Characteristics and Outcomes of Patients With Metastatic KRAS-Mutant Lung Adenocarcinomas: The Lung Cancer Mutation Consortium Experience

7589 Background: The Lung Cancer Mutation Consortium (LCMC) consisting of 14 US Cancer Centers was established to evaluate a panel of molecular mutations in advanced lung adenocarcinoma. ALK gene fusions and MET gene amplification were assessed by FISH in CLIA certified laboratories. Methods: Molecular tests were performed in stage IIIB or IV lung adenocarcinoma. To date, FISH assays have been completed in 901 patients for ALK (ALK break-apart, Abbott Molecular) and in 654 patients for MET (in house/Abbott Molecular reagents). ALK+ specimens were defined by split 3’ALK/5’ALK signals (gap >2 signal diameters) or single 3’ALK signals in >15% of tumor cells. MET gene amplification (MET+) was defined by ratio mean MET/mean CEP7 ≥2. Results: The ALK+ patient subset (N=75, 8.3%) compared to the ALK- had significantly lower age at diagnosis (52 vs. 60, p<0.001) and less frequent heavy smoking history (61% never-smokers among ALK+ vs. 31% among ALK-, p<0.001; pack-year for current/former smokers 17 vs. 40, p=0.003). Liver metastases were significantly more frequent among ALK+ than ALK- (23% vs.10%, p=0.004); no difference was detected in bone, brain and adrenal gland metastases. MET+ (N=29, 4.4%) was significantly associated with female sex (72% female among MET+ vs. 39% among MET-, p<0.001) and marginally more frequent in patients with adrenal metastasis; no difference was detected for age at diagnosis and smoking history. Follow-up on 73 ALK+ patients indicated that 56% received crizotinib as targeted therapy. Response was unknown in 8% and unreportable in 22% patients enrolled in ongoing randomized trials. Among patients with evaluable response, complete response, partial response, stable disease, and progressive disease were found respectively in 3%, 66%, 28%, and 3%. Conclusions: The LCMC successfully tested ALK and MET FISH in a large number of lung adenocarcinomas. It was demonstrated that directing positive patients to specific interventions is feasible, and that grouping of testing and trials within consortia may maximise relevant trial accrual in rare molecular subtypes. Supported by NCI-GO award. Submitted on behalf of the LCMC.

Download Full-text

MET IHC Is a Poor Screen for MET Amplification or MET Exon 14 Mutations in Lung Adenocarcinomas: Data from a Tri-Institutional Cohort of the Lung Cancer Mutation Consortium

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2019.06.009 ◽

2019 ◽

Vol 14 (9) ◽

pp. 1666-1671 ◽

Cited By ~ 18

Author(s):

Robin Guo ◽

Lynne D. Berry ◽

Dara L. Aisner ◽

Jamie Sheren ◽

Theresa Boyle ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Mutation ◽

Met Amplification ◽

Lung Adenocarcinomas

Download Full-text

HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium

Cancer ◽

10.1002/cncr.30869 ◽

2017 ◽

Vol 123 (21) ◽

pp. 4099-4105 ◽

Cited By ~ 43

Author(s):

Rathi N. Pillai ◽

Madhusmita Behera ◽

Lynne D. Berry ◽

Mike R. Rossi ◽

Mark G. Kris ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Mutation ◽

Lung Adenocarcinomas

Download Full-text

Faculty Opinions recommendation of RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725386175.793510338 ◽

2015 ◽

Author(s):

Elaine Mardis

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

Egfr Mutant ◽

Lung Adenocarcinomas

Download Full-text

Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation?

Neuro-Oncology ◽

10.1093/neuonc/nov043 ◽

2015 ◽

Vol 17 (7) ◽

pp. 1022-1028 ◽

Cited By ~ 21

Author(s):

Tony J. C. Wang ◽

Shumaila Saad ◽

Yasir H. Qureshi ◽

Ashish Jani ◽

Tavish Nanda ◽

...

Keyword(s):

Lung Cancer ◽

Targeted Therapy ◽

Brain Metastases ◽

Local Control ◽

Mutation Status ◽

Cancer Mutation

Download Full-text

Role of INSL4 Signaling in Sustaining the Growth and Viability of LKB1-Inactivated Lung Cancer

JNCI Journal of the National Cancer Institute ◽

10.1093/jnci/djy166 ◽

2018 ◽

Vol 111 (7) ◽

pp. 664-674 ◽

Cited By ~ 1

Author(s):

Rongqiang Yang ◽

Steven W Li ◽

Zirong Chen ◽

Xin Zhou ◽

Wei Ni ◽

...

Keyword(s):

