Genomic Mutations of Primary and Metastatic Lung Adenocarcinoma in Chinese Patients

Lung cancer is still the leading cause of cancer-related death worldwide. Of lung cancer, lung adenocarcinoma (LUAD) is the most common subtype. Most patients with LUAD would develop into metastasis, which limits the available treatment. Targeted therapy and immunotherapy provided options for those advanced patients. But they also broached up challenges to identify the appropriate patients. This study aims to reveal the landscapes of genomic mutations in primary and metastatic LUAD and their actionability. This study enrolled 636 patients with LUAD, of whom 85 and 551 were from patients with and without metastasis, respectively. Next-generation sequencing technology was used to retrieve their genomic information. Genomic mutations including short nucleotide variation, long variation, copy number variations, and fusions were called. The corresponding actionability was revealed. A comparison of genomic mutations and actionability between primary and metastatic LUAD was performed. In primary tumors, BRCA2 and FAT3 were significantly mutated in older patients; while in metastases, ALK and NOTCH2 were significantly mutated in younger patients. Primary tumors in male patients were significantly mutated in LRP1B and KRAS. Compared to primary tumors, metastases harbored less short nucleotide variations but more copy number variations and fusions. In metastases, chromosome 1 and chromosome 9 had less short nucleotide variations and more CNV than in primary tumors. Genomic variations of activated dendritic cells were more frequently mutated in metastases. EGFR genomic variations were negatively associated with PD-L1 and TMB. Patients with EGFR inhibitor treatment tend to have lower PD-L1 expression. The revealed discrepancy between primary and metastatic lung cancer could help guide the treatment strategies and the development of novel drugs.

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Rapid/warm autopsy to reveal APOBEC-mutagenesis as driver of heterogeneity of metastatic thoracic tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.9023 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 9023-9023

Author(s):

Nitin Roper ◽

Tapan K Maity ◽

Shaojian Gao ◽

Abhilash Karavattu Venugopalan ◽

Xu Zhang ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Copy Number ◽

Thymic Carcinoma ◽

Driver Mutations ◽

Patient Specific ◽

Primary Tumors ◽

Metastatic Lung ◽

Organ Specific ◽

Proteomic Analyses ◽

Copy Number Changes

9023 Background: Intratumor heterogeneity has been characterized among multiple cancer types. In lung adenocarcinoma, APOBEC-mutagenesis has been shown to be a source of heterogeneity. However, these data are largely limited to early stage primary tumors. There is limited information about the role of APOBEC-mutagenesis and somatic variants, copy number changes, transcript and protein expression in influencing tumor heterogeneity in metastatic lung adenocarcinoma and other thoracic tumors. Methods: We applied whole exome sequencing, RNA-seq, OncoScan CNV and mass spectrometry-based proteomic analyses on 46 tumor regions from metastatic sites including lung, liver and kidney, obtained by rapid/warm autopsy from 4 patients (pts) with stage IV lung adenocarcinoma, 1 pt each with pleural mesothelioma and thymic carcinoma. The autopsy procedure was initiated between 2-4 hours of death. Results: All tumors displayed organ-specific, branched evolution that was consistent across exome, transcriptome and proteomic analyses. The degree of heterogeneity at the genomic and proteomic level was patient-specific. There was extensive heterogeneity within the tumors of one of four patients with lung adenocarcinoma and in the thymic carcinoma patient (both non-smokers) with multiple driver mutations and copy number changes occurring in only some of the tumors suggesting ongoing late tumor evolution. Further examination of the heterogenous thymic and lung adenocarcinoma tumors showed strong enrichment with the APOBEC-mutagenesis pattern and high associated levels of APOBEC3B mRNA. Conclusions: Metastatic lung adenocarcinoma, thymic carcinoma and mesothelioma evolve through a branched, organ-specific process with marked differences in the acquisition of significant driver mutations and copy number changes. APOBEC3B is a potential driver of heterogeneity in pts with advanced, heterogeneous metastatic lung adenocarcinoma and thymic carcinoma and needs to be evaluated further.

