SMAD4 mutations identified in Iranian patients with colorectal cancer and polyp
Gastroenterology and Hepatology from Bed to Bench,
Vol. 14 No. Supplement 1 (2021),
30 Dey 2021
https://doi.org/10.22037/ghfbb.vi.1925
Abstract
Aim: Search for SMAD4 mutations in Colorectal cancer (CRC) or polyp in Iran.
Background: Colorectal cancer is one of the five prevalent cancers among the Iranian population; however, its molecular mechanisms are not fully understood. The vast majority of CRCs arise from neoplastic polyp
Methods: Colorectal cancer and polyp lesions with matched normal tissues from patients who had undergone colonoscopy in Taleghani Hospital (January 2009 – November 2010) were included in the study. DNA extraction and PCR-sequencing for exons 5-11 of the SMAD-4 gene were carried out on 39 and 30 specimens of polyp and adenocarcinoma, respectively.
Results Of cancer and polyp specimens, 33.3% and 28.2%, respectively, were mutated in the Smad-4 gene. The majority of SMAD4 mutations, especially in the MH2 domain were missense mutations (63.6% and 68.75, respectively). In cancer, codon 435 and in polyp, codons 435 and 399 were the most common alterations. Unlike cancer specimens, transversion was found frequently in the polyp (56.25% vs. 35.7%). CG>TA transition was about 18.75% and 14.3% in cancer and polyp samples, respectively. Mutations of codon 264 and C.483-4 were seen both in cancer and neoplastic polyps.
Conclusion: As frequent alterations, missense mutations are presumably selected during tumorigenesis and polyposis due to their structural impacts on SMAD4 functions and TGF-ß signaling pathway. The lower frequency of CG>TA can be attributed to global genome hypomethylation. Presumably, SMAD4 mutations had occurred in the primary polyps, and some of these mutated cells then developed into carcinoma. On the other hand, polyp-specific mutations may lower the risk of CRC.
- SMAD4
- MADH4
- DPC4
- colorectal cancer
- MH2 domain
- cancer
- polyp
- neoplastic polyp
- Transition
- transversion
How to Cite
References
Iacobuzio-Donahue, C.A., J. Song, G. Parmiagiani, C.J. Yeo, R.H. Hruban, and S.E. Kern, Missense Mutations of MADH4 Characterization of the Mutational Hot Spot and Functional Consequences in Human Tumors. Clin Cancer Res, 2004; 10: 1597-1604.
Hata, A., R.S. Lo, D. Wotton, G. Lagna, and J. Massague, Mutations increasing autoinhibition inactivate tumour suppressors Smad2 and Smad4. Nature, 1997; 388: 82-7.
Kuang, C. and Y. Chen, Tumor-derived C-terminal mutations of Smad4 with decreased DNA binding activity and enhanced intramolecular interaction. Oncogene, 2004; 23: 1021-1029.
Yang, G. and X. Yang, Smad4-mediated TGF-beta signaling in tumorigenesis. Int J Biol Sci., 2010; 6: 1-8.
Li, Q., L. Wu, D.K. Oelschlager, M. Wan, C.R. Stockard, W.E. Grizzle, et al., Smad4 inhibits tumor growth by inducing apoptosis in estrogen receptor-alpha-positive breast cancer cells. J Biol Chem, 2005; 280: 27022-8.
Morén, A., S. Itoh, A. Moustakas, P.t. Dijke, and C.-H. Heldin, Functional consequences of tumorigenic missense mutations in the amino-terminal domain of Smad4. Oncogene, 2000; 19: 4396-404.
Liu, F., C. Pouponnot, and J. Massague, Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes. Genes Dev, 1997; 11: 3157-67.
Fleming, N.I., R.N. Jorissen, D. Mouradov, M. Christie, A. Sakthianandeswaren, M. Palmieri, et al., SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer Research, 2013; 73: 725-35.
Zhao, M., L. Mishra, and C.X. Deng, The role of TGF-beta/SMAD4 signaling in cancer. Int J Biol Sci., 2018; 14: 111-123.
De Bosscher, K., C.S. Hill, and F.J. Nicolas, Molecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells. Biochem J., 2004; 379: 209-16.
Koyama, M., M. Ito, H. Nagai, M. Emi, and Y. Moriyama, Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients. Mutat. Res., 1999; 406: 71-7.
Miyaki, M. and T. Kuroki, Role of Smad4 (DPC4) inactivation in human cancer. Biochem. Biophys. Res. Commun., 2003; 306: 799-804.
Takagi, Y., H. Kohmura, M. Futamura, H. Kida, H. Tanemura, K. Shimokawa, et al., Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. Gastroenterology, 1996; 111: 1369-72.
