The Degree of Segmental Aneuploidy Measured by Total Copy Number Abnormalities Predicts Survival and Recurrence in Superficial Gastroesophageal Adenocarcinoma

62 Background: Prognostic biomarkers are needed for superficial gastroesophageal adenocarcinoma (EAC) to predict clinical outcomes and select therapy. Although recurrent mutations have been characterized in EAC, little is known about their clinical and prognostic significance. Aneuploidy is predictive of clinical outcome in many malignancies but has not been evaluated in superficial EAC. SNP arrays offer the opportunity to evaluate segmental aneuploidy at high resolution throughout the genome. Methods: We quantified copy number changes in 41 superficial EAC using Affymetrix SNP 6.0 arrays. We identified recurrent chromosomal gains and losses and calculated the total copy number abnormality (CNA) count for each tumor as a measure of aneuploidy. We correlated CNA count with overall survival and time to first recurrence in univariate and multivariate analyses. Results: Recurrent segmental gains and losses involved multiple genes, including: HER2, EGFR, MET, CDK6 , KRAS (recurrent gains); and FHIT, WWOX, CDKN2A/B, SMAD4, RUNX1 (recurrent losses). There was a 40-fold variation in CNA count across all cases. Tumors with the lowest and highest quartile CNA count had significantly better overall survival (p=0.032, log rank test) and time to first recurrence (p=0.010, log rank test) compared to those with intermediate CNA counts. In multivariate Cox analysis, there was a 3.4-fold (95% CI, 1.1–10.4) increased hazard of death among cases with intermediate CNA counts after adjusting for other predictors of survival (N stage, angiolymphatic invasion and tumor size). Similarly, there was a 7.3-fold (95% CI, 1.5-34) increased risk of recurrence for these patients. Conclusions: SNP arrays facilitate the assessment of recurrent chromosomal gain and loss and allow high resolution, quantitative assessment of segmental aneuploidy (total CNA count).The non-monotonic association of segmental aneuploidy with survival has been described in other tumors such as breast and ovarian carcinoma. The degree of segmental aneuploidy is a promising prognostic biomarker in a potentially curable form of EAC.

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Expression of a retroposon-like sequence upstream of the putative Trypanosoma brucei variant surface glycoprotein gene expression site promoter

Molecular and Cellular Biology ◽

10.1128/mcb.13.11.7036-7044.1993 ◽

1993 ◽

Vol 13 (11) ◽

pp. 7036-7044

Author(s):

M J Lodes ◽

B L Smiley ◽

A W Stadnyk ◽

J L Bennett ◽

P J Myler ◽

...

Keyword(s):

Gene Expression ◽

Trypanosoma Brucei ◽

Copy Number ◽

Surface Glycoprotein ◽

Variant Surface Glycoprotein ◽

Putative Promoter ◽

Glycoprotein Gene ◽

Active Expression ◽

Expression Site ◽

Total Copy Number

We have cloned the region spanning the putative promoter from two variant surface glycoprotein gene expression sites that are at each end of chromosome M4 of Trypanosoma brucei IsTat 7. Both expression sites contain a retroposon-like sequence (ESR) pseudogene whose 3' end is approximately 30 bp upstream of the putative expression site promoter. The ESRs from both expression sites share considerable sequence homology and are related to LINE-like elements, especially the T. brucei ingi retroposon. Other ESRs are located on large, but not intermediate or mini-, chromosomes in the IsTaR 1 serodeme, and the total copy number is 10 to 20, similar to that estimated for variant surface glycoprotein expression sites. No DNA rearrangements in the vicinity of the ESR and putative expression site promoter were detected following antigenic switches in the IsTaR 1 serodeme. ESR transcripts are present in bloodstream, but not procyclic, forms. Variation in transcript size and sequence between bloodstream variant antigenic types implies that only the ESR from the active expression site is transcribed. This pattern of expression reflects that of sequences downstream of the putative expression site promoter, suggesting that the region of coordinately controlled expression extends upstream of this promoter.

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Expression of a retroposon-like sequence upstream of the putative Trypanosoma brucei variant surface glycoprotein gene expression site promoter.

