plate (u-bottom) for the following 7 days in standard culture medium. The 3D-sphere was harvested and RNA was extracted afterwards. Molecular analysis was performed using qPCR and the Human Cancer Pathway Profiler. Protein interaction and pathway analysis were conducted using STRING and Reactome online tools. Results : Following initial seeding, primary CRC 3D-spheres were grown for 14–16 days. Gene profiling and in silico analyses suggest that CDC20, AURKA, and ACLY are expressed at lower levels than the positive control in the 3D-sphere. These markers have been implicated in metastasis, CRC proliferation, and as a drug target ligand. Conclusion : A combination of 3D culture, gene profiling, and in silico analysis is feasible to detect CRC for Indonesia and other low- and middle-income countries. A future possibility is to use minicolorectal cancer in a dish for ex vivo cancer modeling and pharmacological testing.