Genetic Heterogeneity Between Paired Primary and Brain Metastases in 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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Genomic Mutations of Primary and Metastatic Lung Adenocarcinoma in Chinese Patients

Journal of Oncology ◽

10.1155/2020/6615575 ◽

2020 ◽

Vol 2020 ◽

pp. 1-9

Author(s):

Xinyu Chen ◽

Qing Bu ◽

Xuexin Yan ◽

Ye Li ◽

Qian Yu ◽

...

Keyword(s):

Lung Cancer ◽

Lung Adenocarcinoma ◽

Copy Number ◽

Copy Number Variations ◽

Chromosome 9 ◽

Chromosome 1 ◽

Chinese Patients ◽

Primary Tumors ◽

Genomic Variations ◽

Metastatic Lung

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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EPID-04. THE SINGLE CENTER STUDY FOR BRAIN METASTASES OF UNDIAGNOSED PRIMARY TUMOR AND THE ROLE OF SURGICAL REMOVAL

Neuro-Oncology ◽

10.1093/neuonc/noaa215.322 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii79-ii79

Author(s):

Yuzaburo Shimizu ◽

Mario Suzuki ◽

Osamu Akiyama ◽

Akihide Kondo

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Cell Carcinoma ◽

Small Cell Carcinoma ◽

Primary Tumor ◽

Surgical Intervention ◽

Small Cell ◽

Surgical Removal ◽

Primary Tumors

Abstract BACKGROUND The diagnosis of a brain metastases is generally made during the follow up examinations of patients with primary known cancer. However, there are some patients presenting brain metastases as the first manifestation of a previously undiagnosed primary tumor (UDP) pathological confirmation of the diagnosis. The timing of a subsequent neurosurgical intervention is influenced by the distribution of primary tumors in UDP patients. The purpose of this study was to investigate the optimal diagnostic approach and the role of surgery for UDP patients. METHODS In a retrospective study, 35 patients admitted to our institution and underwent brain tumor removal from 2017 to 2019 with the diagnosis of cerebral metastases and diagnosed lung cancer as primary tumor subsequently, or previously diagnosed lung cancer. RESULTS UDP patients represented 46% of the whole group. Primary tumor subtype was the adenocarcinoma (n=13, 81%), small cell carcinoma (n=2, 13%), and neuroendocrine carcinoma (n=1, 6%). They did not have bronchoscopy nor excision of lung cancer. On the other hand, the patients previously diagnosed lung cancer represented 54% and subtype was adenocarcinoma (n=14, 74%) and small cell carcinoma (n=5, 26%). EGFR mutation was detected from 7 patients (44%) in UDP group and treated by EGFR tyrosine kinase inhibitor. CONCLUSION The significance of surgical intervention in metastatic brain tumors has been limited. However, active surgical intervention in UDP patients could identify not only histological diagnosis but also molecular biological characteristics. Our study suggests the possibility to avoid whole brain radiation in UDP patient by the active surgery.

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Targeted next-generation sequencing for cancer-associated gene mutation and copy number detection in 206 patients with non–small-cell lung cancer

Bioengineered ◽

10.1080/21655979.2021.1890382 ◽

2021 ◽

Vol 12 (1) ◽

pp. 791-802 ◽

Cited By ~ 1

Author(s):

Songbai Zheng ◽

Xiaodan Wang ◽

Ying Fu ◽

Beibei Li ◽

Jianhua Xu ◽

...

Keyword(s):

Lung Cancer ◽

Next Generation Sequencing ◽

Small Cell Lung Cancer ◽

Gene Mutation ◽

Copy Number ◽

Small Cell ◽

Small Cell Lung ◽

Targeted Next Generation Sequencing ◽

Copy Number Detection ◽

Generation Sequencing

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SURG-13. EVALUATION OF 5-ALA FLUORESCENCE IN BRAIN METASTASES OF VARIOUS PRIMARY TUMORS: A MULTICENTER STUDY WITH EXPERIENCE IN 157 CASES

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz014.148 ◽

2019 ◽

Vol 1 (Supplement_1) ◽

pp. i33-i33

Author(s):

Petra Andreea Mercea ◽

Franz Marhold ◽

Florian Scheichel ◽

Barbara Kiesel ◽

Mario Mischkulnig ◽

...