Molecular and Cellular Biology ◽

10.1128/mcb.13.11.7036 ◽

1993 ◽

Vol 13 (11) ◽

pp. 7036-7044 ◽

Cited By ~ 11

Author(s):

M J Lodes ◽

B L Smiley ◽

A W Stadnyk ◽

J L Bennett ◽

P J Myler ◽

...

Keyword(s):

Gene Expression ◽

Trypanosoma Brucei ◽

Copy Number ◽

Surface Glycoprotein ◽

Variant Surface Glycoprotein ◽

Putative Promoter ◽

Glycoprotein Gene ◽

Active Expression ◽

Expression Site ◽

Total Copy Number

We have cloned the region spanning the putative promoter from two variant surface glycoprotein gene expression sites that are at each end of chromosome M4 of Trypanosoma brucei IsTat 7. Both expression sites contain a retroposon-like sequence (ESR) pseudogene whose 3' end is approximately 30 bp upstream of the putative expression site promoter. The ESRs from both expression sites share considerable sequence homology and are related to LINE-like elements, especially the T. brucei ingi retroposon. Other ESRs are located on large, but not intermediate or mini-, chromosomes in the IsTaR 1 serodeme, and the total copy number is 10 to 20, similar to that estimated for variant surface glycoprotein expression sites. No DNA rearrangements in the vicinity of the ESR and putative expression site promoter were detected following antigenic switches in the IsTaR 1 serodeme. ESR transcripts are present in bloodstream, but not procyclic, forms. Variation in transcript size and sequence between bloodstream variant antigenic types implies that only the ESR from the active expression site is transcribed. This pattern of expression reflects that of sequences downstream of the putative expression site promoter, suggesting that the region of coordinately controlled expression extends upstream of this promoter.

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Genetic characterization of large parathyroid adenomas

Endocrine Related Cancer ◽

10.1530/erc-11-0140 ◽

2012 ◽

Vol 19 (3) ◽

pp. 389-407 ◽

Cited By ~ 19

Author(s):

Luqman Sulaiman ◽

Inga-Lena Nilsson ◽

C Christofer Juhlin ◽

Felix Haglund ◽

Anders Höög ◽

...

Keyword(s):

Copy Number ◽

Clinical Manifestations ◽

Relative Number ◽

Copy Number Gain ◽

Proliferation Index ◽

Chromosome 11 ◽

Parathyroid Adenomas ◽

Independent Observations ◽

Total Copy Number

In this study, we genetically characterized parathyroid adenomas with large glandular weights, for which independent observations suggest pronounced clinical manifestations. Large parathyroid adenomas (LPTAs) were defined as the 5% largest sporadic parathyroid adenomas identified among the 590 cases operated in our institution during 2005–2009. The LPTA group showed a higher relative number of male cases and significantly higher levels of total plasma and ionized serum calcium (P<0.001). Further analysis of 21 LPTAs revealed low MIB1 proliferation index (0.1–1.5%),MEN1mutations in five cases, and oneHRPT2(CDC73) mutation. Total or partial loss of parafibromin expression was observed in ten tumors, two of which also showed loss of APC expression. Using array CGH, we demonstrated recurrent copy number alterations most frequently involving loss in 1p (29%), gain in 5 (38%), and loss in 11q (33%). Totally, 21 minimal overlapping regions were defined for losses in 1p, 7q, 9p, 11, and 15q and gains in 3q, 5, 7p, 8p, 16q, 17p, and 19q. In addition, 12 tumors showed gross alterations of entire or almost entire chromosomes most frequently gain of 5 and loss of chromosome 11. While gain of 5 was the most frequent alteration observed in LPTAs, it was only detected in a small proportion (4/58 cases, 7%) of parathyroid adenomas. A significant positive correlation was observed between parathyroid hormone level and total copy number gain (r=0.48,P=0.031). These results support that LPTAs represent a group of patients with pronounced parathyroid hyperfunction and associated with specific genomic features.

