bluuebunny/crossref_metadata_2025_split huggingface dataset:
Relationship between circulating tumor cells and ZEB1 expression in tumor cells in colorectal cancer.
Authors: Novikova Inna A. , Kit Oleg I. , Zlatnik Elena Yu. , Ulianova Elena P. , Sagakyants Aleksandr B. , Sitkovskaya Anastasia O. , Shulgina Oksana G. , Gevorkyan Yuriy A. , Soldatkina Natalya V. , Kolesnikov Vladimir E. , Aleksandrovich Maksim K. , Dashkov Andrey V. , Poluektov Sergey I. , Kaymakchi Dmitry O. , Mirzoyan Ellada A. , Pavlov Vladislav K. , Dzhenkova Elena A. , Shaposhnikov Aleksandr V. , Vereshchak Maksim A. , Katelnitskaya Oksana V. 
Published: June 2021

e15509 Background: Intravasation and circulation of tumor cells involves active invasion of cells with an enhanced migration potential as a result of the epithelial-mesenchymal transition (EMT). The ZEB1 protein is one of the key regulators of this process. Our purpose was to evaluate the association between the amount of circulating tumor cells (CTCs) in the peripheral blood of patients with different stages of colorectal cancer and the expression of ZEB1 by tumor cells. Methods: The study included 299 patients (aged 42-86 years, mean age 64.2±1.7) with stage II-IV CRC T1-4N0-2M0-1; histologically verified G1-G3 adenocarcinoma in all patients. The numbers of CTCs were measured in the peripheral blood before surgery using the Veridex CellSearch system (Janssen). CTCs were registered taking into account morphological characteristics and expression of epithelial cell adhesion markers EpCAM, CD45, cytokeratins 8,18,19. The blood sample was evaluated according to the following criteria: 0 CTCs, 1-3 CTCs, and more than 3 CTCs. Tissues of surgically removed tumors were studied with IHC analysis using rabbit polyclonal anti-ZEB1 antibodies (Biorbyt Ltd.) diluted 1:200 and the Reveal Polyvalent HRP-DAB Detection System. The percentage and the intensity of staining were assessed: 0, 1+ weak, 2+ moderate, 3+ strong. ZEB1 expression was considered positive when staining was detected in more than 10% (cut-off) tumor cells with intensities of 2+ and 3+. Statistical analysis of results was performed in the Statistica 13.0 program (StatSoftInc., USA). Results: From 1 to 402 CTCs were determined in 62.9% cases (in 188 of 299 patients); CTCs were not registered in 37.1% cases (111 of 299). Positive ZEB1 expression was observed in 80.6% (241 of 299 patients), while the negative one was much more rare – 19.4% (58 of 299 patients). The rates of CTC detection significantly increased with the positive ZEB1+ expression, compared to the negative expression (75.1% vs. 12.1%). CTCs >3 were detected in the blood in 39.0% in ZEB1+ tumors, but not in ZEB1- tumors. 1-3 CTCs were observed 3 times more often in ZEB1+ tumors (36.1% vs. 12.1; p≤0.05). Conclusions: Statistically significant association was revealed between the epithelial-mesenchymal transition marker ZEB1 expression by tumor cells and the amount of CTCs in the peripheral blood (p < 0.001).
Methylated DNA markers for monitoring palliative chemotherapy response in advanced colorectal cancer.
Authors: Zhu Mojun , Mahoney Douglas W. , Burger Kelli , Foote Patrick H. , Doering Karen A. , Taylor William R. , Then Sara S. , Xie Hao , Allawi Hatim T. , Kaiser Michael W. , Lidgard Graham P. , Hubbard Joleen M. , Kisiel John B. 
Published: June 2021