Lung Cancer ◽

Transcriptome Profiling ◽

Cancer Genome ◽

The Cancer Genome Atlas ◽

Growth And Survival ◽

Cancer Genome Atlas ◽

Lung Adenocarcinomas ◽

Genome Atlas

Abstract Background The LKB1 tumor suppressor gene is commonly inactivated in non-small cell lung carcinomas (NSCLC), a major form of lung cancer. Targeted therapies for LKB1-inactivated lung cancer are currently unavailable. Identification of critical signaling components downstream of LKB1 inactivation has the potential to uncover rational therapeutic targets. Here we investigated the role of INSL4, a member of the insulin/IGF/relaxin superfamily, in LKB1-inactivated NSCLCs. Methods INSL4 expression was analyzed using global transcriptome profiling, quantitative reverse transcription PCR, western blotting, enzyme-linked immunosorbent assay, and RNA in situ hybridization in human NSCLC cell lines and tumor specimens. INSL4 gene expression and clinical data from The Cancer Genome Atlas lung adenocarcinomas (n = 515) were analyzed using log-rank and Fisher exact tests. INSL4 functions were studied using short hairpin RNA (shRNA) knockdown, overexpression, transcriptome profiling, cell growth, and survival assays in vitro and in vivo. All statistical tests were two-sided. Results INSL4 was identified as a novel downstream target of LKB1 deficiency and its expression was induced through aberrant CRTC-CREB activation. INSL4 was highly induced in LKB1-deficient NSCLC cells (up to 543-fold) and 9 of 41 primary tumors, although undetectable in all normal tissues except the placenta. Lung adenocarcinomas from The Cancer Genome Atlas with high and low INSL4 expression (with the top 10th percentile as cutoff) showed statistically significant differences for advanced tumor stage (P < .001), lymph node metastasis (P = .001), and tumor size (P = .01). The INSL4-high group showed worse survival than the INSL4-low group (P < .001). Sustained INSL4 expression was required for the growth and viability of LKB1-inactivated NSCLC cells in vitro and in a mouse xenograft model (n = 5 mice per group). Expression profiling revealed INSL4 as a critical regulator of cell cycle, growth, and survival. Conclusions LKB1 deficiency induces an autocrine INSL4 signaling that critically supports the growth and survival of lung cancer cells. Therefore, aberrant INSL4 signaling is a promising therapeutic target for LKB1-deficient lung cancers.

Download Full-text

Aberrant Fucosylation of Saliva Glycoprotein Defining Lung Adenocarcinomas Malignancy

10.1101/2021.12.16.472888 ◽

2021 ◽

Author(s):

Shuang Yang ◽

Ziyuan Gao ◽

Zhen Wu ◽

Ying Han ◽

Xumin Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Early Diagnosis ◽

Lung Adenocarcinoma ◽

Tumor Progression ◽

Cancer Patients ◽

Solid Phase ◽

Clinical Specimens ◽

Aberrant Glycosylation ◽

Lung Adenocarcinomas ◽

Core Fucosylation

Aberrant glycosylation is a hallmark of cancer found during tumorigenesis and tumor progression. Lung cancer induced by oncogene mutations has been detected in the patient's saliva, and saliva glycosylation has been altered. Saliva contains highly glycosylated glycoproteins, the characteristics of which may be related to various diseases. Therefore, elucidating cancer-specific glycosylation in the saliva of healthy, non-cancer, and cancer patients can reveal whether tumor glycosylation has unique characteristics for early diagnosis. In this work, we used a solid-phase chemoenzymatic method to study the glycosylation of saliva glycoproteins in clinical specimens. The results showed that the alpha1,6-core fucosylation of glycoproteins in cancer patients was significant increased. The fucosylation of alpha1,2 or alpha1,3 is also increased in cancer patients. We further analyzed the expression of fucosyltransferases responsible for alpha1,2, alpha1,3, alpha1,6 fucosylation. The fucosylation of the saliva of cancer patients is drastically different from that of non-cancer or health controls. These results indicate that the glycoform of saliva fucosylation distinguishes lung cancer from other diseases, and this feature has the potential to diagnose lung adenocarcinoma.

Download Full-text

Competing endogenous RNA (ceRNA) hypothetic model based on comprehensive analysis of long non-coding RNA expression in lung adenocarcinoma

PeerJ ◽

10.7717/peerj.8024 ◽

2019 ◽

Vol 7 ◽

pp. e8024 ◽

Cited By ~ 5

Author(s):

Xiwen Wang ◽

Rui Su ◽

Qiqiang Guo ◽

Jia Liu ◽

Banlai Ruan ◽

...

Keyword(s):

Lung Cancer ◽

Inverse Correlation ◽

The Cancer Genome Atlas ◽

Competing Endogenous Rna ◽

Cerna Network ◽

Kaplan Meier ◽

Non Coding Rna ◽

Pathway Analyses ◽

Lung Adenocarcinomas ◽

Cancer Tissues

Background Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer with high malignancy and bad prognosis, consisted of lung adenocarcinomas (LUAD) and lung squamous cell carcinomas (LUSC) chiefly. Multiple studies have indicated that competing endogenous RNA (ceRNA) network centered long noncoding RNAs (lncRNAs) can regulate gene expression and the progression of various cancers. However, the research about lncRNAs-mediated ceRNA network in LUAD is still lacking. Methods In this study, we analyzed the RNA-seq database from The Cancer Genome Atlas (TCGA) and obtained dysregulated lncRNAs in NSCLC, then further identified survival associated lncRNAs through Kaplan–Meier analysis. Quantitative real time PCR (qRT-PCR) was performed to confirm their expression in LUAD tissues and cell lines. The ceRNA networks were constructed based on DIANA-TarBase and TargetScan databases and visualized with OmicShare tools. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to investigate the potential function of ceRNA networks. Results In total, 1,437 and 1,699 lncRNAs were found to be up-regulated in LUAD and LUSC respectively with 895 lncRNAs overlapping (|log2FC| > 3, adjusted P value <0.01). Among which, 222 lncRNAs and 46 lncRNAs were associated with the overall survival (OS) of LUAD and LUSC, and 18 out of 222 up-regulated lncRNAs were found to have inverse correlation with LUAD patients’ OS (|log2FC| > 3, adjusted P value < 0.02). We selected 3 lncRNAs (CASC8, LINC01842 and VPS9D1-AS1) out of these 18 lncRNAs and confirmed their overexpression in lung cancer tissues and cells. CeRNA networks were further constructed centered CASC8, LINC01842 and VPS9D1-AS1 with 3 miRNAs and 100 mRNAs included respectively. Conclusion Through comprehensively analyses of TCGA, our study identified specific lncRNAs as candidate diagnostic and prognostic biomarkers for LUAD. The novel ceRNA network we created provided more insights into the regulatory mechanisms underlying LUAD.

Download Full-text