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Rawcopy: Improved copy number analysis with Affymetrix arrays

10.1101/027409 ◽

2015 ◽

Author(s):

Markus Mayrhofer ◽

Bjorn Viklund ◽

Anders Isaksson

Keyword(s):

Copy Number ◽

Signal To Noise Ratio ◽

R Package ◽

Copy Number Analysis ◽

Genome Wide ◽

Microarray Sample ◽

Allele Specific ◽

Log Ratio ◽

Reference Samples ◽

Total Copy Number

Rawcopy is an R package for processing of Affymetrix CytoScan HD, CytoScan 750k and SNP 6.0 microarray raw intensities (CEL files). It uses data from a large number of reference samples to produce log ratio for total copy number analysis and B-allele frequency for allele-specific copy number and heterozygosity analysis. Rawcopy achieves higher signal-to-noise ratio than commonly used free and proprietary alternatives, leading to improved identification of copy number alterations. In addition, Rawcopy visualises each microarray sample for assessment of technical quality, patient identity and genome-wide absolute copy number states.

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Establishing a prognostic threshold for total copy number variation within adult IDH-mutant grade II/III astrocytomas

Acta Neuropathologica Communications ◽

10.1186/s40478-019-0778-3 ◽

2019 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Kanish Mirchia ◽

Matija Snuderl ◽

Kristyn Galbraith ◽

Kimmo J. Hatanpaa ◽

Jamie M. Walker ◽

...

Keyword(s):

Copy Number Variation ◽

Copy Number ◽

Number Variation ◽

Grade Ii ◽

Total Copy Number

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Possible Phenotypic Consequences of Structural Differences in Idic(15) in a Small Cohort of Patients

International Journal of Molecular Sciences ◽

10.3390/ijms20194935 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4935

Author(s):

Márta Czakó ◽

Ágnes Till ◽

András Szabó ◽

Réka Ripszám ◽

Béla Melegh ◽

...

Keyword(s):

Copy Number ◽

Clinical Symptoms ◽

Copy Number Gain ◽

Genomic Region ◽

Comparative Genomic ◽

Chromosome 15 ◽

Factors Influencing ◽

15Q Duplication ◽

Segmental Aneuploidy ◽

Structural Differences

Among human supernumerary marker chromosomes, the occurrence of isodicentric form of 15 origin is relatively well known due to its high frequency, both in terms of gene content and associated clinical symptoms. The associated epilepsy and autism are typically more severe than in cases with interstitial 15q duplication, despite copy number gain of approximately the same genomic region. Other mechanisms besides segmental aneuploidy and epigenetic changes may also cause this difference. Among the factors influencing the expression of members of the GABAA gene cluster, the imprinting effect and copy number differences has been debated. Limited numbers of studies investigate factors influencing the interaction of GABAA cluster homologues. Five isodicentric (15) patients are reported with heterogeneous symptoms, and structural differences of their isodicentric chromosomes based on array comparative genomic hybridization results. Relations between the structure and the heterogeneous clinical picture are discussed, raising the possibility that the structure of the isodicentric (15), which has an asymmetric breakpoint and consequently a lower copy number segment, would be the basis of the imbalance of the GABAA homologues. Studies of trans interaction and regulation of GABAA cluster homologues are needed to resolve this issue, considering copy number differences within the isodicentric chromosome 15.

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Mouse Models of Aneuploidy

The Scientific World JOURNAL ◽

10.1100/2012/214078 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 7

Author(s):

Olivia Sheppard ◽

Frances K. Wiseman ◽

Aarti Ruparelia ◽

Victor L. J. Tybulewicz ◽

Elizabeth M. C. Fisher

Keyword(s):

Mouse Models ◽

Copy Number ◽

Gene Dosage ◽

Altered States ◽

Cognitive Effects ◽

Complex Phenotype ◽

Animal System ◽

Segmental Aneuploidy ◽

Number Of Genes ◽

Number Variation

Abnormalities of chromosome copy number are called aneuploidies and make up a large health load on the human population. Many aneuploidies are lethal because the resulting abnormal gene dosage is highly deleterious. Nevertheless, some whole chromosome aneuploidies can lead to live births. Alterations in the copy number of sections of chromosomes, which are also known as segmental aneuploidies, are also associated with deleterious effects. Here we examine how aneuploidy of whole chromosomes and segmental aneuploidy of chromosomal regions are modeled in the mouse. These models provide a whole animal system in which we aim to investigate the complex phenotype-genotype interactions that arise from alteration in the copy number of genes. Although our understanding of this subject is still in its infancy, already research in mouse models is highlighting possible therapies that might help alleviate the cognitive effects associated with changes in gene number. Thus, creating and studying mouse models of aneuploidy and copy number variation is important for understanding what it is to be human, in both the normal and genomically altered states.

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