e15511 Background: Aberrantly methylated DNA marker (MDM) candidates are strongly associated with primary colorectal cancer (CRC) before treatment and detect CRC recurrence with high sensitivity when assayed from plasma. The relationship of these MDMs in association to chemotherapy treatment response is unknown. Methods: In a prospective cohort of patients receiving systemic therapy for advanced CRC, peripheral blood was collected serially during restaging visits. 15 patients were retrospectively identified to have partial response (PR), stable disease (SD) and progressive disease (PD) to treatment (n=5 for each group) based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Using paired samples from each patient before and after response assessment, we analyzed 11 MDMs ( GRIN2D, ZNF671, ANKRD13B, QKI, VAV3, JAM3, SFMBT2, CHST2, ZNF568, FER1L4 and CNNM1) to assess correlation with treatment response. Cell-free DNA was extracted and bisulfite treated before MDMs were quantified by target enrichment long-probe quantitative-amplified signal assay and normalized to a methylated sequence of B3GALT6. Continuous variables are summarized as a median with corresponding interquartile ranges (IQR) and comparisons between subgroups were based on the Wilcox Rank Sums test. Results: The median interval between pre- and post-response assessment visits was 69 days (IQR: 63-83 days) and the level of tumor burden at pre-assessment was similar across all response types (Table 1). Patients with PD had higher levels of methylated GRIN2D, ZNF671 and ANKRD13B than those with PR or SD at baseline and may offer additional prognostic value over CEA which was similar in the PR and PD groups before treatment (Table 1). Elevation of pre-assessment MDMs preceded radiographic evidence of disease progression by 82 days (IQR 69-83 days). Conclusions: Three MDMs, GRIN2D, ZNF671 and ANKRD13B, were found to reflect treatment response (PD vs. PR + SD) as shown in the table. Although this pilot study was limited by a small sample size, it demonstrated the feasibility of using plasma-based MDMs in monitoring treatment response to systemic therapy for advanced CRC and should be compared to CEA in a larger study.[Table: see text]
MYC as a candidate upstream controller involved in TYMS gene expression and 5-FU/folate treatment efficacy in colorectal cancer.
Authors: Drubin David A. , Hess Anne-Katrin , Catlett Natalie L. , Di Cara Alessandro , Wettergren Yvonne , Tell Roger 
Published: June 2021

e15512 Background: One of the target enzymes of 5-fluorouracil (5-FU)-based therapies is thymidylate synthase (TS) encoded by the TYMS gene. To enhance the effect of 5-FU, a folate analogue is often provided as part of the treatment. In this context, it has previously been shown in the ISO-CC-005 clinical study that TYMS gene expression can be predictive of response to 5-FU + folate analogue Arfolitixorin. Methods: To better understand the role of TYMS expression as a predictor of response to 5-FU + folate-based therapies and identify potential mechanisms and biomarkers of sensitivity/resistance, we leveraged data from the publicly available cancer genome atlas database (TCGA). We combined this information with a knowledgebase of causal biological relationships extracted from peer reviewed publications, to identify other relevant genes and candidate upstream controllers directly or indirectly related to TYMS expression and 5-FU + folate efficacy. Results: In TCGA subjects suffering from colorectal cancer (CRC) (stage IV tumors, treated with FOLFOX/FOLFIRI (n = 38)), lower TYMS expression was associated with a better overall survival (OS). This is consistent with what has been observed in the ISO-CC-005 study. Applying our causal biology knowledgebase to both genes identified as correlated to TYMS expression in TCGA CRC tumors and other published sets of genes associated with FOLFOX or FOLFIRI efficacy, we identified overlap with a MYCN signature. Notably MYC has been shown to directly activate TYMS expression. Thus, the MYC family is a compelling candidate upstream controller of these genes. We scored TCGA CRC tumors for inferred MYC activity, using this MYCN gene signature, and evaluated the inferred activity with respect to OS. In stage IV tumors, higher inferred MYC activity appears to be associated with worse OS. To further characterize this inferred MYC activity, we employed a transcriptomics-based cell deconvolution estimation of immune cell population proportions in the TCGA CRC cohort. We found inferred MYC activity inversely correlated with immune cell proportions overall, specifically strongest with those of pDCs and classical monocytes. Conclusions: MYC activation, a known transcriptional regulator of TYMS, has been identified as a potentially relevant common upstream controller of a group of genes involved in 5-FU + folate analogue efficacy. Here we have also observed a similar relationship to OS between TYMS and inferred MYC activity in Stage IV CRC. MYC family activity (and activated protein forms), genes of the MYCN signature, or the identified immune cell proportions are all potential biomarker candidates to explore as factors in 5-FU + folate analogue efficacy.
Associations of mutation profiles with clinical outcomes among metastatic colorectal cancer patients at the United States-Mexico border.
Authors: Ghafouri Reshad , Philipovskiy Alexander , Corral Javier Chavez , Gaur Sumit , Hakim Nawar , McCallum Richard , Konstantinidis Ioannis , Maegava Felipe 
Published: June 2021

