Exploration of the Effects of Methylation of N6 Adenosine (m6A) Related lncRNA on Prognosis and Treatment in “Driver-Gene-Negative” Lung Adenocarcinoma (LUAD)

Abstract Background: Few oncogenic drivers of long noncoding RNAs (lncRNAs) have been identified and investigated. Identifying noncoding drivers provides potential strategies for novel interventions in lung adenocarcinoma (LUAD). Methods: We constructed a machine learning model for driver gene annotation using pan-cancer and clinical prognosis data from OncoKB and TCGA to predict potential oncogenic drivers of lncRNAs; then, we used zebrafish models to validate the biological function of candidate targets. The full length of FAM83H-AS1 was obtained by rapid amplification of the cDNA ends (RACE) assay. RNA pull-down, RNA immunoprecipitation (RIP), quantative mass spectrometry (QMS) and RNA sequencing (RNA-Seq) assays were utilized to explore the potential mechanisms. Additionally, we used CRISPR interference (CRISPRi) system and patient-derived tumor xenograft (PDTX) model to evaluate the therapeutic potential of targeting FAM83H-AS1 in vivo.Results: The results suggested that FAM83H-AS1 was a potential oncogenic driver from the chromosome 8q24 amplicon; increases in the expression of FAM83H-AS1 resulted in poor prognosis for LUAD patients both in JSCH and TCGA cohorts. Functional assays revealed that FAM83H-AS1 promotes malignant progression and inhibits apoptosis. Mechanistically, FAM83H-AS1 binds with HNRNPK to enhance the translation of oncogenes RAB8B and RAB14. Experiments using CRISPR interference (CRISPRi)-mediated xenografts and patient-derived tumor xenograft (PDTX) models indicated that targeting FAM83H-AS1 inhibited LUAD progression in vivo. Conclusions: Our work demonstrated that FAM83H-AS1 is a potential oncogenic driver that inhibits LUAD-mediated apoptosis via the FAM83H-AS1-HNRNPK-RAB8B/RAB14 axis. Importantly, we suggest targeting of FAM83H-AS1 as a potential therapeutic strategy for LUAD.

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Lung adenocarcinoma patient progression with gastrointestinal metastasis response to subsequent tyrosine kinase inhibitors (TKIs) from re-biopsy of new occurring driver gene mutation

Journal of Thoracic Disease ◽

10.21037/jtd.2018.07.97 ◽

2018 ◽

Vol 10 (8) ◽

pp. E605-E611

Author(s):

Chunhua Zhou ◽

Binjie Yan ◽

Liang Zeng ◽

Yi Xiong ◽

Li Liu ◽

...

Keyword(s):

Tyrosine Kinase ◽

Lung Adenocarcinoma ◽

Tyrosine Kinase Inhibitors ◽

Gene Mutation ◽

Kinase Inhibitors ◽

Driver Gene ◽

Gastrointestinal Metastasis ◽

Lung Adenocarcinoma Patient

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P2.01-08 Conversion Surgery for Locally Advanced Lung Adenocarcinoma Harboring Driver Gene Mutation After TKI Followed by Cytotoxic Agent

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2018.08.1062 ◽

2018 ◽

Vol 13 (10) ◽

pp. S667-S668

Author(s):

M. Aoki ◽

T. Umehara ◽

G. Kamimura ◽

T. Tokunaga ◽

T. Nagata ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Gene Mutation ◽

Locally Advanced ◽

Cytotoxic Agent ◽

Driver Gene ◽

Conversion Surgery

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The utility of the proposed IASLC/ATS/ERS lung adenocarcinoma subtypes for disease prognosis and correlation of driver gene alterations

Lung Cancer ◽

10.1016/j.lungcan.2013.06.012 ◽

2013 ◽

Vol 81 (3) ◽

pp. 371-376 ◽

Cited By ~ 125

Author(s):

Koji Tsuta ◽

Mitsumasa Kawago ◽

Eisuke Inoue ◽

Akihiko Yoshida ◽

Fumiaki Takahashi ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Driver Gene ◽

Disease Prognosis ◽

Gene Alterations

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Prognostic Significance of Gene Signature of Tertiary Lymphoid Structures in Patients With Lung Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.693234 ◽

2021 ◽

Vol 11 ◽

Author(s):

Hong Feng ◽

Fujun Yang ◽

Lihong Qiao ◽

Kai Zhou ◽

Junfei Wang ◽

...

