Browsing by Author "Despotovic, Jovana (57189992944)"

Purpose: There are limited data on expression of epithelial–mesenchymal transition (EMT) markers in patients with colorectal liver metastases (CRLM). The study aim was to evaluate the expression and prognostic significance of E-cadherin (CDH1), fibronectin (FN1) and vimentin (VIM) in patients with CRLM after curative-intent liver resection. Patients and Methods: Thirty patients with CRLM managed by curative-intent liver resection were included in this prospective pilot study. Blood samples, colorectal liver metastases and surrounding non-tumor liver tissue were collected. Expression of CDH1, FN1 and VIM was analyzed by quantitative real-time polymerase chain reaction. Expression in CRLM and non-tumor liver tissue was compared, while expression in serum was correlated with CRLM expression. One-year recurrence-free survival was compared between patients with low and high CDH1, FN1 and VIM expression. Results: The expression of CDH1 was similar in CRLM and non-tumor liver tissues, while FN1 and VIM expression was significantly lower in metastatic tissue (P=0.003 and pP<0.001, respectively). Serum expression of CDH1 and VIM was detected in 66.7% and 93.3% of patients, respectively, while FN1 was not detected in any of the patients. The correlation of CDH1 and VIM expression between CRLM and serum was not statistically significant. Decreased CDH1 expression in CRLM and decreased VIM expression in serum were associated with early recurrence after surgical treatment of CRLM. Conclusion: Lower expression of CDH1 in CRLM and lower serum expression of VIM were found to be associated with early recurrence after liver resection for CRLM. © 2021 Bogdanovic et al.

Abstract: In colorectal cancer (CRC), inactivation of SMAD4 occurs early in the disease development and SMAD4 represents one of key driver genes in progression and metastasis. Loss of SMAD4 protein expression is a relatively common feature of sporadic colorectal cancers, and it was observed to be even more frequent in tumors of patients with early onset disease and also more frequent in microsatellite stable tumors. Pathogenic variants in the SMAD4 gene are usually missense or nonsense mutations, and they are more frequent in the C-terminal domain. The aim of this study was to perform genetic analysis of SMAD4 C-terminal domain in colorectal cancer patients with early onset disease and microsatellite stable tumors. This pilot study was conducted with a purpose of investigating if such genetic screening strategy would be useful for diagnostic purposes in this specific subgroup of CRC patients. The study was conducted in a selected set of DNA samples extracted from the tumors of CRC patients who had less than 50 years at the time of diagnosis. Genetic analysis of C-terminal domain has encompassed analysis of exons 9, 10, 11 and 12 of the SMAD4 gene by PCR and direct DNA sequencing. Among the twenty analyzed tumor DNAs, one sample was found to harbor a SMAD4 variant: NC_000018.9:g.48591918C > T; (NM005359.5: c.1081C > T; Arg361Cys). The variant was discovered in exon 9, affecting the codon 361, which represents a mutational hot spot within the SMAD4 gene. This variant was discovered in homozygous state in the tumor of a 47 yr old female with T3 stage carcinoma of the right colon. Considering the incidence and functional consequences of SMAD4 exon 9 variants, the screening of this region could be a useful low cost strategy for the genetic analysis of colorectal tumors from patients with early onset disease, as well as for susceptibility testing. © 2022, Allerton Press, Inc.

