scholarly journals Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 574
Author(s):  
Ege Ülgen ◽  
Sıla Karacan ◽  
Umut Gerlevik ◽  
Özge Can ◽  
Kaya Bilguvar ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Alteration ◽  
Age At Diagnosis ◽  
Copy Number Alterations ◽  
Primary Tumors ◽  
Double Minutes ◽  
Molecular Features ◽  
Genetic Landscape ◽  
Underlying Mechanisms ◽  
Mutational Processes

Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but IDH-mutant gliomas as well as diffuse midline gliomas H3-K27M were excluded to search for the possible presence of new entities among the very heterogenous group of IDH-WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including TERT promoter mutations, 7/10 pattern, or EGFR-amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and “Others” differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA.

scholarly journals Copy-Number Alteration Burden Differentially Impacts Immune Profiles and Molecular Features of Hepatocellular Carcinoma

2020 ◽  
Vol 26 (23) ◽  
pp. 6350-6361 ◽  
Author(s):  
Laia Bassaganyas ◽  
Roser Pinyol ◽  
Roger Esteban-Fabró ◽  
Laura Torrens ◽  
Sara Torrecilla ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Molecular Features

scholarly journals A network of epigenetic modifiers and DNA repair genes controls tissue-specific copy number alteration preference

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Dina Cramer ◽  
Luis Serrano ◽  
Martin H Schaefer
Keyword(s):  
Copy Number ◽  
Copy Number Alteration ◽  
Patient Survival ◽  
Cancer Type ◽  
Copy Number Alterations ◽  
Large Variability ◽  
Epigenetic Modifiers ◽  
Physical Interactions ◽  
Tissue Of Origin ◽  
Repair Genes

Copy number alterations (CNAs) in cancer patients show a large variability in their number, length and position, but the sources of this variability are not known. CNA number and length are linked to patient survival, suggesting clinical relevance. We have identified genes that tend to be mutated in samples that have few or many CNAs, which we term CONIM genes (COpy Number Instability Modulators). CONIM proteins cluster into a densely connected subnetwork of physical interactions and many of them are epigenetic modifiers. Therefore, we investigated how the epigenome of the tissue-of-origin influences the position of CNA breakpoints and the properties of the resulting CNAs. We found that the presence of heterochromatin in the tissue-of-origin contributes to the recurrence and length of CNAs in the respective cancer type.

Genomic profiling of breast cancer brain metastases reveals targetable alterations.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2525-2525
Author(s):  
Sheheryar Kairas Kabraji ◽  
Liam F. Spurr ◽  
Melissa E Hughes ◽  
Yvonne Y. Li ◽  
Jose Pablo Leone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Copy Number ◽  
Enrichment Analysis ◽  
Fisher Exact Test ◽  
Copy Number Alterations ◽  
Genomic Alterations ◽  
Primary Tumors ◽  
Significant Difference ◽  
Breast Cancer Brain Metastases

2525 Background: Genomic characterization of breast cancer brain metastases (BCBMs) has thus far been limited. The objective of this study was to describe the landscape of genomic alterations in patients (pts) with BCBMs. Methods: Targeted next-generation DNA sequencing of > 300 cancer-related genes (OncoPanel) was prospectively performed on primary and metastatic (met) tumors in 321 pts with a diagnosis of BCBM between August 2016 and April 2019 at Dana-Farber Cancer Institute (table). Enrichment analysis of genomic alterations was performed using a two-sided Fisher exact test and differences in tumor mutation burden (TMB) between groups were assessed using two-sided Mann-Whitney U test. Multiple comparison correction was performed using the Benjamini-Hochberg procedure. Results: All subtypes were represented in BCBM (25 HR+/HER2-; 24 HR+/HER2+; 27 HR-/HER2+; 18 TNBC; 5 unknown; n = 99) and extracranial (EC) samples: (96 HR+/HER2-; 32 HR+/HER2+; 22 HR-/HER2+; 41 TNBC; 31 unknown; n = 222). BCBMs were found most commonly to have mutations or copy number alterations in TP53, ERBB2, PIK3CA, GATA3, PTEN, ESR1, CDH1, BRCA2, ARID1A, BRCA1 (>5% frequency, table). Two pts acquired ERBB2 amplification (amp) between the matched primary breast sample and brain met. In pair-wise comparisons of BCBMs to unmatched primaries or EC mets, only ERBB2 amp was significantly enriched (table, † = adjusted p < 0.05). There was no significant difference in TMB between BCBM and EC mets (median 9.12 vs 7.26, p = 0.15). In contrast, TMB was significantly higher in BCBMs compared to unmatched primaries (median 9.12 vs 7.26, p=0.005). Conclusions: BCBMs display similar mutations and copy number alterations compared to primary tumors and EC mets in pts with BCBM. These data suggest that BCBMs contain actionable genomic alterations that are most often also reflected in EC disease. Alterations in ERBB2, PIK3CA/PTEN, and BRCA1/2 represent potentially targetable alterations in pts with BCBM. [Table: see text]

scholarly journals Integrated Molecular Genetic Profiling of Pediatric High-Grade Gliomas Reveals Key Differences With the Adult Disease

2010 ◽  
Vol 28 (18) ◽  
pp. 3061-3068 ◽  
Author(s):  
Barbara S. Paugh ◽  
Chunxu Qu ◽  
Chris Jones ◽  
Zhaoli Liu ◽  
Martyna Adamowicz-Brice ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
De Novo ◽  
Molecular Genetic ◽  
High Grade Glioma ◽  
Cranial Irradiation ◽  
High Grade ◽  
Copy Number Alterations ◽  
Molecular Features ◽  
Diffuse Intrinsic Pontine Gliomas

