Immunohistochemically Detected Expression of 3 Major Genes (CDKN2A/p16, TP53, and SMAD4/DPC4) Strongly Predicts Survival in Patients With Resectable Pancreatic Cancer
Abstract
OBJECTIVE: The goal of this retrospective study was to clarify the clinical implications of the status of the 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4). BACKGROUND: Recent whole-exome sequencing had shown that the landscape of the pancreatic ductal adenocarcinoma (PDAC) genome is notable for 4 frequently mutated genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4). METHODS: We determined immunohistochemically the status of TP53, CDKN2A/p16, and SMAD4/DPC4 among the 4 genes because the KRAS gene is mutated in virtually all PDAC patients, and analyzed relationships with clinicopathological findings, including survival and patterns of disease progression, in 106 patients with PDAC undergoing radical surgery. RESULTS: Abnormal immunolabeling of p53 was detected in 81.1% of PDACs and was significantly associated with tumor dedifferentiation (P = 0.022) and the presence of locoregional recurrence (P = 0.020). Loss of p16 and Smad4/Dpc4 immunolabeling was identified in 67.0% and 60.4%, respectively. Loss of p16 immunolabeling was associated with lymphatic invasion (P = 0.012) and postoperative widespread metastases (P < 0.001). A significant correlation was found between Smad4/Dpc4 immunolabeling and tumor size (P = 0.006), lymphatic invasion (P = 0.033), and lymph node metastasis (P = 0.006). Interestingly, all of the 6 patients demonstrating 5-year survival had intact SMAD4/DPC4. Kaplan-Meier survival analysis showed that lymph node metastasis (P = 0.001), lymphatic invasion (P = 0.008), the tumor (T) factor (T3 vs. T1/T2, P = 0.004), loss of p16 immunolabeling (P = 0.029), and loss of Smad4/Dpc4 immunolabeling (P < 0.001) were significantly associated with shorter overall survival. Multivariate analysis revealed that loss of Smad4/Dpc4 immunolabeling was an independent and significant poor prognostic factor for overall and disease-free survival. On analysis of combinations of the status of these 3 genes, increasing number of alterations reflected poorer survival. CONCLUSIONS: Genetic alterations of these 3 genes and their accumulation are strongly associated with malignant behavior of PDAC. Their immunohistochemical assessment at the time of diagnosis may provide a new prognostic tool, assisting in deciding optimal therapeutic strategies for patients.
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Multivariate analysis identified loss of SMAD4/DPC4 immunolabeling as an independent prognostic factor for overall and disease-free survival.
“Multivariate analysis identified the loss of SMAD4/DPC4 immunolabeling as an independent prognostic factor for overall and disease-free survival.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [75]
Loss of p16 and SMAD4/DPC4 immunolabeling is associated with significantly shorter OS and DFS.
“The loss of p16 and SMAD4/DPC4 immunolabeling has been associated with significantly shorter OS and DFS.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [75]
SMAD4 loss is associated with distant metastases.
“Notably, SMAD4 loss is associated with distant metastases, highlighting its role in disease progression patterns [72,73,74,75,76,118].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [75]
Patients with DPC4-expressed cancers exhibit longer survival.
“Patients with DPC4-expressed cancers exhibit longer survival, emphasizing the significance of SMAD4 in treatment outcomes.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [75]
Number of altered genes correlates with survival outcomes, with patients harboring three altered genes exhibiting significantly worse survival than those with one or two altered genes.
“The number of altered genes correlated with survival outcomes, with patients harboring three altered genes exhibiting significantly worse survival than those with one or two altered genes.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [75]
DPC4 gene frequently experiences inactivation in PDAC, leading to enhanced metastasis and worse prognosis.
“The DPC4 gene, encoding SMAD4, frequently experiences inactivation in PDAC, leading to enhanced metastasis and worse prognosis.”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [75]
Cites
Distant metastasis occurs late during the genetic evolution of pancreatic cancer
Yachida, S., Jones, S., Bozic, I., Antal, T., Leary, R., Fu, B., Kamiyama, M., Hruban, R. H., Eshleman, J. R., Nowak, M. A., et al. (2010) · Nature · doi:10.1038/nature09515 · Cited by 2,502 · see citing works
Self-citation<i>DPC4</i> , A Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1
Hahn, S. A., Schutte, M., Shamsul Hoque, A. T. M., Moskaluk, C. A., da Costa, L. T., Rozenblum, E., Weinstein, C. L., Fischer, A., Yeo, C. J., Hruban, R. H., et al. (1996) · Science · doi:10.1126/science.271.5247.350 · Cited by 2,337 · see citing works
The patterns and dynamics of genomic instability in metastatic pancreatic cancer
