TSitologiya i Genetika 2022, vol. 56, no. 3, 68-69
Cytology and Genetics 2022, vol. 56, no. 3, 273–276, doi: https://www.doi.org/10.3103/S0095452722030082

SMAD4 gene analysis in patients with early onset colorectal cancer: a pilot study

Nikolic A., Despotovic J., Babic T., Antic J., Markovic S., Krivokapic Z., Radojkovic D.

  1. Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444A, Belgrade, Serbia
  2. Institute of Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia, Dr Subotica 13, Belgrade, Serbia
  3. Center for Gastroenterology and Hepatology, University Clinical Center Zvezdara, Dimitrija Tucovica 161, Belgrade, Serbia
  4. Faculty of Medicine, University of Belgrade, Dr Subotica 8, Belgrade, Serbia
  5. First Surgical Clinic, Clinical Center of Serbia, Dr Koste Todorovica 6, Belgrade, Serbia
  6. Serbian Academy of Sciences and Arts, Knez Mihailova 35, Belgrade, Serbia

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 C­terminal domain. The aim of this study was to perform genetic analysis of SMAD4 C­terminal 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 C­terminal 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; (NM_005359.5: 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 47­years 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.

Keywords: colorectal cancer, early onset disease, genetic testing, pathogenic variant, SMAD4

TSitologiya i Genetika
2022, vol. 56, no. 3, 68-69

Current Issue
Cytology and Genetics
2022, vol. 56, no. 3, 273–276,
doi: 10.3103/S0095452722030082

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