AUTHOR=Frille Armin , Boeschen Myriam , Wirtz Hubert , Stiller Mathias , Bläker Hendrik , von Laffert Maximilian 

TITLE=TP53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside KRAS, STK11 and KEAP1 mutations

JOURNAL=Frontiers in Oncology

VOLUME=14

YEAR=2024

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1357583

DOI=10.3389/fonc.2024.1357583

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Recently, we could show that the co-mutations of <italic>KRAS</italic> + <italic>KEAP1</italic>, <italic>STK11</italic> + <italic>KEAP1</italic> and <italic>KRAS</italic> + <italic>STK11</italic> + <italic>KEAP1</italic> lead to a significantly shorter median overall survival (mOS) in patients with lung cancer across treatments by analyzing multiple dataset. <italic>TP53</italic>, a tumor suppressor gene, plays a crucial role in regulating cell cycle progression. Its mutations occur in approximately 40-50% of non-small lung cancer (NSCLC). Co-occurrence of all four mentioned mutations has been a matter of debate for years. The aim of this study was to assess the distribution of these four mutations and the influence of the different co-mutational patterns on survival.</p></sec><sec><title>Methods</title><p>We present a comparative bioinformatic analysis and refer to data of 4,109 patients with lung adenocarcinoma (LUAD).</p></sec><sec><title>Results</title><p>Most of the mutations within the LUAD belong to <italic>TP53</italic>-only (29.0%), quadruple-negative (25.9%) and <italic>KRAS</italic>-only (13.4%). Whereas TP53-mutations seem to have protective effects in the context of further <italic>KEAP1</italic>- and <italic>KRAS</italic> + <italic>KEAP1</italic>-alterations (improved mOS), their role seems contrary if acquired in an already existing combination of mutations as <italic>KRAS</italic> + <italic>STK11</italic>, <italic>KRAS</italic> + <italic>STK11</italic> + <italic>KEAP1</italic> and <italic>STK11</italic> + <italic>KEAP1</italic>. <italic>TP53</italic> co-mutations had a negative influence on <italic>KRAS</italic>-only mutated LUAD (mOS reduced significantly by more than 30%).</p></sec><sec><title>Discussion</title><p>These data underline the need for complex mutational testing to estimate prognosis more accurately in patients with advanced LUAD.</p></sec>