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

Authors :
Brian Houck-Loomis
Joshua K. Sabari
Ryma Benayed
Laetitia Borsu
Kyuichi Kadota
Helen Won
Prasad S. Adusumilli
Alison M. Schram
Maria E. Arcila
Jason C. Chang
Vasilisa A. Rudneva
Natasha Rekhtman
Sarah Teed
Valerie W. Rusch
Christina Falcon
Khedoudja Nafa
Marc Ladanyi
Patrice Desmeules
Michael Offin
Fanli Meng
Bob T. Li
William D. Travis
Alexander Drilon
David N Brown
Sharon Amir
Joseph Montecalvo
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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Clin Cancer Res
Accession number :
edsair.doi.dedup.....ad052c7f9ffadb045d00d009287605df