e15519 Background: The incidence of CRC among Hispanics living in the USA varies according to their country of origin, supports the idea that differences in ancestry may contribute to the differences in the incidence of CRC. Moreover, Hispanics-Latino(HL) patients usually present with a more advanced stage and have a higher mortality rate compared to other ethnic cohorts. Although it is unknown, the incidence of CRC has been substantially increasing among younger Hispanics. We sought to characterize the tumor mutation profile of mCRC patients and associate with clinical outcomes among Hispanic population. Methods: We retrospectively collected the data from next generation sequencing of 49 patients with metastatic CRC (treated at TTUHSC from 2012 to 2020. We identified the most frequent alterations in our study sample and associated with the clinical outcomes. Association analyses were performed using chi square test, unpaired t-test, log rank test and the Cox proportional hazards regressions. Results: Of 49 patients with mCRC, the average age of patients at the time of diagnosis was 57 years with 98% Hispanic, and 32(65%) male. Most of the patients had stage IV disease (98%) and left side CRC (31, 67%). In our study cohort, the most commonly mutated genes identified as APC (37/11, 77.08%), TP53 (29/19, 60.42%), KRAS (23/25, 47.92%), NOTCH 12/36 (25.00%), BRCA 1&2 11/37 (22.92%) and FLT1 11/37 (22.92%). None of the identified mutations were found to be associated with overall survival. However, the presence of the FLT1 mutation was associated with a reduced risk of progression to additional chemotherapy (P=0.031). Compared to the left side CRC, the BRCA mutation appeared slightly higher on the right side of the CRC (p=0.057). In compare to data from larger national and international colon cancer databases ( COSMIC and METABRICS); HL patients showed a significantly higher proportion of frequent mutations. Compared to other ethnic cohorts, HL patients were relatively younger (57 vs. 63 years) and the male to female ratio was observed to be remarkably higher as well (1.77:1 vs. 1.32:1). In our study, the combination of mutations (TP53, APC, and KRAS) was associated with worse clinical outcomes. Our study demonstrated that worse clinical outcomes were correlated with. Conclusions: Our study is the first to characterize the most common genetic alterations among HL patients with mCRC. The most frequent identified mutations including TP53, APC, KRAS, NOTCH, and BRCA were even higher in HL cohort than the national and international databases ( COSMIC and METABRICS). Our data support the motion that molecular drivers of colon cancer might be different in HL patients.
Somatic and germline mutation profiles of Chinese young colorectal cancer patients.
Authors: Li Hongxia , Duan Qianqian , Tan Yuan 
Published: June 2021

e15522 Background: In recently years, although CRC morbidity and mortality can be mitigated through appropriate screening and surveillance, the incidence rate of colorectal cancer (CRC) younger than 50 years old increased annually. Limited studies have investigated the underpinnings driving CRC development in Chinese younger population. In our study, we aim to explore the comprehensive mutational profile of Chinese CRC patients old (＞50) and young (≤50) diagnosed with CRC. Methods: Targeted sequencing with a 539 cancer-related genes panel was performed on 235 patients diagnosed with CRC. We investigate the landscape and difference of old and young CRC somatic and germline mutations in our Chinese cohort and compare with TCGA CRC cohort (N = 592). Results: Analysis revealed an overall 20.9% (49/235) mutation detection rate of young CRC in our Chinese cohort, which is higher than TCGA cohort (13.9%, 82/592). In our cohort, all Chinese young CRC patients can detect mutation and median mutation count is 10 mutations which is similar to old CRC patients (11 mutations). Comparing high frequency somatic mutations (young group with top 20), we found that BRCA2 mutation in young CRC group is significantly higher than old group (18.4% vs 7.0%, P = 0.025). In TCGA cohort, there is no difference between two groups with top 20 mutations and frequency of BRCA2 is 13.4% (11/82) in young CRC. For germline mutation, 12.29% (29/236) patients in our Chinese cohort harbored pathogenic and likely pathogenic (P/LP) germline mutations and 24.1% (7/29) CRC with P/LP germline mutations is young patients. In these seven P/LP mutation young patients, three patients have MMR gene mutation, two patients harbor ATM mutation, one patient has APC and another has SLX4 mutation. Moreover, young CRC have higher frequency MSI-H than old CRC patients (28.6% vs 18.2%). Conclusions: Our study has identified that young CRC patients account for a higher proportion in Chinese population and BRAC2 mutation may be an important factor in the early development of colorectal tumors in younger patients. In addition, our results also support the role of MSI statues in tumor oncogenesis in Chinese patients with early-onset CRC, indicating the need to include a more comprehensive germline mutation and genetic screening in our population.
TRIM29 expression and its survival predictor value in colorectal cancer with different primary tumor location.
Authors: Han Jing , Zhang Xue , Fan Zhisong , Wang Yudong , Feng Li , Zuo Jing , Wang Long , Li Dan , Liu Jiayin 
Published: June 2021