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Genetic Heterogeneity Between Paired Primary and Brain Metastases in Lung Adenocarcinoma

Clinical Medicine Insights Oncology ◽

10.1177/1179554920947335 ◽

2020 ◽

Vol 14 ◽

pp. 117955492094733

Author(s):

Li Li ◽

Zhulin Liu ◽

Rui Han ◽

Lin Li ◽

Mengyao Wang ◽

...

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Lung Adenocarcinoma ◽

Gene Mutation ◽

Genetic Heterogeneity ◽

Primary Tumor ◽

Copy Number ◽

Primary Tumors ◽

Paired Samples ◽

Primary Lung Adenocarcinoma

Purpose: About one-third of nonsmall cell lung cancer (NSCLC) patients develop brain metastases (BM). However, there is an unmet need for early diagnosis and treatment of BM. The precise mechanism for BM is still unknown. However, the genetic heterogeneity between primary tumor and paired BM indicates that sampling from the primary tumor may not be able to fully represent the mutational status in metastases. In this study, the genetic heterogeneity of primary lung adenocarcinoma and paired BM was analyzed. Patients and methods: A total of 11 paired samples of primary tumors and BM from lung cancer patients were included, in which 7 paired samples of patients were finally analyzed. Samples were sequenced by whole-exome sequencing (WES) to investigate the common and unique mutations in the primary tumors and BM, and the similarities and differences in copy number variation (CNV). Results: The consistency of gene mutation between primary lung adenocarcinoma and paired BM was 33% to 86%. FAM129C and ADAMTSs specifically mutated in BM, along with NKX2-1 high amplification and SAMD2/4 copy number deletion. Conclusion: The consistency of gene mutation between primary lung adenocarcinoma and corresponding BM is relatively high, while the individual differences were significant. FAM129C and ADAMTSs mutations and high amplification of NKX2-1 may be related to BM of lung cancer. The loss of copy number of SAMD2/4 may be a potential therapeutic target for BM from lung adenocarcinoma.

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Analysis of genomic and transcriptomic variations as prognostic signature for lung adenocarcinoma

BMC Bioinformatics ◽

10.1186/s12859-020-03691-3 ◽

2020 ◽

Vol 21 (S14) ◽

Author(s):

Talip Zengin ◽

Tuğba Önal-Süzek

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Lung Adenocarcinoma ◽

Clinical Data ◽

Copy Number ◽

Risk Groups ◽

Gene Signature ◽

Copy Number Variations ◽

Single Nucleotide ◽

Single Nucleotide Variations

Abstract Background Lung cancer is the leading cause of the largest number of deaths worldwide and lung adenocarcinoma is the most common form of lung cancer. In order to understand the molecular basis of lung adenocarcinoma, integrative analysis have been performed by using genomics, transcriptomics, epigenomics, proteomics and clinical data. Besides, molecular prognostic signatures have been generated for lung adenocarcinoma by using gene expression levels in tumor samples. However, we need signatures including different types of molecular data, even cohort or patient-based biomarkers which are the candidates of molecular targeting. Results We built an R pipeline to carry out an integrated meta-analysis of the genomic alterations including single-nucleotide variations and the copy number variations, transcriptomics variations through RNA-seq and clinical data of patients with lung adenocarcinoma in The Cancer Genome Atlas project. We integrated significant genes including single-nucleotide variations or the copy number variations, differentially expressed genes and those in active subnetworks to construct a prognosis signature. Cox proportional hazards model with Lasso penalty and LOOCV was used to identify best gene signature among different gene categories. We determined a 12-gene signature (BCHE, CCNA1, CYP24A1, DEPTOR, MASP2, MGLL, MYO1A, PODXL2, RAPGEF3, SGK2, TNNI2, ZBTB16) for prognostic risk prediction based on overall survival time of the patients with lung adenocarcinoma. The patients in both training and test data were clustered into high-risk and low-risk groups by using risk scores of the patients calculated based on selected gene signature. The overall survival probability of these risk groups was highly significantly different for both training and test datasets. Conclusions This 12-gene signature could predict the prognostic risk of the patients with lung adenocarcinoma in TCGA and they are potential predictors for the survival-based risk clustering of the patients with lung adenocarcinoma. These genes can be used to cluster patients based on molecular nature and the best candidates of drugs for the patient clusters can be proposed. These genes also have a high potential for targeted cancer therapy of patients with lung adenocarcinoma.

