Journal of Pathology and Translational Medicine

Original Articles

Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma: Seung-Yeon Yoo, Ji-Ae Lee, Yunjoo Shin, Nam-Yun Cho, Jeong Mo Bae, Gyeong Hoon Kang; J Pathol Transl Med. 2019;53(5):289-297. Published online June 24, 2019; DOI: https://doi.org/10.4132/jptm.2019.06.07

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Background
SMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC.
Methods
We retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs.
Results
A loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p=.042) and 7-year cancerspecific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p=.022).
Conclusions
We confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.

Citations

Citations to this article as recorded by

Unraveling Resistance to Immunotherapy in MSI-High Colorectal Cancer
Ronald Heregger, Florian Huemer, Markus Steiner, Alejandra Gonzalez-Martinez, Richard Greil, Lukas Weiss
Cancers.2023; 15(20): 5090. CrossRef
Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis
Hongfeng Yan, Fuquan Jiang, Jianwu Yang, Ying-Kun Xu
Genetics Research.2022; 2022: 1. CrossRef
Comprehensive genetic features of gastric mixed adenoneuroendocrine carcinomas and pure neuroendocrine carcinomas
Jiwon Koh, Soo Kyung Nam, Yoonjin Kwak, Gilhyang Kim, Ka‐Kyung Kim, Byung‐Chul Lee, Sang‐Hoon Ahn, Do Joong Park, Hyung‐Ho Kim, Kyoung Un Park, Woo Ho Kim, Hye Seung Lee
The Journal of Pathology.2021; 253(1): 94. CrossRef
Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay
Menha Swellam, Entsar A. Saad, Shimaa Sabry, Adel Denewer, Camelia Abdel Malak, Amr Abouzid
Journal of Genetic Engineering and Biotechnology.2021; 19(1): 54. CrossRef
Molecular Characterization and Functional Analysis of Two Steroidogenic Genes TSPO and SMAD4 in Yellow Catfish
Fang Chen, Chong-Chao Zhong, Chang-Chun Song, Shu-Wei Chen, Yang He, Xiao-Ying Tan
International Journal of Molecular Sciences.2021; 22(9): 4505. CrossRef
SMAD7 and SMAD4 expression in colorectal cancer progression and therapy response
Jovana Rosic, Sandra Dragicevic, Marko Miladinov, Jovana Despotovic, Aleksandar Bogdanovic, Zoran Krivokapic, Aleksandra Nikolic
Experimental and Molecular Pathology.2021; 123: 104714. CrossRef
Actionable Potentials of Less Frequently Mutated Genes in Colorectal Cancer and Their Roles in Precision Medicine
Ryia Illani Mohd Yunos, Nurul Syakima Ab Mutalib, Francis Yew Fu Tieng, Nadiah Abu, Rahman Jamal
Biomolecules.2020; 10(3): 476. CrossRef

The Smad4/PTEN Expression Pattern Predicts Clinical Outcomes in Colorectal Adenocarcinoma: Yumin Chung, Young Chan Wi, Yeseul Kim, Seong Sik Bang, Jung-Ho Yang, Kiseok Jang, Kyueng-Whan Min, Seung Sam Paik; J Pathol Transl Med. 2018;52(1):37-44. Published online October 23, 2017; DOI: https://doi.org/10.4132/jptm.2017.10.20

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Abstract PDF Supplementary Material

Background
Smad4 and PTEN are prognostic indicators for various tumor types. Smad4 regulates tumor suppression, whereas PTEN inhibits cell proliferation. We analyzed and compared the performance of Smad4 and PTEN for predicting the prognosis of patients with colorectal adenocarcinoma.
Methods
Combined expression patterns based on Smad4+/– and PTEN+/– status were evaluated by immunostaining using a tissue microarray of colorectal adenocarcinoma. The relationships between the protein expression and clinicopathological variables were analyzed.
Results
Smad4–/PTEN– status was most frequently observed in metastatic adenocarcinoma, followed by primary adenocarcinoma and tubular adenoma (p<.001). When Smad4–/PTEN– and Smad4+/PTEN+ groups were compared, Smad4–/PTEN– status was associated with high N stage (p=.018) and defective mismatch repair proteins (p=.006). Significant differences in diseasefree survival and overall survival were observed among the three groups (Smad4+/PTEN+, Smad4–/PTEN+ or Smad4+/PTEN–, and Smad4–/PTEN–) (all p<.05).
Conclusions
Concurrent loss of Smad4 and PTEN may lead to more aggressive disease and poor prognosis in patients with colorectal adenocarcinoma compared to the loss of Smad4 or PTEN alone.