Keyword(s):

Brain Metastases ◽

Primary Tumor ◽

Aminolevulinic Acid ◽

World Health ◽

Incomplete Resection ◽

Strong Fluorescence ◽

Primary Tumors ◽

Fluorescence Pattern ◽

Fluorescence Characteristics ◽

Intraoperative Visualization

Abstract INTRODUCTION: Local recurrence of brain metastases following incomplete resection is not uncommon. One reason is insufficient intraoperative visualization of tumor tissue. Recently, visible intraoperative 5-aminolevulinic acid (5-ALA) fluorescence was reported in the first brain metastases series. Thus, the aim of this study was to investigate intraoperative 5-ALA fluorescence in brain metastases at two specialized centers in the largest patient cohort up to date. METHODS: 5-ALA was administered prior to resection of 157 brain metastases in 154 patients. Intraoperatively, the fluorescence quality (strong, vague or none) and fluorescence homogeneity (homogeneous or heterogeneous) of each brain metastasis was investigated. These 5-ALA fluorescence characteristics were correlated with primary tumor and histopathological subtype according to the current World Health Organization (WHO) 2016 criteria. RESULTS: Visible 5-ALA fluorescence was observed in 104 brain metastases (66%), whereas fluorescence was absent in the remaining 53 cases (34%).53/104 (51%) brain metastases showed strong fluorescence and 51/104 (49%) vague fluorescence. The majority of brain metastases (84%) demonstrated a heterogeneous fluorescence pattern. In context of primary tumor, visible fluorescence was less frequent in brain metastases of melanomas compared to all other tumors (p=0.037). Moreover, visible fluorescence was more common for ductal breast cancer subtype than other subtypes (p=0.008). CONCLUSION: Our data indicate that 5-ALA fluorescence is a valuable for intraoperative visualization of brain metastases to improve the extent of resection and thus patient prognosis. However, the frequent heterogeneous 5-ALA fluorescence pattern and lack of strong fluorescence limits the use of 5-ALA in brain metastases, claiming for further technical refinement.

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Clinical and pathologic characteristics of patients with breast cancer and a second non-breast primary tumor.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e11539 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e11539-e11539

Author(s):

Gul Atalay Basaran ◽

Aziz Yazar ◽

Cihan Uras ◽

Evrim Tezcanli ◽

Devrim Cabuk ◽

...

Keyword(s):

Breast Cancer ◽

Lung Cancer ◽

Primary Tumor ◽

Breast Tumor ◽

Cancer Metastasis ◽

Histological Grade ◽

Breast Tumors ◽

Second Primary ◽

Primary Tumors ◽

Second Primary Tumors

e11539 Background: We aimed to investigate the clinical and pathologic characteristics of patients with breast cancer (BC) who had a non-breast primary tumor and treated in our hospital. Methods: We identified BC patients with a second non-breast primary tumor retrospectively in our database. The tumors arising in a sequence by less than 2 months are accepted as synchronous malignancies. We noted clinical and pathological characteristics of breast tumors and analyzed the relapse patterns, the frequency and type of second non-breast primary tumors. Results: A total of 48 patients were identified. Median age was 59 years old. Thirty-four patients were postmenopausal, 41 tumors were IDC, 2 were DCIS only, eight were multiffocal. Two patients had metastatic BC at the time of diagnosis. Ninety-three (n: 26) % patients had breast conserving surgery, 2 had bilateral BC. Twenty-eight patients had node negative disease, 12 had node positive disease and 2 had micrometatatic nodal involvement. Fifty-four % were T1, 31% were T2 tumors. Histological grade was 3 for 14, 2 for 15 and 1 for 7 breast tumors. Forty patients had ER positive disease, 4 had ER/ PR negative disease, 2 tumors were triple negative and 6 tumors were Her-2 positive. Among non-breast second primary tumors; 29 arose after, 11 arose before the diagnosis of BC and 8 arose synchronously with BC. The most common non-breast second primary tumors were as follows: 15% lung cancer, 20% colorectal cancers, 13% ovarian cancer, 10% thyroid cancer, and 8% lymphoma/leukemia. With a median follow up of 76 months, there were 6 relapses; 4 of them were BC relapses. Among these 4 BC relapses, 3 patients had brain metastases and one patient had bone metastasis. There were 4 deaths; 2 were due to BC metastases, one was due to rectal cancer metastasis and the other was due to relapse of sarcoma. Conclusions: Most breast tumors were at early stage and were hormone sensitive. The most common second non-breast primary tumors arising after diagnosis of BC were colorectal, thyroid and lung cancers. The most common second non-breast tumor arising synchronously with BC was lung cancer and the most common second non-breast tumor arising before diagnosis of BC was lymphoma/leukemia.