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EGFR TKI Combined with PD1 Inhibitor for EGFR Mutated Lung Cancer with Breast Metastasis

10.21203/rs.3.rs-431147/v1 ◽

2021 ◽

Author(s):

Xuyu Gu ◽

Chanchan Gao ◽

Longfei Wang ◽

Shiya Zheng

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Left Breast ◽

Axillary Lymph ◽

Breast Metastasis ◽

Lung Cancer Patients ◽

Metastatic Lung ◽

New Ideas ◽

Recurrent Pleural Effusion ◽

Egfr Tki

Abstract Background: Lung adenocarcinoma with breast metastasis is rare. In the present study, a case of an advanced patient with breast metastasis from lung adenocarcinoma with EGFR 21 exon p.L858R mutation who underwent EGFR TKI combined with PD1 inhibitor is reported.Case presentation: A 62-year-old female patient diagnosed with lung adenocarcinoma who had undergone six times disease progress and breast metastasis in fifth-time disease progress.The patient underwent left breast puncture and axillary lymph node in ultrasound-guided and the postoperative pathological diagnosis of metastatic lung adenocarcinoma was confirmed. And then gene detection showed EGFR 21 exon p.L858R mutation. Breast metastasis from lung adenocarcinoma was diagnosed and the patient is being treated with Almonertinib combined with PD1 inhibitor.Conclusion: Breast metastasis is rare and lung adenocarcinoma might be the primary disease. Gene indection is important. And for lung cancer patients with recurrent pleural effusion, visit of the breast should be included in the follow-up process. In addition, the treatment model of interspersed immunotherapy after EGFR resistance has brought new ideas for the treatment of lung cancer with breast metastasis.

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Prognostic significance of the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of stage I lung adenocarcinoma: A retrospective study based on analysis of 110 Chinese patients

Thoracic Cancer ◽

10.1111/1759-7714.12464 ◽

2017 ◽

Vol 8 (6) ◽

pp. 565-571 ◽

Cited By ~ 4

Author(s):

Xin Zhao ◽

Yi Zhang ◽

Kun Qian ◽

Lan Zhao ◽

Wei Wang ◽

...

Keyword(s):

Lung Cancer ◽

Retrospective Study ◽

Lung Adenocarcinoma ◽

International Association ◽

Prognostic Significance ◽

American Thoracic Society ◽

Stage I ◽

Chinese Patients ◽

European Respiratory Society

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Almonertinib in the treatment of lung cancer with breast metastasis: a case report

10.21203/rs.3.rs-128250/v1 ◽

2020 ◽

Author(s):

Xuyu Gu ◽

Chanchan Gao ◽

Longfei Wang ◽

Shiya Zheng

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Left Breast ◽

Axillary Lymph ◽

Breast Metastasis ◽

Gene Detection ◽

Lung Cancer Patients ◽

Metastatic Lung ◽

Recurrent Pleural Effusion

Abstract BackgroundLung adenocarcinoma with breast metastasis is rare. In the present study, a case of an advanced patient with breast metastasis from lung adenocarcinoma with EGFR 21 exon p.L858R mutation who underwent TKI-inhibitors is reported.Case presentationA 62-year-old female patient diagnosed with lung adenocarcinoma who had undergone seven times disease progress and breast metastasis in sixth time disease progress.The patient underwent left breast puncture and axillary lymph node in ultrasound-guided and the postoperative pathological diagnosis of metastatic lung adenocarcinoma was confirmed. And then gene detection showed EGFR 21 exon p.L858R mutation. Breast metastasis for lung adenocarcinoma was diagnosed and the patient are being treated with Almonertinib.ConclusionBreast metastasis is rare and lung adenocarcinoma might be the primary disease. Gene indection is important. And for lung cancer patients with recurrent pleural effusion, visit of the breast should be included in the follow-up process.