Purpose To define copy number alterations and gene expression signatures underlying pediatric high-grade glioma (HGG). Patients and Methods We conducted a high-resolution analysis of genomic imbalances in 78 de novo pediatric HGGs, including seven diffuse intrinsic pontine gliomas, and 10 HGGs arising in children who received cranial irradiation for a previous cancer using single nucleotide polymorphism microarray analysis. Gene expression was analyzed with gene expression microarrays for 53 tumors. Results were compared with publicly available data from adult tumors. Results Significant differences in copy number alterations distinguish childhood and adult glioblastoma. PDGFRA was the predominant target of focal amplification in childhood HGG, including diffuse intrinsic pontine gliomas, and gene expression analyses supported an important role for deregulated PDGFRα signaling in pediatric HGG. No IDH1 hotspot mutations were found in pediatric tumors, highlighting molecular differences with adult secondary glioblastoma. Pediatric and adult glioblastomas were clearly distinguished by frequent gain of chromosome 1q (30% v 9%, respectively) and lower frequency of chromosome 7 gain (13% v 74%, respectively) and 10q loss (35% v 80%, respectively). PDGFRA amplification and 1q gain occurred at significantly higher frequency in irradiation-induced tumors, suggesting that these are initiating events in childhood gliomagenesis. A subset of pediatric HGGs showed minimal copy number changes. Conclusion Integrated molecular profiling showed substantial differences in the molecular features underlying pediatric and adult HGG, indicating that findings in adult tumors cannot be simply extrapolated to younger patients. PDGFRα may be a useful target for pediatric HGG, including diffuse pontine gliomas.

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 Association of Cell-Free DNA Tumor Fraction and Somatic Copy Number Alterations With Survival in Metastatic Triple-Negative Breast Cancer

2018 ◽  
Vol 36 (6) ◽  
pp. 543-553 ◽  
Author(s):  
Daniel G. Stover ◽  
Heather A. Parsons ◽  
Gavin Ha ◽  
Samuel S. Freeman ◽  
William T. Barry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Copy Number ◽  
Triple Negative ◽  
Copy Number Alterations ◽  
Cell Free Dna ◽  
Primary Tumors ◽  
Free Dna ◽  
Genome Wide ◽  
Somatic Copy Number Alterations

Purpose Cell-free DNA (cfDNA) offers the potential for minimally invasive genome-wide profiling of tumor alterations without tumor biopsy and may be associated with patient prognosis. Triple-negative breast cancer (TNBC) is characterized by few mutations but extensive somatic copy number alterations (SCNAs), yet little is known regarding SCNAs in metastatic TNBC. We sought to evaluate SCNAs in metastatic TNBC exclusively via cfDNA and determine if cfDNA tumor fraction is associated with overall survival in metastatic TNBC. Patients and Methods In this retrospective cohort study, we identified 164 patients with biopsy-proven metastatic TNBC at a single tertiary care institution who received prior chemotherapy in the (neo)adjuvant or metastatic setting. We performed low-coverage genome-wide sequencing of cfDNA from plasma. Results Without prior knowledge of tumor mutations, we determined tumor fraction of cfDNA for 96.3% of patients and SCNAs for 63.9% of patients. Copy number profiles and percent genome altered were remarkably similar between metastatic and primary TNBCs. Certain SCNAs were more frequent in metastatic TNBCs relative to paired primary tumors and primary TNBCs in publicly available data sets The Cancer Genome Atlas and METABRIC, including chromosomal gains in drivers NOTCH2, AKT2, and AKT3. Prespecified cfDNA tumor fraction threshold of ≥ 10% was associated with significantly worse metastatic survival (median, 6.4 v 15.9 months) and remained significant independent of clinicopathologic factors (hazard ratio, 2.14; 95% CI, 1.4 to 3.8; P < .001). Conclusion We present the largest genomic characterization of metastatic TNBC to our knowledge, exclusively from cfDNA. Evaluation of cfDNA tumor fraction was feasible for nearly all patients, and tumor fraction ≥ 10% is associated with significantly worse survival in this large metastatic TNBC cohort. Specific SCNAs are enriched and prognostic in metastatic TNBC, with implications for metastasis, resistance, and novel therapeutic approaches.

scholarly journals Clustering-Based Method for Developing a Genomic Copy Number Alteration Signature for Predicting the Metastatic Potential of Prostate Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Alexander Pearlman ◽  
Christopher Campbell ◽  
Eric Brooks ◽  
Alex Genshaft ◽  
Shahin Shajahan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Copy Number ◽  
Copy Number Alteration ◽  
Proportional Hazards Model ◽  
Metastatic Potential ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Data Set ◽  
Primary Tumors

The transition of cancer from a localized tumor to a distant metastasis is not well understood for prostate and many other cancers, partly, because of the scarcity of tumor samples, especially metastases, from cancer patients with long-term clinical follow-up. To overcome this limitation, we developed a semi-supervised clustering method using the tumor genomic DNA copy number alterations to classify each patient into inferred clinical outcome groups of metastatic potential. Our data set was comprised of 294 primary tumors and 49 metastases from 5 independent cohorts of prostate cancer patients. The alterations were modeled based on Darwin’s evolutionary selection theory and the genes overlapping these altered genomic regions were used to develop a metastatic potential score for a prostate cancer primary tumor. The function of the proteins encoded by some of the predictor genes promote escape from anoikis, a pathway of apoptosis, deregulated in metastases. We evaluated the metastatic potential score with other clinical predictors available at diagnosis using a Cox proportional hazards model and show our proposed score was the only significant predictor of metastasis free survival. The metastasis gene signature and associated score could be applied directly to copy number alteration profiles from patient biopsies positive for prostate cancer.

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