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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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Human leukocyte antigen expression in paired primary lung lesions and brain metastases in non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.5_suppl.43 ◽

2020 ◽

Vol 38 (5_suppl) ◽

pp. 43-43

Author(s):

Jarrett Failing ◽

Marie-Christine Aubry ◽

Aaron Scott Mansfield

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Human Leukocyte ◽

Small Cell ◽

Small Cell Lung ◽

Primary Tumors ◽

Primary Nsclc

43 Background: Human leukocyte antigens (HLA) are crucial for cytotoxic T cell responses to cancer. Loss of HLA expression is a mechanism of tumor immune escape and may contribute to resistance to immunotherapy. In patients with non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors we have observed discordant responses between brain metastases and extracranial disease and reported on differential PD-L1 expression and clonal T cell infiltration between paired primary lung lesions and brain metastases. In this project we sought to evaluate whether HLA expression was retained in metastatic NSCLC. Methods: Adult patients with paired primary NSCLC and brain metastases were identified from our institution’s tissue registry. HLA-A cell membrane expression on tumor cells was determined by immunohistochemistry with an anti-HLA-A antibody. Tumors with greater than 10% HLA expression were considered positive. Agreement statistics (κ) and Fisher’s exact test were used for analysis. Results: 51 patients with paired primary NSCLC and brain lesions were identified. The median HLA expression was 20% in the primary tumors (IQR 0-65%) and 10% in the brain metastases (IQR 5-40%). 27 primary tumors and 24 brain metastases were positive for HLA expression. There was disagreement in HLA positivity between paired lesions in 11 patients (22%, 95% CI 12-35%)(κ = 0.57, 95% CI 0.35-0.79)(p = 0.0001). There was no significant difference in the time between the primary tumor and brain metastasis resections in patients with HLA expression disagreement compared to those with HLA expression agreement. None of the patients received immune checkpoint inhibitors for treatment of these lesions. Conclusions: We found significant differences in HLA-A expression on tumor cells in nearly one quarter of paired primary lung cancers and brain metastases. Differences in HLA expression may help explain the discrepancies in response to immune checkpoint inhibitors at different sites of disease and warrants further study.

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Aggressive Treatment of Primary Tumor in Patients With Non–Small-Cell Lung Cancer and Exclusively Brain Metastases

Clinical Lung Cancer ◽

10.1016/j.cllc.2012.05.002 ◽

2013 ◽

Vol 14 (1) ◽

pp. 6-13 ◽

Cited By ~ 16

Author(s):

Cynthia Villarreal-Garza ◽

Dolores de la Mata ◽

Diego G. Zavala ◽

Eleazar O. Macedo-Perez ◽

Oscar Arrieta

Keyword(s):

Lung Cancer ◽

Brain Metastases ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Primary Tumor ◽

Small Cell ◽

Aggressive Treatment ◽

Small Cell Lung

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Gene Expression Profile in Primary Tumor Is Associated with Brain-Tropism of Metastasis from Lung Adenocarcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms222413374 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13374

Author(s):

Yen-Yu Lin ◽

Yu-Chao Wang ◽

Da-Wei Yeh ◽

Chen-Yu Hung ◽

Yi-Chen Yeh ◽

...

Keyword(s):

Gene Expression ◽

Brain Metastasis ◽

Brain Metastases ◽

Dna Sequencing ◽

Lung Adenocarcinoma ◽

Rna Sequencing ◽

Cell Lines ◽

Differentially Expressed Genes ◽

Primary Tumor ◽

The Brain

Lung adenocarcinoma has a strong propensity to metastasize to the brain. The brain metastases are difficult to treat and can cause significant morbidity and mortality. Identifying patients with increased risk of developing brain metastasis can assist medical decision-making, facilitating a closer surveillance or justifying a preventive treatment. We analyzed 27 lung adenocarcinoma patients who received a primary lung tumor resection and developed metastases within 5 years after the surgery. Among these patients, 16 developed brain metastases and 11 developed non-brain metastases only. We performed targeted DNA sequencing, RNA sequencing and immunohistochemistry to characterize the difference between the primary tumors. We also compared our findings to the published data of brain-tropic and non-brain-tropic lung adenocarcinoma cell lines. The results demonstrated that the targeted tumor DNA sequencing did not reveal a significant difference between the groups, but the RNA sequencing identified 390 differentially expressed genes. A gene expression signature including CDKN2A could identify 100% of brain-metastasizing tumors with a 91% specificity. However, when compared to the differentially expressed genes between brain-tropic and non-brain-tropic lung cancer cell lines, a different set of genes was shared between the patient data and the cell line data, which include many genes implicated in the cancer-glia/neuron interaction. Our findings indicate that it is possible to identify lung adenocarcinoma patients at the highest risk for brain metastasis by analyzing the primary tumor. Further investigation is required to elucidate the mechanism behind these associations and to identify potential treatment targets.

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