scholarly journals Origins of cancer genome complexity revealed by haplotype-resolved genomic analysis of evolution of Barretts esophagus to esophageal adenocarcinoma

2021 ◽  
Author(s):  
Cheng-Zhong Zhang ◽  
Matthew Stachler ◽  
Chunyang Bao ◽  
Richard Tourdot ◽  
Gregory J. Brunette ◽  
...  
Keyword(s):  
Esophageal Adenocarcinoma ◽  
Copy Number ◽  
Precancerous Lesions ◽  
Genomic Analysis ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
Chromosomal Alterations ◽  
Dicentric Chromosomes ◽  
Abnormal Mitosis ◽  
Barretts Esophagus

Complex chromosomal alterations are a hallmark of advanced cancers but rarely seen in normal tissue. The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations that can drive their transformation through focal oncogenic amplifications. However, the etiology and evolution dynamics of these alterations are poorly understood. Here we study chromosomal copy-number evolution in the progression of Barretts esophagus (BE) to esophageal adenocarcinoma (EAC) by multi-regional whole-genome sequencing analysis of BE samples with dysplasia and microscopic EAC foci. Through haplotype-specific copy-number analysis of BE genome evolution, we identified distinct patterns of episodic copy-number evolution consistent with the outcomes of abnormal mitosis and dicentric chromosome breakage. While abnormal mitosis, including whole-genome duplication, accounts for most chromosome or arm-level copy-number changes, segmental copy-number alterations display signatures of multi-generational evolution of unstable dicentric chromosomes. Continuous evolution of dicentric chromosomes through breakage-fusion-bridge cycles and chromothripsis rapidly increases genomic complexity and diversity among BE cells, culminating in the generation of distinct focal amplifications. These mutational processes enable multiple subclones within small dysplastic areas to undergo parallel transformation to cancer following acquisition of distinct oncogenic amplifications. Our results demonstrate how chromosomal instability drives clonal diversification in precancer evolution and promotes tumorigenesis in primary human samples.

scholarly journals Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3394
Author(s):  
Fereshteh Izadi ◽  
Benjamin Sharpe ◽  
Stella Breininger ◽  
Maria Secrier ◽  
Jane Gibson ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
Copy Number ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Genomic Analysis ◽  
Tumor Regression Grade ◽  
Comparative Genomic ◽  
Mutation Burden ◽  
Response To Neoadjuvant Chemotherapy

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20–37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1–2 (n = 27) and non-responders classified as TRG4–5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

scholarly journals Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define premalignant neurofibromatosis type 1–associated atypical neurofibromas

2019 ◽  
Vol 21 (8) ◽  
pp. 981-992 ◽  
Author(s):  
Alexander Pemov ◽  
Nancy F Hansen ◽  
Sivasish Sindiri ◽  
Rajesh Patidar ◽  
Christine S Higham ◽  
...  
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Copy Number ◽  
Meta Analysis ◽  
Chromosomal Rearrangements ◽  
Genomic Analysis ◽  
Neurofibromatosis Type ◽  
Intermediate Step ◽  
Nerve Sheath Tumor ◽  
Sequencing Analysis

Abstract Background Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8–16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from preexisting benign plexiform neurofibromas (PNs) and atypical neurofibromas (ANFs). ANFs are distinct from both PN and MPNST, representing an intermediate step in malignant transformation. Methods In the first comprehensive genomic analysis of ANF originating from multiple patients, we performed tumor/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of 3 MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of 5 ANFs and 5 MPNSTs. Results We identified a low number of mutations (median 1, range 0–5) in the exomes of ANFs (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/B (69%) and SMARCA2 (42%). We determined that polycomb repressor complex 2 (PRC2) genes EED and SUZ12 were frequently mutated, deleted, or downregulated in MPNSTs but not in ANFs. Our pilot gene expression study revealed upregulated NRAS, MDM2, CCND1/2/3, and CDK4/6 in ANFs and MPNSTs, and overexpression of EZH2 in MPNSTs only. Conclusions The PN-ANF transition is primarily driven by the deletion of CDKN2A/B. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction and cell-cycle and pluripotency self-renewal genes.

scholarly journals Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

2021 ◽  
Author(s):  
Fereshteh Izadi ◽  
Benjamin P Sharpe ◽  
Stella P Breininger ◽  
Maria Secrier ◽  
Jane Gibson ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
Copy Number ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Genomic Analysis ◽  
Tumor Regression Grade ◽  
Comparative Genomic ◽  
Mutation Burden ◽  
Response To Neoadjuvant Chemotherapy