Fleming, N.I., R.N. Jorissen, D. Mouradov, M. Christie, A. Sakthianandeswaren, M. Palmieri, et al., SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer. Cancer research, 2013; 73: 725-735.
Mesker, W.E., G.J. Liefers, J.M. Junggeburt, G.W. van Pelt, P. Alberici, P.J. Kuppen, et al., Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients. Cell Oncol, 2009; 31: 169-78.
Bray, F., J. Ferlay, I. Soerjomataram, R.L. Siegel, L.A. Torre, and A. Jemal, Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018.
Mousavi, S.M., M.M. Gouya, R. Ramazani, M. Davanlou, N. Hajsadeghi, and Z. Seddighi, Cancer incidence and mortality in Iran. Ann Oncol, 2009; 20: 556-563.
Radmard, A.R., Five common cancers in Iran. Arch Iran Med, 2010; 13: 143-146.
Sadjadi, A., M. Nouraie, M.A. Mohagheghi, A. Mousavi-Jarrahi, R. Malekezadeh, and D.M. Parkin, Cancer occurrence in Iran in 2002, an international perspective. Asian Pac J Cancer Prev, 2005; 6: 359-63.
Siegel, R., C. DeSantis, and A. Jemal, Colorectal cancer statistics, 2014. CA Cancer J. Clin., 2014; 64: 104-117.
Jemal, A., F. Bray, M.M. Center, J. Ferlay, E. Ward, and D. Forman, Global cancer statistics. CA Cancer J. Clin., 2011; 61: 69-90.
Malekzadeh, R., F. Bishehsari, M. Mahdavinia, and R. Ansari, Epidemiology and molecular genetics of colorectal cancer in iran: a review. Arch Iran Med, 2009; 12: 161-9.
Dolatkhah, R., M.H. Somi, M.J. Bonyadi, I. Asvadi Kermani, F. Farassati, and S. Dastgiri, Colorectal Cancer in Iran: Molecular Epidemiology and Screening Strategies. J. Cancer Epidemiol., 2015; 2015.
Oines, M., L.M. Helsingen, M. Bretthauer, and L. Emilsson, Epidemiology and risk factors of colorectal polyps. Best Pract Res Clin Gastroentero, 2017; 31: 419-424.
Aarons, C.B., S. Shanmugan, and J.I. Bleier, Management of malignant colon polyps: current status and controversies. World J Gastroenterol, 2014; 20: 16178-83.
Bujanda, L., A. Cosme, I. Gil, and J.I. Arenas-Mirave, Malignant colorectal polyps. World J Gastroenterol, 2010; 25: 3103-11.
Holme, Ø., M. Bretthauer, T.J. Eide, E.M. Løberg, K. Grzyb, M. Løberg, et al., Long-term risk of colorectal cancer in individuals with serrated polyps. Gut, 2015; 64: 929-936.
Netzer, P., C. Forster, R. Biral, C. Ruchti, J. Neuweiler, E. Stauffer, et al., Risk factor assessment of endoscopically removed malignant colorectal polyps. Gut, 1998; 43: 669-674.
Nusko, G., U. Mansmann, U. Partzsch, A. Altendorf-Hofmann, H. Groitl, C. Wittekind, et al., Invasive carcinoma in colorectal adenomas: multivariate analysis of patient and adenoma characteristics. Endoscopy, 1997; 29: 626-631.
Soetikno, R.M., T. Kaltenbach, R.V. Rouse, W. Park, A. Maheshwari, T. Sato, et al., Prevalence of nonpolypoid (flat and depressed) colorectal neoplasms in asymptomatic and symptomatic adults. Jama, 2008; 299: 1027-1035.
Volk, E.E., J.R. Goldblum, R.E. Petras, W.D. Carey, and V.W. Fazio, Management and outcome of patients with invasive carcinoma arising in colorectal polyps. Gastroenterology, 1995; 109: 1801-1807.
Miyaki, M., T. Iijima, M. Konishi, K. Sakai, A. Ishii, M. Yasuno, et al., Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene, 1999; 18: 3098-3103.
Tarafa, G., A. Villanueva, L. Farre, J. Rodriguez, E. Musulen, G. Reyes, et al., DCC and SMAD4 alterations in human colorectal and pancreatic tumor dissemination. Oncogene, 2000; 19: 546-55.
Takaku, K., M. Oshima, H. Miyoshi, M. Matsui, M.F. Seldin, and M.M. Taketo, Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell, 1998; 92: 645-56.
Miyaki, M., T. Iijima, M. Konishi, K. Sakai, A. Ishii, M. Yasuno, et al., Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene, 1999; 18: 3098-103.
Ueda, T., A. Komiya, M. Emi, H. Suzuki, T. Shiraishi, R. Yatani, et al., Allelic losses on 18q21 are associated with progression and metastasis in human prostate cancer. Genes Chromosomes Cancer, 1997; 20: 140-7.
