Beschreibung:
<jats:p>Lung adenocarcinoma (LUAD) is the most common cause of global cancer‐related mortality and the major risk factor is smoking consumption. By analyzing 486 LUAD samples from The Cancer Genome Atlas, we detected a higher mutational burden among younger patients in the global cohort as well as in the <jats:italic>TP53‐</jats:italic>mutated subcohort. The interaction effect of patient age and <jats:italic>TP53</jats:italic> mutations significantly affected the mutational rate of younger <jats:italic>TP53</jats:italic>‐mutated patients. Furthermore, we detected a significant enrichment of the smoking‐related signature SI4 (SI4) among younger <jats:italic>TP53</jats:italic>‐mutated patients, meanwhile the age‐related Signature 1 (SI1) significantly increased in proportion to patient age. Although present and past smoking is reported in the <jats:italic>TP53</jats:italic> wild‐type patients, we observed a lower average number of somatic mutations, with no correlation with patient age. Overall, <jats:italic>TP53</jats:italic> mutations were significantly higher in younger patients and mainly characterized by SI4 and Signature 24 (SI24). Therefore, <jats:italic>TP53</jats:italic> seemed to acquire a particular sensitivity to smoking related C>A mutations in younger patients. We hypothesize that <jats:italic>TP53</jats:italic> mutations at a younger age might be a crucial factor enhancing the sensitivity to smoking‐related mutations leading to a burst of somatic alterations. The mutational profile of cancer cell might reflect the mutational processes operative in aging in a given tissue. Therefore, <jats:italic>TP53</jats:italic>‐mutated and <jats:italic>TP53</jats:italic> wild‐type patient groups might represent phenotypes which endure aging‐related mutational processes with different strength. Our study provides indications of age‐dependent differences in mutational backgrounds that might be relevant for cancer prevention and age‐adjusted treatment approaches.</jats:p>