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

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.