Tanaka, T., T. Watanabe, Y. Kazama, J. Tanaka, T. Kanazawa, S. Kazama, et al., Chromosome 18q deletion and Smad4 protein inactivation correlate with liver metastasis: A study matched for T- and N- classification. Br. J. Cancer, 2006; 95: 1562-7.
Kern, S.E., E.R. Fearon, K.W. Tersmette, J.P. Enterline, M. Leppert, Y. Nakamura, et al., Clinical and pathological associations with allelic loss in colorectal carcinoma [corrected]. JAMA, 1989; 261: 3099-103.
Herbst, A., G.T. Bommer, L. Kriegl, A. Jung, A. Behrens, E. Csanadi, et al., ITF-2 is disrupted via allelic loss of chromosome 18q21, and ITF-2B expression is lost at the adenoma-carcinoma transition. Gastroenterology, 2009; 137: 639-48, 648 e1-9.
Carethers, J.M., M.T. Hawn, J.K. Greenson, C.L. Hitchcock, and C.R. Boland, Prognostic significance of allelic lost at chromosome 18q21 for stage II colorectal cancer. Gastroenterology, 1998; 114: 1188-95.
Shi, Y., A. Hata, R.S. Lo, J. Massague, and N.P. Pavletich, A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature, 1997; 388: 87-93.
Li, Q., L. Wu, D.K. Oelschlager, M. Wan, C.R. Stockard, W.E. Grizzle, et al., Smad4 inhibits tumor growth by inducing apoptosis in estrogen receptor-alpha-positive breast cancer cells. The Journal of biological chemistry, 2005; 280: 27022-8.
Kamburov, A., M.S. Lawrence, P. Polak, I. Leshchiner, K. Lage, T.R. Golub, et al., Comprehensive assessment of cancer missense mutation clustering in protein structures. Proc Natl Acad Sci U S A, 2015; 112: 21.
Nishi, H., M. Tyagi, S. Teng, B.A. Shoemaker, K. Hashimoto, E. Alexov, et al., Cancer missense mutations alter binding properties of proteins and their interaction networks. PLoS One, 2013; 8: e66273.
Stehr, H., S.-H.J. Jang, J.M. Duarte, C. Wierling, H. Lehrach, M. Lappe, et al., The structural impact of cancer-associated missense mutations in oncogenes and tumor suppressors. Molecular cancer, 2011; 10: 1.
Stehr, H., S.H. Jang, J.M. Duarte, C. Wierling, H. Lehrach, M. Lappe, et al., The structural impact of cancer-associated missense mutations in oncogenes and tumor suppressors. Mol. Cancer, 2011; 10: 54.
Sadeghi, R.N., H. Zojaji, S.R. Mohebbi, M. Chiani, M. Vahedi, D. Mirsattari, et al., Evaluation of global genome methylation in gastritis lesion and its correlation with clinicopatological findings. Oncology Research, 2009; 17: 549-558.
Najjar Sadeghi, R., M. Vahedi, H. Zojaji, and M.R. Zali, Correlation between global genome methylation and mutation at CpG codons of p53 gene. j Dig Dis, 2013; 14: 305-310.
Sadeghi, R.N., P. Azimzadeh, M. Vahedi, D. Mirsattari, M. Molaei, S.R. Mohebbi, et al., Profile and frequency of p53 Gene alterations in gastritis lesions from Iran. Digestion, 2010; 83: 65-75.
Pyatt, R.E., R. Pilarski, and T.W. Prior, Mutation screening in juvenile polyposis syndrome. J Mol Diagn, 2006; 8: 84-8.
Pierreux, C.E., F.J. Nicolas, and C.S. Hill, Transforming growth factor beta-independent shuttling of Smad4 between the cytoplasm and nucleus. Mol Cell Biol, 2000; 20: 9041-54.
de Caestecker, M.P., T. Yahata, D. Wang, W.T. Parks, S. Huang, C.S. Hill, et al., The Smad4 activation domain (SAD) is a proline-rich, p300-dependent transcriptional activation domain. The Journal of biological chemistry, 2000; 275: 2115-22.
Bouras, M., E. Tabone, J. Bertholon, P. Sommer, R. Bouvier, J.P. Droz, et al., A novel SMAD4 gene mutation in seminoma germ cell tumors. Cancer Research, 2000; 60: 922-8.
Fukushima, T., M. Mashiko, K. Takita, T. Otake, Y. Endo, K. Sekikawa, et al., Mutational analysis of TGF-beta type II receptor, Smad2, Smad3, Smad4, Smad6 and Smad7 genes in colorectal cancer. J Exp Clin Cancer Res, 2003; 22: 315-20.
- Abstract Viewed: 79 times
- PDF Downloaded: 30 times