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SMAD4 Gene Analysis in Patients with Early Onset Colorectal Cancer: A Pilot Study

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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.

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REFERENCES

  1. Bessa, X., Alenda, C., and Paya, A., et al., Validation microsatellite path score in a population-based cohort of patients with colorectal cancer, J. Clin. Oncol., 2011, vol. 29, no. 25, pp. 3374–3380. https://doi.org/10.1200/JCO.2010.34.3947

    Article  PubMed  Google Scholar 

  2. Bonfiglio, S., Vanni, I., Rossella, V., et al., Performance comparison of two commercial human whole-exome capture systems on formalin-fixed paraffin-embedded lung adenocarcinoma samples, BMC Cancer, 2016, vol. 16, art. ID 692. https://doi.org/10.1186/s12885-016-2720-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Chang, Y.C., Chang, J.G., Liu, T.C., et al., Mutation analysis of 13 driver genes of colorectal cancer-related pathways in Taiwanese patients, World J. Gastroenterol., 2016, vol. 22, no. 7, pp. 2314–2325. https://doi.org/10.3748/wjg.v22.i7.2314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. De Bosscher, K., Hill, C.S., and Nicolás, F.J., Molecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells, Biochem. J., 2004, vol. 379, pp. 209–216. https://doi.org/10.1042/BJ20031886

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Gallione, C.J., Repetto, G.M., Legius, E., et al., A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4), Lancet, 2004, vol. 363, pp. 852–859. https://doi.org/10.1016/S0140-6736(04)15732-2

    Article  CAS  PubMed  Google Scholar 

  6. Gallione, C.J., Richards, J.A., Letteboer, T.G., et al., SMAD4 mutations found in unselected HHT patients, J. Med. Genet., 2006, vol. 43, no. 10, pp. 793–797. https://doi.org/10.1136/jmg.2006.041517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Houlston, R., Bevan, S., Williams, A., et al., Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases, Hum. Mol. Genet., 1998, vol. 7, no. 12, pp. 1907–1912. https://doi.org/10.1093/hmg/7.12.1907

    Article  CAS  PubMed  Google Scholar 

  8. Howe, J.R., Sayed, M.G., Ahmed, A.F., et al., The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations, J. Med. Genet., 2004, vol. 41, pp. 484–491. https://doi.org/10.1136/jmg.2004.018598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Huang, D., Sun, W., Zhou, Y., et al., Mutations of key driver genes in colorectal cancer progression and metastasis, Cancer Metastasis Rev., 2018, vol. 37, pp. 173–187. https://doi.org/10.1007/s10555-017-9726-5

    Article  CAS  PubMed  Google Scholar 

  10. McCarthy, A.J. and Chetty, R., Smad4/DPC4, J. Clin. Pathol., 2018, vol. 71, pp. 661–664. https://doi.org/10.1136/jclinpath-2018-205095

    Article  PubMed  Google Scholar 

  11. Miyaki, M. and Kuroki, T., Role of Smad4 (DPC4) inactivation in human cancer, Biochem. Biophys. Res. Commun., 2003, vol. 306, no. 4, pp. 799–804. https://doi.org/10.1016/s0006-291x(03)01066-0

    Article  CAS  PubMed  Google Scholar 

  12. Nikolic, A., Kojic, S., Knezevic, S., et al., Structural and functional analysis of SMAD4 gene promoter in malignant pancreatic and colorectal tissues: Detection of two novel polymorphic nucleotide repeats, Cancer Epidemiol., 2011, vol. 35, no. 3, pp. 265–271. https://doi.org/10.1016/j.canep.2010.10.002

    Article  CAS  PubMed  Google Scholar 

  13. Perea, J., García-Nebreda, M., Hidalgo, M., et al., SMAD4 in early onset colorectal cancer, Colorectal. Dis., 2010, vol. 12, art. ID 948. https://doi.org/10.1111/j.1463-1318.2010.02296.x

    Article  CAS  PubMed  Google Scholar 

  14. Royce, S.G., Alsop, K., Haydon, A., et al., The role of SMAD4 in early-onset colorectal cancer, Colorectal Dis., 2010, vol. 12, no. 3, pp. 213–219. https://doi.org/10.1111/j.1463-1318.2009.01779.x

    Article  CAS  PubMed  Google Scholar 

  15. Schwenter, F., Faughnan, M.E., Gradinger, A.B., et al., Juvenile polyposis, hereditary hemorrhagic telangiectasia, and early onset colorectal cancer in patients with SMAD4 mutation, J. Gastroenterol., 2012, vol. 47, pp. 795–804. https://doi.org/10.1007/s00535-012-0545-8

    Article  CAS  PubMed  Google Scholar 

  16. Shi, Y., Hata, A., Lo, R.S., et al., A structural basis for mutational inactivation of the tumour suppressor Smad4, Nature, 1997, vol. 388, pp. 87–93. https://doi.org/10.1038/40431

    Article  CAS  PubMed  Google Scholar 

  17. Venook, A.P., Right-sided vs left-sided colorectal cancer, Clin. Adv. Hematol. Oncol., 2017, vol. 15, pp. 22–24.

    PubMed  Google Scholar 

  18. Yang, G. and Yang, X., Smad4-mediated TGF-β signaling in tumorigenesis, Int. J. Biol. Sci., 2010, vol. 6, no. 1, pp. 1–8. https://doi.org/10.7150/ijbs.6.1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhao, M., Mishra, L., and Deng, C.X., The role of TGF-β/SMAD4 signaling in cancer, Int. J. Biol. Sci., 2018, vol. 14, pp. 111–123. https://doi.org/10.7150/ijbs.23230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by the grant 451-03-68/2020-14/200042 of the Ministry of Education, Science and Technological Development of the Republic of Serbia.

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Authors and Affiliations

  1. Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11010, Belgrade, Serbia

    Aleksandra Nikolic, Jovana Despotovic, Tamara Babic & Dragica Radojkovic

  2. Institute of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Belgrade, Serbia

    Jadranka Antic

  3. Center for Gastroenterology and Hepatology, University Clinical Center Zvezdara, Belgrade, Serbia

    Srdjan Markovic

  4. Faculty of Medicine, University of Belgrade, Belgrade, Serbia

    Zoran Krivokapic

  5. First Surgical Clinic, Clinical Center of Serbia, Belgrade, Serbia

    Zoran Krivokapic

  6. Serbian Academy of Sciences and Arts, Belgrade, Serbia

    Zoran Krivokapic

Authors
  1. Aleksandra Nikolic
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  2. Jovana Despotovic
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  3. Tamara Babic
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  4. Jadranka Antic
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  5. Srdjan Markovic
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  6. Zoran Krivokapic
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  7. Dragica Radojkovic
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Correspondence to Aleksandra Nikolic.

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Conflict of interest. The authors declare that they have no conflicts of interest.

Statement of compliance with standards of research involving humans as subjects. The study was conducted in compliance with principles of ethical research involving humans. The study was approved by the Ethics Committee of the Clinical Center of Serbia and cataloged under number 1856/6. Informed consent was obtained from all study subjects.

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Nikolic, A., Despotovic, J., Babic, T. et al. SMAD4 Gene Analysis in Patients with Early Onset Colorectal Cancer: A Pilot Study. Cytol. Genet. 56, 273–276 (2022). https://doi.org/10.3103/S0095452722030082

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  • DOI: https://doi.org/10.3103/S0095452722030082

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