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (<20%), as is the overall survival benefit at 5 years (5%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n=27) and non-responders classified as TRG4-5 (n=38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient, P<0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

0306 Exploring the feasibility of using copy number variants as genetic markers through large-scale whole genome sequencing experiments

2016 ◽  
Vol 94 (suppl_5) ◽  
pp. 146-146
Author(s):  
D. M. Bickhart ◽  
L. Xu ◽  
J. L. Hutchison ◽  
J. B. Cole ◽  
D. J. Null ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genetic Markers ◽  
Genome Sequencing ◽  
Copy Number ◽  
Large Scale ◽  
Copy Number Variants ◽  
Whole Genome

scholarly journals Whole-genome sequencing from the New Zealand Saccharomyces cerevisiae population reveals the genomic impacts of novel microbial range expansion

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Peter Higgins ◽  
Cooper A Grace ◽  
Soon A Lee ◽  
Matthew R Goddard
Keyword(s):  
Saccharomyces Cerevisiae ◽  
New Zealand ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Range Expansion ◽  
Copy Number ◽  
Small Scale ◽  
Whole Genome ◽  
Copy Number Changes ◽  
The Impact

Abstract Saccharomyces cerevisiae is extensively utilized for commercial fermentation, and is also an important biological model; however, its ecology has only recently begun to be understood. Through the use of whole-genome sequencing, the species has been characterized into a number of distinct subpopulations, defined by geographical ranges and industrial uses. Here, the whole-genome sequences of 104 New Zealand (NZ) S. cerevisiae strains, including 52 novel genomes, are analyzed alongside 450 published sequences derived from various global locations. The impact of S. cerevisiae novel range expansion into NZ was investigated and these analyses reveal the positioning of NZ strains as a subgroup to the predominantly European/wine clade. A number of genomic differences with the European group correlate with range expansion into NZ, including 18 highly enriched single-nucleotide polymorphism (SNPs) and novel Ty1/2 insertions. While it is not possible to categorically determine if any genetic differences are due to stochastic process or the operations of natural selection, we suggest that the observation of NZ-specific copy number increases of four sugar transporter genes in the HXT family may reasonably represent an adaptation in the NZ S. cerevisiae subpopulation, and this correlates with the observations of copy number changes during adaptation in small-scale experimental evolution studies.

scholarly journals Whole-Genome DNA Methylation Analysis in Hydrogen Peroxide Overproducing Transgenic Tobacco Resistant to Biotic and Abiotic Stresses

Plants ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 178
Author(s):  
Ana L. Villagómez-Aranda ◽  
Luis F. García-Ortega ◽  
Irineo Torres-Pacheco ◽  
Ramón G. Guevara-González
Keyword(s):  
Hydrogen Peroxide ◽  
Dna Methylation ◽  
Transgenic Tobacco ◽  
Stress Responses ◽  
Abiotic Stresses ◽  
Methylation Status ◽  
Physiological Adaptation ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
Biotic And Abiotic Stresses

Epigenetic regulation is a key component of stress responses, acclimatization and adaptation processes in plants. DNA methylation is a stable mark plausible for the inheritance of epigenetic traits, such that it is a potential scheme for plant breeding. However, the effect of modulators of stress responses, as hydrogen peroxide (H2O2), in the methylome status has not been elucidated. A transgenic tobacco model to the CchGLP gene displayed high H2O2 endogen levels correlated with biotic and abiotic stresses resistance. The present study aimed to determine the DNA methylation status changes in the transgenic model to obtain more information about the molecular mechanism involved in resistance phenotypes. The Whole-genome bisulfite sequencing analysis revealed a minimal impact of overall levels and distribution of methylation. A total of 9432 differential methylated sites were identified in distinct genome regions, most of them in CHG context, with a trend to hypomethylation. Of these, 1117 sites corresponded to genes, from which 83 were also differentially expressed in the plants. Several genes were associated with respiration, energy, and calcium signaling. The data obtained highlighted the relevance of the H2O2 in the homeostasis of the system in stress conditions, affecting at methylation level and suggesting an association of the H2O2 in the physiological adaptation to stress functional linkages may be regulated in part by DNA methylation.

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