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 Genomic Mutations of Primary and Metastatic Lung Adenocarcinoma in Chinese Patients

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.

scholarly journals MBCL-08. INTEGRATIVE MOLECULAR ANALYSIS OF PATIENT-MATCHED DIAGNOSTIC AND RELAPSED MEDULLOBLASTOMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii389-iii389
Author(s):  
Rahul Kumar ◽  
Maximilian Deng ◽  
Kyle Smith ◽  
Anthony Liu ◽  
Girish Dhall ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Copy Number ◽  
Driver Mutations ◽  
P Value ◽  
Next Generation ◽  
Driver Genes ◽  
Methylation Array ◽  
Primary Tumors ◽  
Group 4 ◽  
Group 3

Abstract INTRODUCTION The next generation of clinical trials for relapsed medulloblastoma demands a thorough understanding of the clinical behavior of relapsed tumors as well as the molecular relationship to their diagnostic counterparts. METHODS A multi-institutional molecular cohort of patient-matched (n=126 patients) diagnostic MBs and relapses/subsequent malignancies was profiled by DNA methylation array. Entity, subgroup classification, and genome-wide copy-number aberrations were assigned while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations. RESULTS Comprised of WNT (2%), SHH (41%), Group 3 (18%), Group 4 (39%), primary tumors retained subgroup affiliation at relapse with the notable exception of 10% of cases. The majority (8/13) of discrepant classifications were determined to be secondary glioblastomas. Additionally, rare (n=3) subgroup-switching events of Group 4 primary tumors to Group 3 relapses were identified coincident with MYC/MYCN pathway alterations. Amongst truly relapsing MBs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with Group 3 (55% of alterations shared) and Group 4 tumors (63% alterations shared) sharing a larger proportion of cytogenetic alterations compared to SHH tumors (42% alterations shared; Chi-square p-value < 0.001). Subgroup- and gene-specific patterns of conservation and divergence amongst putative driver genes were also observed. CONCLUSION Integrated molecular analysis of relapsed MB discloses potential mechanisms underlying treatment failure and disease recurrence while motivating rational implementation of relapse-specific therapies. The degree of genetic divergence between primary and relapsed MBs varied by subgroup but suggested considerably higher conservation than prior estimates.

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.

scholarly journals DNA copy number changes in diffuse large B-cell lymphoma--comparative genomic hybridization study

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 5269-5278 ◽  
Author(s):  
O Monni ◽  
H Joensuu ◽  
K Franssila ◽  
S Knuutila
Keyword(s):  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
B Cell Lymphoma ◽  
Comparative Genomic ◽  
Genomic Hybridization ◽  
Primary Tumors ◽  
Large B Cell Lymphoma ◽  
Recurrent Tumors ◽  
Copy Number Changes ◽  
High Level

We studied DNA copy number changes in diffuse large B-cell lymphoma using comparative genomic hybridization analysis on 20 primary tumors and on 12 recurrent tumors excised after chemotherapy or radiotherapy. Twenty-nine (91%) of the cases showed abnormal copy number karyotypes. Chromosomal regions at X (41%), 1q (38%), 7 (31%), 3 (24%), 6p (21%), 11 (21%), 12 (21%), and 18 (21%) were most frequently gained, and the most common losses involved 6q (38%), X (21%), 1p (14%), and 8p (10%). High-level amplifications were observed at 6p23-ter, 10p12–14, 17p1l.2, 18q21-ter, and Xq22-ter, all but 18q appearing only in the recurrent tumors. Gains (median, 2; range, 0 to 10) were more frequent than losses (median, 1; range, 0 to 7; P = .0004). The median number of aberrations found in the recurrent tumors (6.5) was greater than that in the primary tumors (2; P = .01). The copy number changes found in the recurrent tumors were more random than those found in the primary tumors, which were mainly located in the most frequently affected regions. Our findings are in line with those observed using conventional cytogenetic analysis, but especially novel high-level amplifications were detected. Southern blot analysis showed BCL2 amplification, but not translocation t(14;18)(q32;q21), in cases in which a gain at 18q was detected by comparative genomic hybridization, which strongly suggests that, in addition to translocation, gene amplification is another mechanism for the overexpression of the BCL2 protein.

scholarly journals Genetic Heterogeneity Between Paired Primary and Brain Metastases in Lung Adenocarcinoma

