Identification of Novel CD74-NRG2α Fusion From Comprehensive Profiling of Lung Adenocarcinoma in Japanese Never or Light Smokers

Abstract

Introduction: Studies are yet to characterize the differences in molecular profiles of lung adenocarcinoma (LUAD) among divergent ethnic groups. Herein, we conducted comprehensive molecular profiling of LUAD in never or light smokers from Asia to discover novel targetable mutations and prognostic biomarkers of this distinct disease entity. Methods: We analyzed 996 cases of Japanese LUAD and performed whole-exome sequencing and RNA-seq in 125 cases of Japanese LUAD negative for the driver oncogenes defined by conventional laboratory testing. We also investigated the clinical and pathologic characteristics among the 996 cases. Results: Driver oncogenes were identified in 88 cases (70.4%) with specific hotspot mutations differing from those in The Cancer Genome Atlas study. Two actionable novel fusions of FGFR2 and NRG2a were also identified. Clustering on the basis of mRNA expression profiles, but not genetic mutational ones, could predict patient prognosis. The risk score generated by the expression of a three-gene set was a strong prognostic marker for overall survival and progression-free survival in our cohort, and was further validated using The Cancer Genome Atlas cohort. Among the 996 cases, each driver alteration is distributed across all histologic subtypes. Adenocarcinoma in situ was identified to harbor driver mutations, suggesting that these alterations are early events in the pathogenesis of LUAD. ERBB2 mutations were over-represented in young adults. Conclusions: This study indicates the value of applying gene expression profiling for predicting the prognosis after a surgical operation, and that the identification of actionable mutations is important for optimizing targeted drugs in Japanese LUAD.

Histological characteristics of lung adenocarcinoma with uncommon actionable alterations: special emphasis on MET exon 14 skipping alterations

“…In addition to METex14 described above, EGFR , ALK/ROS1 and KRAS‐ altered adenocarcinomas frequently exhibited lepidic, acinar and mucinous histology, respectively, in agreement with previous studies 14‐16,29 . Additionally, ERBB2 ‐mutated LAD, which is over‐represented in young adults, 20 was associated with the micropapillary pattern. In contrast, distinct histological features were not detected in RET , BRAF and MAP2K1 ‐altered LAD, although both BRAF and MAP2K1 ‐mutated LAD frequently exhibited AIS or minimally invasive adenocarcinoma.…”

“…Our archives included data for 996 primary LADs from 920 patients, and comprised details on oncogene alterations such as mutant EGFR , KRAS , ERBB2 , BRAF , MAP2K1 or rearranged ALK , ROS1 , RET , NRG1 or METex14 (Figure ). We previously detected these alterations using the peptide nucleic acid‐locked nucleic acid polymerase chain reaction (PCR) clamp method, break‐apart fluorescence in‐situ hybridisation (FISH), whole‐exome sequencing and RNA sequencing; 20 among 996 LADs, 679 cases had mitogenic alterations. A case with CD74–NRG2 fusion was excluded in this study, and we examined the remaining 678 LADs.…”

Potential Unreliability of Uncommon ALK, ROS1, and RET Genomic Breakpoints in Predicting the Efficacy of Targeted Therapy in NSCLC

“…Thus, rare actionable alterations, such as NRG2 fusions, would be missed. 34 In addition, for common alterations, only "hotspot exons" were sequenced, and thus rare fusion variants involving ALK, ROS1, and RET may have been undetected. However, WTS can detect all coding regions to comprehensively explore known and unknown fusions, which may identify rare alterations that offer an optimal treatment option for patients with non-small cell lung neoplasm.…”

Melanoma with in-frame deletion of MAP2K1: a distinct molecular subtype of cutaneous melanoma mutually exclusive from BRAF, NRAS, and NF1 mutations

“…Some experimental models have investigated MEK inhibitors for MAP2K1 in-frame deletions [ 15 , 16 , 26 , 27 ]. Gao et al reported in vitro experiments where Classes 1 and 2 MAP2K1 mutants were effectively inhibited by allosteric MEK1 inhibitors, while Class 3 mutants, represented by in-frame deletions, were resistant [ 16 ].…”