Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma

Yoo, Seung Seok; Lee, Ji Ae; Shin, Yunjoo; Cho, Nam Yun; Bae, Jeong Mo; Kang, Gyeong Hoon

doi:10.4132/jptm.2019.06.07

Cited by 10 publications

(7 citation statements)

References 50 publications

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“…The number of differently sized repeats involving mononucleotide microsatellite loci was counted and MSI status was deemed positive (MSI‐high) when the fraction of unstable microsatellite loci over the total examined loci was higher than 20%. Conventional MSI testing was performed based on polymerase chain reaction (PCR) using the allele profiles of five microsatellite markers (BAT‐26, BAT‐25, D5S346, D17S250, and S2S123), as described previously [28]; the two tests gave concordant results in all cases.…”

Section: Methodsmentioning

confidence: 99%

Comprehensive genetic features of gastric mixed adenoneuroendocrine carcinomas and pure neuroendocrine carcinomas

Koh

Nam

Kwak

et al. 2020

The Journal of Pathology

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We aimed to determine the pathogenesis of gastric mixed adenoneuroendocrine carcinoma (MANEC) and pure neuroendocrine carcinoma (NEC), which is largely unknown. Targeted DNA sequencing was performed on 34 tumor samples from 21 patients-13 adenocarcinoma (ADC)/NEC components from MANECs and eight pure NECsand 21 matched non-neoplastic gastric tissues. Mutational profiles of MANECs/NECs were compared with those of other tumors using public databases. The majority (64.1%; 59/92) of mutations in MANEC were shared by both ADC and NEC components. TP53 was the most commonly mutated gene in MANEC (69.2%, 9/13) and pure NEC (87.5%, 8/9). All TP53 mutations in MANEC were pathogenic mutations and were shared by both ADC and NEC components. A subset of TP53 WT MANECs had a microsatellite-unstable phenotype or amplifications in various oncogenes including ERBB2 and NMYC, and the only TP53 WT pure NEC harbored MYC amplification. Compared to NEC in other organs, NECs arising from the stomach had unique features including less frequent RB1 mutations. Differentially altered genes of MANEC ADC components were significantly associated with receptor tyrosine kinase signaling pathways, while differentially altered genes of MANEC NEC components were significantly associated with the NOTCH signaling pathway. Our data provide evidence suggesting a possible clonal origin of ADC and NEC components of MANEC, and we found that gastric MANECs and pure NECs are distinct entities with unique mutational profiles and underlying protein networks.

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Section: Methodsmentioning

confidence: 99%

Comprehensive genetic features of gastric mixed adenoneuroendocrine carcinomas and pure neuroendocrine carcinomas

Koh

Nam

Kwak

et al. 2020

The Journal of Pathology

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“…Of these, four studies had evaluated the prognostic value for RFS [ 47 , 81 , 88 , 101 ]. Six studies included cancer-specific survival [ 26 , 46 , 48 , 65 , 98 , 103 ], whereas three reported progression-free survival (PFS) [ 32 , 76 , 84 ]. All others reported either OS and/or DFS.…”

