Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes.

Abstract

Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent <i>KRAS</i> mutations or specific gene fusions, most commonly involving <i>NRG1</i>. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically. A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; <i>n</i> = 136) or hotspot 8-oncogene genotyping (<i>n</i> = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS). Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including <i>KRAS</i> mutations (76%), <i>NRG1</i> fusions (7%), <i>ERBB2</i> alterations (6%), and other less common events. In addition, WTS identified a novel <i>NRG2</i> fusion (<i>F11R</i>-<i>NRG2</i>). Overall, targetable gene fusions were identified in 51% of <i>KRAS</i> wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with <i>KRAS</i>-mutant IMAs, <i>NRG1</i>-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (<i>P</i> < 0.0001). This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of <i>NRG1</i>-rearranged IMAs, <i>ERBB2</i> as the third most common alteration, and a novel <i>NRG2</i> fusion in these tumors. Comprehensive molecular testing of <i>KRAS</i> wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.