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Targeting β-tubulin/CCT-β complex induces apoptosis and suppresses migration and invasion of highly metastatic lung adenocarcinoma

Carcinogenesis ◽

10.1093/carcin/bgz137 ◽

2019 ◽

Vol 41 (5) ◽

pp. 699-710 ◽

Cited By ~ 3

Author(s):

Yan-Jin Liu ◽

Yu-Ju Chang ◽

Yu-Ting Kuo ◽

Po-Huang Liang

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Cancer Cells ◽

Prognostic Marker ◽

Epithelial Mesenchymal Transition ◽

Lung Cancer Cell Line ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Metastatic Lung ◽

Β Tubulin

Abstract Metastasis, the movement of cancer cells from one site to another, is responsible for the highest number of cancer deaths, especially in lung cancer patients. In this study, we first identified a prognostic marker of lung adenocarcinoma, TCP-1 β subunit (chaperonin-containing TCP-1β; CCT-β). We showed a compound that disrupted the interaction of CCT-β with β-tubulin killed a highly metastatic non-small cell lung cancer cell line CL1-5 through inducing Endoplasmic reticulum stress and caspases activation. Moreover, at the dosage of EC20, the compound inhibited migration and invasion of the lung cancer cells by suppressing matrix metalloproteinase (MMP)-2/9 and epithelial–mesenchymal transition (EMT)-related proteins through downregulating mitogen-activated protein kinases (MAPKs), Akt/β-catenin and integrin–focal adhesion kinase signaling pathways. Unlike the anticancer drugs, such as Taxol, that target the adenosine triphosphate site of β-tubulin, this study reveals a therapeutic target, β-tubulin/CCT-β complex, for metastatic human lung adenocarcinoma. The study demonstrated CCT-β as a prognostic marker. Targeting β-tubulin/CCT-β complex caused apoptosis and inhibited invasion/migration of CCT-β overexpressed, highly metastatic lung adenocarcinoma.

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Leukemoid reaction causing arterial thrombus in a patient with lung adenocarcinoma

BMJ Case Reports ◽

10.1136/bcr-2020-235389 ◽

2020 ◽

Vol 13 (10) ◽

pp. e235389

Author(s):

Zena Chahine ◽

Yazan Samhouri ◽

Thejus Jayakrishnan ◽

Dulabh Monga

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Cancer Progression ◽

Venous Stasis ◽

Leukemoid Reaction ◽

Painful Ulceration ◽

Metastatic Lung ◽

Arterial Insufficiency ◽

Wbc Count ◽

The Right

A leukemoid reaction is typically defined as white blood cell (WBC) count >50×109/L, predominantly neutrophil precursors, that are not due to tumour involvement in the bone marrow and not derived from clones. Leukemoid reactions associated with malignancy, known as paraneoplastic leukemoid reactions, are less common and are most notably seen with non-small cell lung cancer. A 64-year-old woman presented with right leg painful ulceration. On examination, she had multiple venous stasis ulcers more severe on the right, with no palpable pulses in her lower extremities. Her WBC count was 124×109/L and platelets were 517×109/L. Arterial dopplers showed limb-threatening arterial insufficiency which prompted right femoral endarterectomy. Few months earlier she was diagnosed with metastatic lung adenocarcinoma to the bone and she had leukemoid reaction with WBC 43.920× 109/L with 90% neutrophils. Repeat imaging showed progression of her malignancy and she passed shortly after. Inflammation is a key element of carcinogenesis and cancer progression. Among the different tumours, lung cancer is a non-haematologic malignancy that is most closely associated with leucocytosis. Some studies have found that leucocytosis was significantly associated with metastasis and shorter survival irrespective of other factors such as age or sex. The mechanism remains unclear however elevated levels of granulocyte colony-stimulating factor (CSF), granulocyte macrophage-CSF and interleukin 6 have been linked to this phenomena. The degree of leucocytosis seen in our patient is suggestive of CSF production leading to a paraneoplastic leukemoid reaction.

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