Abstract A182: Apobec-mutagenesis drives mutational heterogeneity while copy number alterations drive transcriptomic and proteogenomic heterogeneity in metastatic lung adenocarcinoma and thymic carcinoma

2018 ◽  
Author(s):  
Nitin Roper ◽  
James Gao ◽  
Rouf Banday ◽  
Tapan Maity ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Thymic Carcinoma ◽  
Copy Number Alterations ◽  
Metastatic Lung

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

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.

scholarly journals LiquidCNA: tracking subclonal evolution from longitudinal liquid biopsies using somatic copy number alterations

2021 ◽  
Author(s):  
Eszter Lakatos ◽  
Helen Hockings ◽  
Maximilian Mossner ◽  
Michelle Lockley ◽  
Trevor A. Graham
Keyword(s):  
Copy Number ◽  
Evolutionary Dynamics ◽  
Cost Effective ◽  
Copy Number Alterations ◽  
Liquid Biopsies ◽  
Metastatic Lung ◽  
Low Pass ◽  
Somatic Copy Number Alterations

AbstractCell-free DNA (cfDNA) measured via liquid biopsies provides a way for minimally-invasive monitoring of tumour evolutionary dynamics during therapy. Here we present liquidCNA, a method to track subclonal evolution from longitudinally collected cfDNA samples based on somatic copy number alterations (SCNAs). LiquidCNA utilises SCNA profiles derived through cost-effective low-pass whole genome sequencing to automatically and simultaneously genotype and quantify the size of the dominant subclone without requiring prior knowledge of the genetic identity of the emerging clone. We demonstrate the accuracy of liquidCNA in synthetically generated sample sets and in vitro and in silico mixtures of cancer cell lines. Application in vivo in patients with metastatic lung cancer reveals the progressive emergence of a novel tumour sub-population. LiquidCNA is straightforward to use, computationally inexpensive and enables continuous monitoring of subclonal evolution to understand and control therapy-induced resistance.

scholarly journals Integrated proteogenomic analysis of metastatic thoracic tumors identifies APOBEC mutagenesis and copy number alterations as drivers of proteogenomic tumor evolution and heterogeneity

2018 ◽  
Author(s):  
Nitin Roper ◽  
Shaojian Gao ◽  
Tapan K. Maity ◽  
A. Rouf Banday ◽  
Xu Zhang ◽  
...  
Keyword(s):  
Copy Number ◽  
Thymic Carcinoma ◽  
Patient Specific ◽  
Tumor Evolution ◽  
Copy Number Alterations ◽  
Immune Microenvironment ◽  
Mutation Status ◽  
Whole Exome ◽  
Rapid Autopsy ◽  
Insight Into

ABSTRACTElucidation of the proteogenomic evolution of metastatic tumors may offer insight into the poor prognosis of patients harboring metastatic disease. We performed whole-exome and transcriptome sequencing, copy number alterations (CNA) and mass spectrometry-based quantitative proteomics of 37 lung adenocarcinoma (LUAD) and thymic carcinoma (TC) metastases obtained by rapid autopsy and found evidence of patient-specific, multi-dimensional heterogeneity. Extreme mutational heterogeneity was evident in a subset of patients whose tumors showed increased APOBEC-signature mutations and expression of APOBEC3 region transcripts compared to patients with lesser mutational heterogeneity. TP53 mutation status was associated with APOBEC hypermutators in our cohort and in three independent LUAD datasets. In a thymic carcinoma patient, extreme heterogeneity and increased APOBEC3AB expression was associated with a high-risk germline APOBEC3AB variant allele. Patients with CNA occurring late in tumor evolution had corresponding changes in gene expression and protein abundance indicating genomic instability as a mechanism of downstream transcriptomic and proteomic heterogeneity between metastases. Across all tumors, proteomic heterogeneity was greater than copy number and transcriptomic heterogeneity. Enrichment of interferon pathways was evident both in the transcriptome and proteome of the tumors enriched for APOBEC mutagenesis despite a heterogeneous immune microenvironment across metastases suggesting a role for the immune microenvironment in the expression of APOBEC transcripts and generation of mutational heterogeneity. The evolving, heterogeneous nature of LUAD and TC, through APOBEC-mutagenesis and CNA illustrate the challenges facing treatment outcomes.