e15528 Background: It is clear that, in colorectal cancer (CRC), patients with different primary tumor location have variant prognosis and distinct clinicopathological features.So, it is very necessary to find specific tumor markers for different tumor sites.Our previous study have found TRIM29 is higher expressed in right colon cancer(RCC) than left colon cancer(LCC) patients in a small sample size reviewed study.So we speculated TRIM29 have different effect on the patients with different tumor side.But in our previous study, we didn’t investigate the TRIM29 expression in rectal cancer patients(RECC) and observed the effect of TRIM29 on the survival by different tumor side patients.So we decide to explore whether TRIM29 plays a different role in patients with three different tumor sites in a larger sample size study. Methods: 227 CRC cases were included in our retrospectively study,the patients were divided into LCC, RCC and RECC three groups. We first tested TRIM29 mRNA and protein expression level in LCC, RCC and RECC respectively to confirm whether TRIM29 expressed differently in patients with different tumor location. Then we explore the relationship between TRIM29 and clinicopathologic features in the patients with three tumor sites respectively.At last, we explore whether TRIM29 has different effect on the survival of the patients with three different tumor location. Results: TRIM29 mRNA and protein expression was significantly higher in RCC than in LCC and RECC ( P< 0.0001, P< 0.001).High TRIM29 expression was only associated with intestinal obstruction before surgery in LCC patients( P = 0.006) and it was associated with higher frequency of stage TNM IIĨIV and younger patients in RECC( P = 0.015 and 0.000), whereas it was associated with higher frequency of male, elder, stage IIĨIV patients, N+ and intestinal obstruction patients in RCC( P = 0.000,0.000,0.000,0.000 and 0.010).Only in the RCC group, patients with high TRIM29 expression both had a significant difference in the risk of recurrence/metastasis and death compared to patients with low TRIM29 expression( P = 0.020,0.000). Conclusions: TRIM29 plays different role in the patients with different tumor sites.TRIM29 has a greater correlation with clinicopathological features and greater effect on the prognosis in right colon cancer.TRIM29 may serve as a new biomarker and a novel therapeutic target in RCC patients.
The expression of THOX2 in colorectal mucinous adenocarcinoma and its relationship with prognosis.
Authors: Zhang Xue , Han Jing , Fan Zhisong , Feng Li , Wang Long , Zuo Jing , Wang Yudong , Li Dan , Liu Jiayin 
Published: June 2021

e15529 Background: The role of THOX2 in the occurrence and development of tumors has gradually attracted attention, but there is no study on the expression and function of THOX2 in colorectal mucinous adenocarcinoma (MC). The purpose of this study was to investigate the expression of thyroid oxidase 2 (THOX2) in colorectal MC and its relationship with prognosis. Methods: 30 patients with colorectal adenocarcinoma (AC) and 15 patients with MC were selected from The Fourth hospital of Hebei Medical University from October 1, 2018 to July 1, 2019. They were selected to detect the mRNA and protein levels of THOX2 in the colorectal cancer tissues of the two different pathological types using qRT-PCR and immunohistochemistry (IHC) methods. A total of 109 patients with MC who received surgical treatment between January 1, 2015 and January 1, 2015 were selected. The clinicopathological parameters of the patients were collected and survival follow-up was performed. The expression of THOX2 protein in MC tissues was detected by IHC test, and the differences in the expression of THOX2 protein in different tissues were analyzed by χ2 test. Cox univariate and multivariate analyses were used to investigate the relationship between clinicopathological characteristics, THOX2 protein expression level and DFS and OS in patients with MC. Results: The levels of THOX2 mRNA and protein in 15 cases of MC were significantly higher than those in 30 cases of AC. The high expression of THOX2 protein in MC tissues was closely correlated with tumor site, whether mixed with other pathological types, TNM stage, lymph node metastasis, M stage, and liver metastasis, peritoneal metastasis and other site metastasis occurred in patients after initial treatment. Cox regression analysis of 95 patients' survival data showed that high expression of THOX2, right colon and lymph node metastasis were influential factors for DFS in MC patients, and were independent prognostic factors for predicting DFS in MC patients. The expression of THOX2, lymph node metastasis, liver metastasis after adjuvant therapy and peritoneal metastasis are the influencing factors of OS in MC patients. Lymph node metastasis is an independent prognostic factor for OS in MC patients. Conclusions: The expression of THOX2 in MC was significantly higher than that of AC, and it was related to the malignant biological manifestations of tumor. At the same time, the high expression of THOX2 is associated with short DFS and OS in patients with MC, and may be used as a potential biomarker and efficacy predictor for MC patients.
Clinicopathological and genomic characteristics of POLE-mutated colorectal cancer in a Chinese population.
Authors: Zhang Xuhui , Wang Xicheng , Xin Ying , Bai Yuezong , Li Jian , Shen Lin 
Published: June 2021

