TP53 co-mutations in advanced lung adenocarcinoma: comparative bioinformatic analyses suggest ambivalent character on overall survival alongside KRAS, STK11 and KEAP1 mutations
Armin Frille, Myriam Boeschen, Hubert Wirtz, Mathias Stiller, Hendrik Bläker, Maximilian von Laffert
Abstract
Background Recently, we could show that the co-mutations of KRAS + KEAP1 , STK11 + KEAP1 and KRAS + STK11 + KEAP1 lead to a significantly shorter median overall survival (mOS) in patients with lung cancer across treatments by analyzing multiple dataset. TP53 , 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. Methods We present a comparative bioinformatic analysis and refer to data of 4,109 patients with lung adenocarcinoma (LUAD). Results Most of the mutations within the LUAD belong to TP53 -only (29.0%), quadruple-negative (25.9%) and KRAS -only (13.4%). Whereas TP53-mutations seem to have protective effects in the context of further KEAP1 - and KRAS + KEAP1 -alterations (improved mOS), their role seems contrary if acquired in an already existing combination of mutations as KRAS + STK11 , KRAS + STK11 + KEAP1 and STK11 + KEAP1 . TP53 co-mutations had a negative influence on KRAS -only mutated LUAD (mOS reduced significantly by more than 30%). Discussion These data underline the need for complex mutational testing to estimate prognosis more accurately in patients with advanced LUAD.