Keyword(s):

Overall Survival ◽

Lung Adenocarcinoma ◽

Immune Cell ◽

Prognostic Significance ◽

Gene Signature ◽

Driver Gene ◽

Immune Microenvironment ◽

High Group ◽

Tertiary Lymphoid Structures ◽

Lymphoid Structures

BackgroundLung adenocarcinoma (LUAD) is a highly mortal cancer. Tertiary lymphoid structures (TLS) are ectopic lymphoid organs with similar morphological and molecular characters to secondary lymphoid organ. The aim of this study is to investigate the prognostic effect of a gene signature associated with TLSs, including B-cell-specific genes.MethodsClinical data of 515 LUAD patients in the TGCA cohort were used to examine the relationship of TLS signature with immune microenvironment, tumor mutational burden (TMB), and driver gene mutations. Patients were divided into the TLS signature high group and TLS signature low group, and comparative analysis of survival and its influencing factors between the two groups was performed. The resulting data were then validated in the GSE37745 cohort.ResultsTLS signature high group had significantly better overall survival (OS) and progression-free interval (PFI) as well as significantly higher infiltration of immune cell subsets, cancer immune cycle (CIC) signature except for immunogram score2 (IGS2), and expression of major checkpoint genes than the TLS signature low group. Notably, while TLS signature was not markedly associated with TMB and mutation frequencies of driver genes, there were significant differences in overall survival of patients with given mutation status of EGFR, KRAS, BRAF and TP53 genes between the TLS signature high and low groups.ConclusionThis study provided evidence that LUAD patients with high TLS signature had a favorable immune microenvironment and better prognosis, suggesting that TLS signature is an independent positive prognostic factor for LUAD patients.

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Clinical analysis of anlotinib as first-line treatment for elderly patients with advanced lung adenocarcinoma without driver gene mutations

Anti-Cancer Drugs ◽

10.1097/cad.0000000000001186 ◽

2021 ◽

Vol Publish Ahead of Print ◽

Author(s):

Jinxiu Zhu ◽

Qiang Xie ◽

Aihong Zhong ◽

Yuyin Le

Keyword(s):

Elderly Patients ◽

Lung Adenocarcinoma ◽

Gene Mutations ◽

Clinical Analysis ◽

Driver Gene ◽

Line Treatment ◽

First Line ◽

First Line Treatment

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Driver gene alterations in lung adenocarcinoma: Demographic features of 2544 Chinese cases

The International Journal of Biological Markers ◽

10.1177/1724600820967015 ◽

2020 ◽

Vol 35 (4) ◽

pp. 44-50

Author(s):

Mingming Hu ◽

Tongmei Zhang ◽

Yuan Yang ◽

Nanying Che ◽

Jie Li ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Egfr Mutation ◽

Age Groups ◽

Growth Factor Receptor ◽

Distinct Group ◽

Egfr Mutations ◽

Driver Gene ◽

Driver Genes ◽

Anaplastic Lymphoma ◽

Arms Pcr

Background: To understand the association between driver gene variations and age and gender in patients with lung adenocarcinoma, we investigated mutations of the three most important driver genes—epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) fusion genes and c-ros oncogene 1 (ROS1)—in this retrospective cohort study. Methods: Patients newly diagnosed with lung adenocarcinoma who received EGFR and ALK/ROS1 gene tests at our hospital from September 2014 to May 2019 were enrolled. EGFR mutations and ROS1 fusions were examined by ARMS-PCR and ALK fusions by Ventana-D5F3 IHC assay and ARMS-PCR. Results: Of 2544 eligible subjects, 2539 accomplished EGFR mutation tests. The prevalence of EGFR mutations was 62.1% in females, higher than that of 45.1% in males. In females, the EGFR mutation rate remained relatively stable at 60%–65% across the six age groups. Females showed an increased distribution of EGFR L858R and a decreased distribution of exon 19 deletion (19Del) by age. The incidence of ALK/ROS-1 rearrangements decreased significantly with age. Conclusions: EGFR 19Del mutation is more prevalent in younger males and females, while L858R mutation is prevalent in older females. Both ALK and ROS1 rearrangements are more common in younger lung adenocarcinoma. The young lung adenocarcinoma population is a distinct group rich in targetable genomic alterations, and more research is needed to understand the mechanism.

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