Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung

Abstract

Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations.Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases).Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P ¼ 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%).Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/ mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies.

Disparity in clinical outcomes between pure and combined pulmonary large-cell neuroendocrine carcinoma: A multi-center retrospective study

“…However, further studies that take these variables into account need to be undertaken. Regarding combined LCNEC, Miyoshi et al also performed targeted NGS in 10 cases of combined LCNEC, and found that the median concordance rate of candidate somatic mutations between the two components was 71 % [11]. Interestingly, five of 10 cases of LCNEC combined with NSCLC harbored driver gene alterations, all of which were shared between the two components.…”

“…In practice, it is very common for LCNEC to occur in combination with components of other lung cancers, such as SCLC, adenocarcinoma, and squamous cell carcinoma [11]. The failure to consider any of the individual components during pathological diagnosis may result in the choice of a systemic therapy that allows resistance and recurrence to develop [12].…”

Reciprocal expression of INSM1 and YAP1 defines subgroups in small cell lung cancer

“…Compared to other cancers, particularly breast and NSCLC, the use of ‘omics’ to identify subgroups in SCLC is in its infancy. Several whole exome sequencing (WES) studies and one whole genome sequencing (WGS) study on SCLC [ 14 , 15 , 20 - 22 ] are beginning to provide insight into the biology of this disease. Subgroup stratification in SCLC is hindered, however, by the wide heterogeneity and low frequency ( < 10%) of most genes mutated in SCLC beyond the two which define this cancer, TP53 and RB1 .…”

TRP53 Mutants Drive Neuroendocrine Lung Cancer Through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response

“…PTEN mutations and/or loss are detected in 4–9% of human SCLC and LCNEC (6, 36, 43, 44). Loss of PTEN expression in 55% of murine SCLC despite expression in precursor lesions suggests that PTEN loss promotes SCLC progression (28, 29).…”