Campbell, P. J., Yachida, S., Mudie, L. J., Stephens, P. J., Pleasance, E. D., Stebbings, L. A., Morsberger, L. A., Latimer, C., McLaren, S., Lin, M.-L., et al. (2010) · Nature · doi:10.1038/nature09460 · Cited by 1,317 · see citing works
Self-citationAguirre, A. J., Bardeesy, N., Sinha, M., Lopez, L., Tuveson, D. A., Horner, J., Redston, M. S., & DePinho, R. A. (2003) · Genes & Development · doi:10.1101/gad.1158703 · Cited by 1,033 · see citing works
Maitra, A., & Hruban, R. H. (2008) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathmechdis.3.121806.154305 · Cited by 707 · see citing works
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Cited by
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Qian, Z. R., Rubinson, D. A., Nowak, J. A., Morales-Oyarvide, V., Dunne, R. F., Kozak, M. M., Welch, M. W., Brais, L. K., Da Silva, A., Li, T., et al. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2017.3420 · Cited by 260 · see citing works
Boone, B. A., Bahary, N., Zureikat, A. H., Moser, A. J., Normolle, D. P., Wu, W.-C., Singhi, A. D., Bao, P., Bartlett, D. L., Liotta, L. A., et al. (2015) · Annals of Surgical Oncology · doi:10.1245/s10434-015-4566-4 · Cited by 234 · see citing works
Hu, H.-F., Ye, Z., Qin, Y., Xu, X.-W., Yu, X.-J., Zhuo, Q.-F., & Ji, S.-R. (2021) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-00584-2 · Cited by 149 · see citing works
Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer
Stefanoudakis, D., Frountzas, M., Schizas, D., Michalopoulos, N. V., Drakaki, A., & Toutouzas, K. G. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46040177 · Cited by 110 · see citing works
Iwatate, Y., Hoshino, I., Yokota, H., Ishige, F., Itami, M., Mori, Y., Chiba, S., Arimitsu, H., Yanagibashi, H., Nagase, H., et al. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0997-1 · Cited by 101 · see citing works
Prognostic Value of SMAD4 in Pancreatic Cancer: A Meta-Analysis
Shugang, X., Hongfa, Y., Jianpeng, L., Xu, Z., Jingqi, F., Xiangxiang, L., & Wei, L. (2016) · Translational Oncology · doi:10.1016/j.tranon.2015.11.007 · Cited by 72 · see citing works
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Wang, Q., Ni, Q., Wang, X., Zhu, H., Wang, Z., & Huang, J. (2015) · Medical Oncology · doi:10.1007/s12032-014-0372-2 · Cited by 70 · see citing works
SMAD4 Expression Predicts Local Spread and Treatment Failure in Resected Pancreatic Cancer
Yamada, S., Fujii, T., Shimoyama, Y., Kanda, M., Nakayama, G., Sugimoto, H., Koike, M., Nomoto, S., Fujiwara, M., Nakao, A., et al. (2015) · Pancreas · doi:10.1097/mpa.0000000000000315 · Cited by 71 · see citing works
Gu, Y., Ji, Y., Jiang, H., & Qiu, G. (2020) · Genetic Testing and Molecular Biomarkers · doi:10.1089/gtmb.2020.0078 · Cited by 28 · see citing works
Zhang, D., Wang, T., Zhou, Y., & Zhang, X. (2023) · Medicine · doi:10.1097/md.0000000000033468 · Cited by 28 · see citing works
SMAD4 Y353C promotes the progression of PDAC
Wang, Z., Li, Y., Zhan, S., Zhang, L., Zhang, S., Tang, Q., Li, M., Tan, Z., Liu, S., & Xing, X. (2019) · BMC Cancer · doi:10.1186/s12885-019-6251-7 · Cited by 25 · see citing works
Sinha, A., Cherba, D., Bartlam, H., Lenkiewicz, E., Evers, L., Barrett, M. T., & Haab, B. B. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.04.007 · Cited by 11 · see citing works
Prognostic value of SMAD4 in resectable pancreatic cancer
Su, H., & Wang, C. (2022) · Postępy Higieny i Medycyny Doświadczalnej · doi:10.2478/ahem-2022-0036 · Cited by 1 · see citing works
- Authors
- Oshima, M., Okano, K., Muraki, S., Haba, R., Maeba, T., Suzuki, Y., & Yachida, S.
- Affiliations
- Kagawa University (JP)
- Ritsurin Hospital (JP)
- Corresponding author
- Oshima, Minoru
- Okano, Keiichi
- Suzuki, Yasuyuki
- Yachida, Shinichi
- Venue
- Annals of Surgery
- Published
- 2013-08
- Volume
- 258
- Issue
- 2
- Pages
- 336-346
- ISSN
- 0003-4932 (ISSN-L)
- OpenAlex
- W2317459595
- Cited by
- 236
- References
- 5
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 7 · 2023: 16 · 2022: 23 · 2021: 24 · 2020: 20 · 2019: 20 · 2018: 17 · 2017: 26 · 2016: 22 · 2015: 17 · 2014: 22 · 2013: 5
- FWCI
- 11.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Surgery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (23390326, 24659612, 24592029)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- pancreatic ductal adenocarcinoma, CDKN2A/p16, TP53, tumor suppressor loss, prognostic factors, survival prediction, lymph node metastasis, lymphatic invasion, tumor dedifferentiation, locoregional recurrence, resectable pancreatic cancer, immunohistochemistry, KRAS mutation
- MeSH terms
- Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Genetic Markers, Humans, Immunohistochemistry, Male, Middle Aged, Mutation, Pancreatectomy, Pancreatic Neoplasms, Retrospective Studies, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Multivariate Analysis, Survival Analysis, Genes, p53, Tumor Suppressor Protein p53, Pancreaticoduodenectomy, Treatment Outcome, Cyclin-Dependent Kinase Inhibitor p16, Genes, p16, Carcinoma, Pancreatic Ductal, Smad4 Protein
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