Combined analysis of KRAS mutation and p16INK4a and p14ARF methylation status in locally advanced rectal carcinoma treated with preoperative chemoradiotherapy

Authors

  • Bojana R. Kožik Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade 11000, Serbia https://orcid.org/0000-0002-2983-4151
  • Milena M. Krajnović Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade 11000, Serbia https://orcid.org/0000-0001-5638-2042
  • Nikola S. Kokanov Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade 11000, Serbia https://orcid.org/0000-0002-2380-2028
  • Snežana P. Jovanović-Ćupić Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade 11000, Serbia https://orcid.org/0000-0002-3389-7278
  • Ana M. Božović Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade 11000, Serbia https://orcid.org/0000-0002-6487-6365
  • Lidija B. Todorović Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade 11000, Serbia https://orcid.org/0000-0003-0672-0693
  • Vesna Lj. Mandušić Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, Laboratory for Radiobiology and Molecular Genetics, University of Belgrade, Mike Petrovića Alasa 12-14, Belgrade 11000, Serbia https://orcid.org/0000-0002-2221-3707

DOI:

https://doi.org/10.2298/ABS220222011K

Keywords:

Rectal carcinoma; KRAS; p16INK4a; p14ARF; biomarkers

Abstract

Paper description:

  • Patient responses to standard treatment of advanced stages of rectal carcinoma are variable, which emphasizes the need to define reliable predictive and prognostic molecular parameters.
  • We propose a model of simultaneous analysis of KRAS gene mutation status and p16INK4a and p14ARF gene promoter methylation status in pre-treatment tumor biopsies.
  • The simultaneous presence of p14ARF methylation and KRAS mutation was associated with more aggressive tumor behavior. The concurrent presence of alterations in all three examined genes was associated with shorter overall survival.
  • Combined analysis of examined gene alterations revealed patient subgroups with a distinct pattern of tumor response and disease outcome.

Abstract: Current management of locally advanced rectal carcinoma (LARC) involves preoperative chemoradiotherapy (preCRT) before surgery. Despite improved local control rate, the response to preCRT of individual patients is variable and may reflect heterogeneous biological properties among tumors of the same clinical stage. Identifying novel molecular parameters with predictive and/or prognostic value is of great clinical importance for a personalized therapeutic approach. In this study, KRAS mutation status was analyzed by direct sequencing, while methylation-specific polymerase chain reaction (MSP) was used to examine p16INK4a and p14ARF gene methylation status in pretreatment tumor biopsies of 60 patients with LARC. The examined molecular changes of KRAS, p16INK4a and p14ARF genes were mutually independent (p16INK4a/KRAS, P=0.272; p14ARF/KRAS, P=0.923; p16INK4a/p14ARF, P=0.715). However, the simultaneous presence of p14ARF methylation and KRAS mutation was associated with a more frequent appearance of local recurrences and distant metastasis (P=0.027). Moreover, patients with the simultaneous presence of p16INK4a and p14ARF methylation and KRAS mutation had significantly shorter overall survival (P=0.011). The obtained results strongly suggest that combined analyses of examined genetic and epigenetic molecular alterations could contribute to the identification of LARC patient subgroups with more aggressive tumor behavior and worse disease outcome.

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Published

2022-06-27

How to Cite

1.
Kožik BR, Krajnović MM, Kokanov NS, Jovanović-Ćupić SP, Božović AM, Todorović LB, Mandušić VL. Combined analysis of KRAS mutation and p16INK4a and p14ARF methylation status in locally advanced rectal carcinoma treated with preoperative chemoradiotherapy. Arch Biol Sci [Internet]. 2022Jun.27 [cited 2022Aug.9];74(2):127-34. Available from: https://www.serbiosoc.org.rs/arch/index.php/abs/article/view/7519

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