Section: Resultsmentioning

confidence: 99%

Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis

2022

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Objectives. Accumulating evidence indicates that the expression and/or variants of several genes play an essential role in the progress of colorectal cancer (CRC). The current study is a meta-analysis undertaken to estimate the prognosis and survival associated with CTNNB1/β-catenin, APC, Wnt, SMAD3/4, TP53, and Cyclin D1 genes among CRC patients. Methods. The authors searched PubMed, EMBASE, and Science Direct for relevant reports published between 2000 and 2020 and analyzed them to determine any relationship between the (immunohistochemically/sequencing-detected) gene expression and variants of the selected genes and the survival of CRC patients. Results. The analysis included 34,074 patients from 64 studies. To evaluate association, hazard ratios (HRs) were estimated for overall survival (OS) or disease-free survival (DFS), with a 95% confidence interval (CIs). Pooled results showed that β-catenin overexpression, APC mutation, SMAD-3 or 4 loss of expression, TP53 mutations, and Cyclin D1 expression were associated with shorter OS. β-Catenin overexpression (HR: 0.137 (95% CI: 0.131–0.406)), loss of expression of SMAD3 or 4 (HR: 0.449 (95% CI: 0.146–0.753)), the mutations of TP53 (HR: 0.179 (95% CI: 0.126–0.485)), and Cyclin D1 expression (HR: 0.485 (95% CI: 0.772–0.198)) also presented risk for shorter DFS. Conclusions. The present meta-analysis indicates that overexpression or underexpression and variants of CTNNB1/β-catenin, APC, SMAD3/4, TP53, and Cyclin D1 genes potentially acted as unfavorable biomarkers for the prognosis of CRC. The Wnt gene was not associated with prognosis.

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“…SMAD4 is a tumor suppressor gene that regulates cell proliferation, distinction, and extracellular matrix production [ 39 ]. It has been reported that SMAD4 acts as a prognostic biomarker in various human malignancies such as colorectal carcinoma [ 40 ] and pancreatic carcinoma [ 41 ], but its role as a prognostic marker in breast carcinoma is still unclear [ 42 ]. Deckers et al [ 43 ] informed that SMAD4/TGF-β-induced growth protection and apoptosis only happened at early stages of BC.…”

Section: Discussionmentioning

confidence: 99%

Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay

Swellam

Saad

Sabry

et al. 2021

Journal of Genetic Engineering and Biotechnology

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Background Diagnosis of breast cancer is more complicated due to lack of minimal invasive biomarker with sufficient precision. DNA methylation is a promising marker for cancer diagnosis. In this study, authors evaluated methylation patterns for PTEN and SMAD4 in blood samples using EpiTect Methyl II QPCR assay quantitative PCR technology. Results Methylation status for PTEN and SMAD4 were statistically significant as breast cancer patients reported hypermethylation compared to benign and control groups (77.1 ± 17.9 vs. 24.9 ± 4.5 and 15.1 ± 1.4 and 70.1 ± 14.4 vs. 28.2 ± 0.61 and 29.5 ± 3.6, respectively). ROC curve analysis revealed that both PTEN (AUC = 0.992) and SMAD4 (AUC = 0.853) had good discriminative power for differentiating BC from all non-cancer individuals (benign and healthy combined) compared to routine tumor markers CEA (AUC = 0.538) and CA15.3 (AUC = 0.686). High PTEN methylation degree was associated with late stages (84.2 ± 17.4), positive lymph node (84.2 ± 18.5), positive ER (81.3 ± 19.7), positive PgR (79.5 ± 19.1), and positive HER2 (80.7 ± 19.0) vs. 67.4 ± 13.8, 70.6 ± 14.8, 72.8 ± 14.9, 72.5 ± 14.7, and 70.2 ± 13.5 in early stages, negative lymph node, negative ER, negative PgR, and negative HER2, respectively. Similar results were obtained regarding SMAD4 methylation. Sensitivity, specificity, positive and negative predictive values, and accuracy for methylated PTEN were 100%, 95%, 99.1%, 100%, and 95%, respectively when differentiated BC from all-non cancer controls. Interestingly, PTEN could distinguish early BC stages with good sensitivity 84.4%, 51.4%, 69.1%, 72%, and 70%, respectively. Conclusion Methylation status of PTEN and SMAD4 is a promising blood marker for early detection of breast cancer. Future studies are needed for their role as prognostic markers.

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Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma

Cited by 10 publications

References 50 publications

Comprehensive genetic features of gastric mixed adenoneuroendocrine carcinomas and pure neuroendocrine carcinomas

Comprehensive genetic features of gastric mixed adenoneuroendocrine carcinomas and pure neuroendocrine carcinomas

Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis

Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay

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