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Pulmonary adenocarcinoma (ADC) is a very diverse disease, both genetically and histologically, which displays extensive intratumor heterogeneity with numerous acquired mutations. ADC is the most common type of lung cancer and is believed to arise from adenocarcinoma in situ (AIS) which then progresses to minimally invasive adenocarcinoma (MIA). In patients of European ethnicity, we analyzed genetic mutations in AIS (<i>n</i> = 10) and MIA (<i>n</i> = 18) and compared the number of genetic mutations with advanced ADC (<i>n</i> = 2419). Using next-generation sequencing, the number of different mutations detected in both AIS (87.5%) and MIA (94.5%) were higher (<i>p</i> < 0.001) than in advanced ADC (53.7%). In contrast to the high number of mutations in Kirsten rat sarcoma virus gene (<i>KRAS</i>) in advanced ADC (34.6%), there was only one case of AIS with <i>KRAS</i> G12C mutation (3.5%; <i>p</i> < 0.001) and no cases of MIA with <i>KRAS</i> mutation (<i>p</i> < 0.001). In contrast to the modest prevalence of epidermal growth factor receptor (<i>EGFR</i>) mutations in advanced ADC (15.0%), the fraction of <i>EGFR</i> mutant cases was higher in both in AIS (22.2%) and MIA (59.5%; <i>p</i> < 0.001). The <i>EGFR</i> exon 19 deletion mutation was more common in both MIA (50%; <i>n</i> = 6/12) and ADC (41%; <i>n</i> = 149/363), whereas p.L858R was more prevalent in AIS (75%; <i>n</i> = 3/4). In contrast to pulmonary advanced ADC, <i>KRAS</i> driver mutations are less common, whereas mutations in <i>EGFR</i> are more common, in detectable AIS and MIA.