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.

scholarly journals Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V

2018 ◽  
Author(s):  
Xu Zhang ◽  
Khoa Dang Nguyen ◽  
Paul Rudnick ◽  
Nitin Roper ◽  
Emily Kawaler ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Lung Cancer ◽  
Lymph Node ◽  
Lymph Nodes ◽  
Lung Adenocarcinoma ◽  
Mass Spectrometry Data ◽  
Patient Specific ◽  
Metastatic Site ◽  
Metastatic Lung ◽  
Metastatic Sites

AbstractLung cancer is the leading cause of cancer death both in men and women. Tumor heterogeneity is an impediment to targeted treatment of all cancers, including lung cancer. Here, we sought to characterize changes in tumor proteome and phosphoproteome by longitudinal, prospective collection of tumor tissue of an exceptional responder lung adenocarcinoma patient who survived with metastatic lung adenocarcinoma for more than seven years with HER2-directed therapy in combination with chemotherapy. We employed “Super-SILAC” and TMT labeling strategies to quantify the proteome and phosphoproteome of a lung metastatic site and ten different metastatic progressive lymph nodes collected across a span of seven years, including five lymph nodes procured at autopsy. We identified specific signaling networks enriched in lung compared to the lymph node metastatic sites. We correlated the changes in protein abundance with changes in copy number alteration (CNA) and transcript expression. To further interrogate the mass spectrometry data, patient-specific database was built incorporating all the somatic variants identified by whole genome sequencing (WGS) of genomic DNA from the lung, one lymph node metastatic site and blood. An extensive validation pipeline was built for confirmation of variant peptides. We validated 360 spectra corresponding to 55 germline and 6 somatic variant peptides. Targeted MRM assays demonstrated expression of two novel variant somatic peptides, CDK12-G879V and FASN-R1439Q, with expression in lung and lymph node metastatic sites, respectively. CDK12 G879V mutation likely results in a nonfunctional CDK12 kinase and chemotherapy susceptibility in lung metastatic sites. Knockdown of CDK12 in lung adenocarcinoma cells results in increased chemotherapy sensitivity, explaining the complete resolution of the lung metastatic sites in this patient.

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.

scholarly journals DNA Copy Number Changes in Lung Adenocarcinoma in Younger Patients

2002 ◽  
Vol 15 (4) ◽  
pp. 372-378 ◽  
Author(s):  
Irmeli Lindström ◽  
Stig Nordling ◽  
Anna-Maria Nissén ◽  
Lauri Tammilehto ◽  
Karin Mattson ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Copy Number ◽  
Dna Copy Number ◽  
Younger Patients ◽  
Copy Number Changes

scholarly journals Organ Specific Copy Number Variations in Visceral Metastases of Human Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5984
Author(s):  
Orsolya Papp ◽  
Viktória Doma ◽  
Jeovanis Gil ◽  
György Markó-Varga ◽  
Sarolta Kárpáti ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Copy Number ◽  
Lung Metastases ◽  
Ectopic Expression ◽  
Gene Copy Number ◽  
Copy Number Variations ◽  
Gene Copy ◽  
Primary Tumors ◽  
Specific Manner ◽  
Organ Specific

Malignant melanoma is one of the most aggressive skin cancers with high potential of visceral dissemination. Since the information about melanoma genomics is mainly based on primary tumors and lymphatic or skin metastases, an autopsy-based visceral metastasis biobank was established. We used copy number variation arrays (N = 38 samples) to reveal organ specific alterations. Results were partly completed by proteomic analysis. A significant increase of high-copy number gains was found in an organ-specific manner, whereas copy number losses were predominant in brain metastases, including the loss of numerous DNA damage response genes. Amplification of many immune genes was also observed, several of them are novel in melanoma, suggesting that their ectopic expression is possibly underestimated. This “immunogenic mimicry” was exclusive for lung metastasis. We also provided evidence for the possible autocrine activation of c-MET, especially in brain and lung metastases. Furthermore, frequent loss of 9p21 locus in brain metastases may predict higher metastatic potential to this organ. Finally, a significant correlation was observed between BRAF gene copy number and mutant allele frequency, mainly in lung metastases. All of these events may influence therapy efficacy in an organ specific manner, which knowledge may help in alleviating difficulties caused by resistance.

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