EGFR gene copy number alterations are not a useful screening tool for predicting EGFR mutation status in lung adenocarcinoma

Pathology ◽  
2014 ◽  
Vol 46 (1) ◽  
pp. 32-36
Author(s):  
Prudence A. Russell ◽  
Y.U. Yong ◽  
D.O. Hongdo ◽  
Timothy D. Clay ◽  
Melissa M. Moore ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Screening Tool ◽  
Egfr Mutation ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Copy Number Alterations ◽  
Mutation Status ◽  
Egfr Gene

Abstract A26: DNA copy number alterations deregulate expression of miRNAs in lung adenocarcinoma

2012 ◽  
Vol 72 (2 Supplement) ◽  
pp. A26-A26
Author(s):  
Greg L. Stewart ◽  
Katey SS Enfield ◽  
Stephen Lam ◽  
Wan Lam
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Dna Copy Number Alterations

scholarly journals Genomic and immune profiling of pre-invasive lung adenocarcinoma

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Haiquan Chen ◽  
Jian Carrot-Zhang ◽  
Yue Zhao ◽  
Haichuan Hu ◽  
Samuel S. Freeman ◽  
...  
Keyword(s):  
Minimally Invasive ◽  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Adenocarcinoma In Situ ◽  
Copy Number Alterations ◽  
Invasive Adenocarcinoma ◽  
Minimally Invasive Adenocarcinoma ◽  
Invasive Lung Adenocarcinoma ◽  
Hla Loss

AbstractAdenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment.

Distinct genomic instability landscape of lung adenocarcinoma associated with treatment and metastasis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9534-9534
Author(s):  
Chuanxin Wu ◽  
Jing Zhang ◽  
Hua Bao ◽  
Ao Wang ◽  
Zhuang Luo ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Genomic Instability ◽  
Copy Number ◽  
Targeted Sequencing ◽  
Early Event ◽  
Copy Number Alterations ◽  
Term Survival ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Increased Risk

9534 Background: Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer (NSCLC). Genomic instability, defined as genome-wide copy number alterations, is a key pathogenic signature which occurs at the early stage of most cancers and is associated with an increased risk of recurrence or death. We examined the pattern of genomic instability in primary and metastatic LUAD. Methods: We performed deep targeted sequencing (425 genes) of 3395 tissue samples and whole exome sequencing (WES) of 60 tissue samples from LUAD patients. Whole-genome doubling (WGD) and arm level aneuploidy were analyzed to uncover correlation with clinical phenotypes and other genomic alterations including driver mutations, tumor mutation burden (TMB), and microsatellite instability (MSI). Results: Overall, targeted sequencing revealed that WGD occurred in 64.33% LUAD samples, which was comparable with WES results. Compared to primary site, metastasis exhibited higher proportion of WGD (1.14 fold). Specifically, liver metastasis has the highest WGD percentage among metastasis sites (~87.5%; 1.40 fold increase compared to primary). Interestingly, patients who received tyrosine kinase inhibitors (TKI) had higher frequency of WGD than patients without TKI treatment. In addition, TMB was higher in WGD+ patients but MSI status was not significantly different between groups. Arm-level aneuploidy was prevalent in this cohort. The most common amplification events were 7p gain (62%), 5p gain (54%), and 8q gain (53%); top deletion events were 19p loss (47%), 15q loss (42%), and 10 q loss (41%). Patients with EGFR or TP53 mutation were more likely to have aneuploidy compared to wildtypes. Subgroup analysis showed distinct patterns of aneuploidy among metastasis sites, suggesting organ-specific alterations. Evolution analysis showed 7p gain was an early event common in primary tumor whereas metastatic tumor had multiple distinct evolutionary trajectories following 7p gain. Several copy number signatures were associated with specific TKI and chemotherapies. For example, TKI-naïve tumors lacked 7p gain but had 19p loss as the most common alteration. Conclusions: The genomic landscape of LUAD was characterized by widespread large-scale copy number alterations including WGD and chromosomal aneuploidy. Metastasis had elevated level of aneuploidy compared to primary tumors which were specific to metastatic site. Copy number signature associated with different treatments may contribute to distinct long-term survival and side effects among patients.

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