TY - JOUR AU - Kožik, Bojana R. AU - Krajnović, Milena M. AU - Kokanov, Nikola S. AU - Jovanović-Ćupić, Snežana P. AU - Božović, Ana M. AU - Todorović, Lidija B. AU - Mandušić, Vesna Lj. PY - 2022/06/27 Y2 - 2024/03/29 TI - Combined analysis of KRAS mutation and p16INK4a and p14ARF methylation status in locally advanced rectal carcinoma treated with preoperative chemoradiotherapy JF - Archives of Biological Sciences JA - Arch Biol Sci VL - 74 IS - 2 SE - Articles DO - 10.2298/ABS220222011K UR - https://www.serbiosoc.org.rs/arch/index.php/abs/article/view/7519 SP - 127-134 AB - <p><strong>Paper description:</strong></p><ul><li>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.</li><li>We propose a model of simultaneous analysis of <em>KRAS</em> gene mutation status and <em>p16<sup>INK4a</sup></em> and <em>p14<sup>ARF</sup></em> gene promoter methylation status in pre-treatment tumor biopsies.</li><li>The simultaneous presence of <em>p14<sup>ARF</sup></em> methylation and <em>KRAS</em> mutation was associated with more aggressive tumor behavior. The concurrent presence of alterations in all three examined genes was associated with shorter overall survival.</li><li>Combined analysis of examined gene alterations revealed patient subgroups with a distinct pattern of tumor response and disease outcome.</li></ul><p><strong>Abstract: </strong>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, <em>KRAS</em> mutation status was analyzed by direct sequencing, while methylation-specific polymerase chain reaction (MSP) was used to examine <em>p16<sup>INK4a</sup></em> and <em>p14<sup>ARF</sup></em> gene methylation status in pretreatment tumor biopsies of 60 patients with LARC. The examined molecular changes of <em>KRAS</em>,<em> p16<sup>INK4a</sup></em> and <em>p14<sup>ARF</sup></em> genes were mutually independent (<em>p16<sup>INK4a</sup></em>/<em>KRAS</em>, P=0.272; <em>p14<sup>ARF</sup></em>/<em>KRAS</em>, P=0.923; <em>p16<sup>INK4a</sup></em>/<em>p14<sup>ARF</sup></em>, P=0.715). However, the simultaneous presence of <em>p14<sup>ARF</sup></em> methylation and <em>KRAS</em> mutation was associated with a more frequent appearance of local recurrences and distant metastasis (P=0.027). Moreover, patients with the simultaneous presence of <em>p16<sup>INK4a</sup></em> and <em>p14<sup>ARF</sup></em> methylation and <em>KRAS</em> 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.</p> ER -