Citations

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The Potential Role of Genomic Signature in Stage II Relapsed Colorectal Cancer (CRC) Patients: A Mono-Institutional Study
Michela Roberto, Giulia Arrivi, Emanuela Pilozzi, Andrea Montori, Genoveffa Balducci, Paolo Mercantini, Andrea Laghi, Debora Ierinò, Martina Panebianco, Daniele Marinelli, Silverio Tomao, Paolo Marchetti, Federica Mazzuca
Cancer Management and Research.2022; Volume 14: 1353. CrossRef
Alterations of PTEN and SMAD4 methylation in diagnosis of breast cancer: implications of methyl II PCR assay
Menha Swellam, Entsar A. Saad, Shimaa Sabry, Adel Denewer, Camelia Abdel Malak, Amr Abouzid
Journal of Genetic Engineering and Biotechnology.2021; 19(1): 54. CrossRef
E3 ubiquitin ligase HECW1 promotes the metastasis of non-small cell lung cancer cells through mediating the ubiquitination of Smad4
Chen Lu, Guangyao Ning, Panpan Si, Chunsheng Zhang, Wenjian Liu, Wei Ge, Kai Cui, Renquan Zhang, Shenglin Ge
Biochemistry and Cell Biology.2021; 99(5): 675. CrossRef
Computational quantification of global effects induced by mutations and drugs in signaling networks of colorectal cancer cells
Sara Sommariva, Giacomo Caviglia, Silvia Ravera, Francesco Frassoni, Federico Benvenuto, Lorenzo Tortolina, Nicoletta Castagnino, Silvio Parodi, Michele Piana
Scientific Reports.2021;[Epub] CrossRef
Clinicopathological characterization of SMAD4-mutated intestinal adenocarcinomas: A case-control study
Xiaoyan Liao, Yansheng Hao, Xiaofei Zhang, Stephen Ward, Jane Houldsworth, Alexandros D. Polydorides, Noam Harpaz, Aldo Scarpa
PLOS ONE.2019; 14(2): e0212142. CrossRef
Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma
Seung-Yeon Yoo, Ji-Ae Lee, Yunjoo Shin, Nam-Yun Cho, Jeong Mo Bae, Gyeong Hoon Kang
Journal of Pathology and Translational Medicine.2019; 53(5): 289. CrossRef
Dissecting the therapeutic implications of the complex SMAD4 regulatory network in metastatic colorectal cancer
Ion Cristóbal, Blanca Torrejón, Andrea Santos, Melani Luque, Marta Sanz-Alvarez, Federico Rojo, Jesús García-Foncillas
European Journal of Surgical Oncology.2018; 44(8): 1283. CrossRef
Reply to: Dissecting the therapeutic implications of the complex SMAD4 regulatory network in metastatic colorectal cancer
Jordan M. Cloyd, Takashi Mizuno, Jean-Nicolas Vauthey
European Journal of Surgical Oncology.2018; 44(8): 1285. CrossRef

DPC4 Expression in the Small Intestinal Adenocarcinomas: Sun Jae Lee, Eunsil Yu, Young Kyung Bae, Kee-Taek Jang, Joon Mee Kim, Han-Ik Bae, Seung-Mo Hong, Ghil Suk Yoon; Korean J Pathol. 2012;46(5):415-422. Published online October 25, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.5.415

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Abstract PDF

Background

Small intestinal adenocarcinomas (SACs) are rare malignancies of the alimentary tract with uncertain carcinogenesis.

Methods

We investigated the expression of deleted in pancreatic cancer 4 (DPC4) in 188 cases of surgically resected SACs, using tissue microarray technology.

Results

Twenty-four of the 188 tumors showed complete loss of Smad4/DPC4 expression in cytoplasm (score, 0; 12.8%). Eighty-four and 31 cases were moderately and strongly positive, respectively (score, 2 and 3; 44.7% and 16.5%, respectively) and 49 cases were focally or weakly stained (score, 1; 29.1%). Immunohistochemistry analysis showed that the expression of Smad4/DPC4 was related to an increased risk of lymphatic invasion but not to other clinicopathological features of the tumors (tumor location, differentiation, growth pattern, T stage, direct invasion, vascular invasion, and nodal metastasis). There was no significant association between Smad4/DPC4 expression and patient survival.

Conclusions

The present research is the first study to evaluate Smad4/DPC4 expression in a large sample of SACs with clinicopathologic correlation. Future studies should focus on the immunohistochemical and molecular characteristics of SACs to clarify their tumorigenesis.

Citations

Citations to this article as recorded by

American Registry of Pathology Expert Opinions: Evaluation of poorly differentiated malignant neoplasms on limited samples - Gastrointestinal mucosal biopsies
Andrew M. Bellizzi, Elizabeth A. Montgomery, Jason L. Hornick
Annals of Diagnostic Pathology.2020; 44: 151419. CrossRef

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