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Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes
- Source :
- Clin Cancer Res
- Publication Year :
- 2021
-
Abstract
- Purpose:Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. 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.Experimental Design:A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping (n = 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).Results:Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion (F11R–NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (P < 0.0001).Conclusions: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 NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.
- Subjects :
- 0301 basic medicine
Adult
Male
Cancer Research
Lung Neoplasms
medicine.medical_treatment
Biology
medicine.disease_cause
Mutually exclusive events
Article
Targeted therapy
03 medical and health sciences
0302 clinical medicine
medicine
Humans
Neoplasm Invasiveness
Gene
Genotyping
Aged
Aged, 80 and over
High prevalence
Middle Aged
medicine.disease
Adenocarcinoma, Mucinous
Mucinous Adenocarcinomas
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Mutation
Cancer research
Adenocarcinoma
Female
KRAS
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Clin Cancer Res
- Accession number :
- edsair.doi.dedup.....ad052c7f9ffadb045d00d009287605df