®ecent years have witnessed a dramatic expansion in our knowledge of the genetic diversity of non–small-cell lung cancer (NSCLC), and in particular adenocarcinoma. This appreciation of the genetic landscape of the disease has resulted in the development of targeted therapies that are directed to ward activated oncogenes. Several of these drugs have been approved for use in patients and many more are being investigated in clinical trials. However, there have been only been limited studies that have focused on histologic subtypes within NSCLC and more complete analyses of these specific disease entities are needed. In this issue of the Journal of Thoracic Oncology, Shim et al. explore the genomic alterations and clinical characteristics associated with invasive mucinous adenocarcinoma, a relatively rare histologic subtype of NSCLC. In confirmation of previous studies that have examined the genetic basis of this disease, the authors observed a high rate of KRAS mutation (63%). 1 Interestingly, while the G12C variant is the most prevalent KRAS alteration in lung adenocarcinoma as a whole, G12D and G12V accounted for the majority (73%) of KRAS mutations in this cohort of mucinous adenocarcinomas, with G12C making up only 11%. The authors then examined cases lacking KRAS mutation in more detail using two targeted deep sequencing approaches. In one, the RNA component of extracted total nucleic acid was evaluated for gene rearrangements. They observed that nine of the KRAS wild-type cases were positive for rearrangements involving genes that have previously been found to be involved in fusions that create oncogenic chimeric proteins. As has been seen in other studies examining mucinous adenocarcinoma, rearrangements involving the ERBB family ligand NRG1 were particularly prevalent. 2–4 By examining genomic DNA by deep sequencing using a separate targeted approach, well-characterized activating mutations in ERBB2, BRAF, a PIK3CA were detected in four of the KRAS wild-type cases. Notably, these oncogenic alterations all occurred independently of each other. However, since the deep sequencing approaches were only applied to the initial KRAS wild-type cohort, the exclusivity between these activated oncogenes requires further analysis. Nevertheless, when taking the initial KRAS mutant cohort into account, the majority (81%) of examined cases in the entire cohort were found to be positive for an activated oncogene. Remarkably, mutations in the tumor suppressor gene TP53, which occur in approximately 50% of lung adenocarcinomas and commonly overlap with activating oncogenic alterations, were rare in this cohort of mucinous adenocarcinomas, occurring in only two of 50 evaluated cases. The authors expanded on this finding by querying publicly available TCGA lung adenocarcinoma data and found only one TP53 mutated case out of 12 mucinous tumors. In the TCGA dataset, the low rate of TP53 mutation correlated with a low mutational burden in mucinous versus nonmucinous tumors. While smoking status alone correlated with mutational burden in adenocarcinoma as a whole, multivariate analysis suggested that TP53 status likely contributed to low mutational burden in mucinous tumors but that smoking status did