e15531 Background: DNA polymerase ε (POLE) is essential for proofreading and fidelity in DNA replication and repair. Previous studies found that mutation in POLE associated with higher tumor mutational burden (TMB), which is an approved biomarker for immunotherpy in solid tumors. However, the clinicopathological and mutational analyses of POLE-mutated colorectal cancer in a large Chinese population have not yet been reported. Methods: Hybrid capture-based next-generation sequencing (NGS) were performed in 4628 samples of colorectal tumors and matched normal pairs in a CAP/CLIA-approved laboratory (3DMed). NGS testing for gene mutations, TMB and MSI was implemented. Results: Of 4628 colorectal cancer patients, POLE mutations were observed in 67 patients (1.45%). A total of 11 different POLE mutations were identified, mostly associated with exonucleas domain. P286R(32,0.69%), V411L(13,0.28%), A456P(7,0.15%), S459F(3,0.06%) and S297F(3,0.06%) were the most frequently mutated sites of POLE. We also detected 1 V758L and 1 W1130R mutation outside the exonuclease domain in separate cases. Among the 4628 patients, 2157 patients were detectable for TMB by NGS panel, including 2128 POLE wild type and 29 POLE mutation patients. The TMB of patients with POLE mutations was significantly higher than that in wide type POLE tumors (mean TMB 252.3 vs 13.4 muts/Mb, P ＜0.0001). All the 29 POLE-mutated patients were TMB-H (≥10 muts/Mb) and 28 of them were MSS. A MSS patient with metastatic colon cancer harboring A456P POLE mutation responsed well to the immunotherpy and achieved a partial response. Conclusions: Our results realved a remarkable positive correlation between POLE mutation and TMB level in a Chinese colorectal cancer population, which suggests POLE gene will be a promising biomarker of immunotherpy for MSS colorectal tumor.[Table: see text]
Antiangiogenic drug-induced proteinuria as a predictive factor in metastatic colorectal cancer.
Authors: Marinca Mihai Vasile , Moisuc Diana Cornelia , Gafton Bogdan , Stratulat Alexa Teodora , Cianga Petru 
Published: June 2021

e15538 Background: Treatment with bevacizumab, a humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) is known to cause adverse effects such as proteinuria, hypertension, fistulas, and thromboembolic events which, in addition to chemotherapy-induced toxicity, affect the quality of life. However, while bevacizumab-induced hypertension has been linked to increased overall survival, data on proteinuria are controversial. Methods: We performed a retrospective analysis to observe the influence of adverse effects (AEs) on the results of treatment with bevacizumab and chemotherapy in patients with metastatic colorectal cancer (mCRC). Results: Out of the 3497 mCRC patients admitted to our center between 2014 and 2019, 150 met the criteria for inclusion in our analysis. Of these, 50.7% experienced proteinuria and had reached a longer overall survival (OS, 40 versus 25 months, p = 0.015) and progression free survival (PFS, 15 versus 12 months, p = 0.039). Patients with anemia during treatment, regardless of grade, had a 20-month shorter survival. The following groups were identified as having a lower risk of death: patients with proteinuria (HR 0.630; 95% CI 0.424-0.935; p = 0.022), disease control (HR 0.436; 95% CI 0.291-0.653; p< 0.001) and non-metastatic stage at diagnosis (HR 0.477; 95% CI 0.300-0.757; p = 0.002). Anemia was a negative prognostic factor (HR 2.153; 95% CI 1.343-3.454; p = 0.001). Conclusions: Proteinuria seems to be a useful predictive factor in mCRC patients undergoing bevacizumab-based systemic therapy. Since it is already routinely assessed in this clinical setting, proteinuria could be easily integrated in the decision-making process and thus allow physicians to further individualize systemic treatments. Retrospective analyses, as our study, are setting the basis for prospective studies, required for the validation of these results.