Abstract: In colorectal cancer (CRC), inactivation of SMAD4 occurs early in the disease development and SMAD4 represents one of key driver genes in progression and metastasis. Loss of SMAD4 protein expression is a relatively common feature of sporadic colorectal cancers, and it was observed to be even more frequent in tumors of patients with early onset disease and also more frequent in microsatellite stable tumors. Pathogenic variants in the SMAD4 gene are usually missense or nonsense mutations, and they are more frequent in the C-terminal domain. The aim of this study was to perform genetic analysis of SMAD4 C-terminal domain in colorectal cancer patients with early onset disease and microsatellite stable tumors. This pilot study was conducted with a purpose of investigating if such genetic screening strategy would be useful for diagnostic purposes in this specific subgroup of CRC patients. The study was conducted in a selected set of DNA samples extracted from the tumors of CRC patients who had less than 50 years at the time of diagnosis. Genetic analysis of C-terminal domain has encompassed analysis of exons 9, 10, 11 and 12 of the SMAD4 gene by PCR and direct DNA sequencing. Among the twenty analyzed tumor DNAs, one sample was found to harbor a SMAD4 variant: NC_000018.9:g.48591918C > T; (NM005359.5: c.1081C > T; Arg361Cys). The variant was discovered in exon 9, affecting the codon 361, which represents a mutational hot spot within the SMAD4 gene. This variant was discovered in homozygous state in the tumor of a 47 yr old female with T3 stage carcinoma of the right colon. Considering the incidence and functional consequences of SMAD4 exon 9 variants, the screening of this region could be a useful low cost strategy for the genetic analysis of colorectal tumors from patients with early onset disease, as well as for susceptibility testing. © 2022, Allerton Press, Inc.

Inhibitory SMAD7 and common mediator SMAD4 play crucial roles in SMAD-dependent TGF-β signaling that is often disrupted in colorectal cancer (CRC). This study aimed to profile the expression of SMAD7 and SMAD4 in primary and metastatic CRC and to evaluate their significance in disease progression and therapy response. The expression of SMAD7 and SMAD4 genes was analyzed by quantitative real-time PCR in tissues from 35 primary and metastatic CRC patients and in vitro in 7 human cell lines originating from colon tissue. Expression levels of SMAD7 and SMAD4, as well as their ratio, were determined and their association with tumor characteristics and response to therapy were evaluated. SMAD4 level was significantly lower in tumors compared to non-tumor tissues in both primary (p = 0.001) and metastatic (p = 0.001) CRC patients, while tumor expression of SMAD7 was significantly lower from non-tumor tissue only in metastatic patients (p = 0.017). SMAD7/SMAD4 ratio was elevated in CRC primary tumor tissues and cell lines compared to corresponding non-tumor tissues and cell line, respectively (p = 0.003). SMAD7 expression was significantly elevated in primary tumor tissues obtained from responders to neoadjuvant chemoradiotherapy (nCRT) compared to non-responders (p = 0.014). Alterations of expression and ratio of SMAD7 and SMAD4 in CRC cell lines, primary rectal cancer, and liver metastasis emphasize the importance of these genes in different stages of disease progression. Differential expression of SMAD7 in responders versus non-responders to nCRT should be further investigated for its potential predictive value. © 2021 Elsevier Inc.

Inhibitory SMAD7 and common mediator SMAD4 play crucial roles in SMAD-dependent TGF-β signaling that is often disrupted in colorectal cancer (CRC). This study aimed to profile the expression of SMAD7 and SMAD4 in primary and metastatic CRC and to evaluate their significance in disease progression and therapy response. The expression of SMAD7 and SMAD4 genes was analyzed by quantitative real-time PCR in tissues from 35 primary and metastatic CRC patients and in vitro in 7 human cell lines originating from colon tissue. Expression levels of SMAD7 and SMAD4, as well as their ratio, were determined and their association with tumor characteristics and response to therapy were evaluated. SMAD4 level was significantly lower in tumors compared to non-tumor tissues in both primary (p = 0.001) and metastatic (p = 0.001) CRC patients, while tumor expression of SMAD7 was significantly lower from non-tumor tissue only in metastatic patients (p = 0.017). SMAD7/SMAD4 ratio was elevated in CRC primary tumor tissues and cell lines compared to corresponding non-tumor tissues and cell line, respectively (p = 0.003). SMAD7 expression was significantly elevated in primary tumor tissues obtained from responders to neoadjuvant chemoradiotherapy (nCRT) compared to non-responders (p = 0.014). Alterations of expression and ratio of SMAD7 and SMAD4 in CRC cell lines, primary rectal cancer, and liver metastasis emphasize the importance of these genes in different stages of disease progression. Differential expression of SMAD7 in responders versus non-responders to nCRT should be further investigated for its potential predictive value. © 2021 Elsevier Inc.