Allelic Copy Number Variation Research Articles

Roseate and merest-acinar cell carcinoma-pancreas

Acinar cell carcinoma pancreas is an epithelial, malignant neoplasm of exocrine pancreas comprised of cells resembling pancreatic acinar cells which are immune reactive to BCL10 and trypsin. Tumefaction arises due to accumulated genetic alterations, chromosomal instability or allelic copy number variation. Cogent clinical symptoms as abdominal pain, dorso-lumbar pain, loss of weight, nausea or vomiting or subcutaneous fat necrosis may ensue. Grossly, a solid, enlarged, well circumscribed, partially encapsulated tumefaction of fleshy consistency is encountered. Neoplastic cells demonstrate granular, eosinophilic cytoplasm pervaded with zymogen granules stainable with periodic acid Schiff’s (PAS) stain with diastase resistance, uniform nuclei and a singular, prominent nucleolus. Scanty and fibrous encompassing stroma exhibits foci of perineural and vascular invasion. Acinar cell carcinoma pancreas is immune reactive to keratins as CK7, CK8, CK18, CK19, BCL10, trypsin nuclear beta catenin or CD200. Computerized tomography (CT) and magnetic resonance imaging (MRI) delineates an enlarged tumefaction with well-defined perimeter, an exophytic pattern of tumour evolution and heterogeneous image enhancement. Surgical resection, chemotherapy with gemcitabine or radiofrequency ablation are appropriate modes of therapy.

Mutations in ASIP and MC1R: dominant black and recessive black alleles segregate in native Swedish sheep populations.

By studying genes associated with coat colour, we can understand the role of these genes in pigmentation but also gain insight into selection history. North European short-tailed sheep, including Swedish breeds, have variation in their coat colour, making them good models to expand current knowledge of mutations associated with coat colour in sheep. We studied ASIP and MC1R, two genes with known roles in pigmentation, and their association with black coat colour. We did this by sequencing the coding regions of ASIP in 149 animals and MC1R in 129 animals from seven native Swedish sheep breeds in individuals with black, white or grey fleece. Previously known mutations in ASIP [recessive black allele: g.100_105del (D5 ) and/or g.5172T>A] were associated with black coat colour in Klövsjö and Roslag sheep breeds and mutations in both ASIP and MC1R (dominant black allele: c.218T>A and/or c.361G>A) were associated with black coat colour in Swedish Finewool. In Gotland, Gute, Värmland and Helsinge sheep breeds, coat colour inheritance was more complex: only 11 of 16 individuals with black fleece had genotypes that could explain their black colour. These breeds have grey individuals in their populations, and grey is believed to be a result of mutations and allelic copy number variation within the ASIP duplication, which could be a possible explanation for the lack of a clear inheritance pattern in these breeds. Finally, we found a novel missense mutation in MC1R (c.452G>A) in Gotland, Gute and Värmland sheep and evidence of a duplication of MC1R in Gotland sheep.

Abstract 3581: GATK ACNV: allelic copy-number variation discovery from SNPs and coverage data

Abstract The presence of somatic copy-number alterations in tumor genomes can be used to predict both patient sensitivity to treatments as well as outcomes. The inclusion of allelic data improves statistical power to detect copy-number events and allows for discovery of copy-neutral events. We present GATK ACNV, an allelic copy-number variation method built on the Genome Analysis Toolkit. ACNV is a tool for detecting somatic copy-number activity from whole exome and whole genome sequencing data by segmenting the genome into regions of constant copy number and estimating copy ratio and minor-allele fraction in those regions. ACNV uses a novel probabilistic model to account for reference bias (optionally using a panel of normals), which improves the estimation of minor-allele fraction. We combine this with the coverage model from GATK CNV by segmenting with a unified hidden Markov model, improving the statistical power to detect copy-number variation. We validate ACNV using a purity series of the cell line HCC1143 and cancer samples from The Cancer Genome Atlas. Our results show that ACNV is able to discover regions of somatic copy-number activity accurately and with high resolution in both whole exome and whole genome sequencing data. Citation Format: Aaron Chevalier, Lee Lichtenstein, Andrey Smirnov, Samuel K. Lee, Mehrtash Babidi, David I. Benjamin, Valentin Ruano-Rubio. GATK ACNV: allelic copy-number variation discovery from SNPs and coverage data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3581. doi:10.1158/1538-7445.AM2017-3581

Subclassification of diffuse glioma tumours based on gene expression and allele copy number variation

Subclassification of diffuse glioma tumours based on gene expression and allele copy number variation

MHC gene copy number variation in Tasmanian devils: implications for the spread of a contagious cancer.

Tasmanian devils face extinction owing to the emergence of a contagious cancer. Devil facial tumour disease (DFTD) is a clonal cancer spread owing to a lack of major histocompatibility complex (MHC) barriers in Tasmanian devil populations. We present a comprehensive screen of MHC diversity in devils and identify 25 MHC types and 53 novel sequences, but conclude that overall levels of MHC diversity at the sequence level are low. The majority of MHC Class I variation can be explained by allelic copy number variation with two to seven sequence variants identified per individual. MHC sequences are divided into two distinct groups based on sequence similarity. DFTD cells and most devils have sequences from both groups. Twenty per cent of individuals have a restricted MHC repertoire and contain only group I or only group II sequences. Counterintuitively, we postulate that the immune system of individuals with a restricted MHC repertoire may recognize foreign MHC antigens on the surface of the DFTD cell. The implication of these results for management of DFTD and this endangered species are discussed.

Allelic Copy Number Variation inFSCN2Detected Using Allele-Specific Genotyping and Multiplex Real-Time PCRs

Allelic copy number variation (CNV) may alter the functional effects of a heterozygous mutation. The underlying mechanisms and their roles in hereditary diseases, however, are largely unknown. In the present study an FSCN2 mutation was examined that has been reported, not only in patients with retinitis pigmentosa (RP), but also in the normal population. Experiments were performed to investigate the gene and allele copy numbers of FSCN2 in patients with RP who have the c.72delG mutation as well as healthy subjects with or without the mutation. A real-time PCR-based genotyping approach was established that used a real-time PCR assay to qualify the copy numbers of both the wild-type and mutant alleles of the FSCN2 gene. Three patients with RP and three normal subjects had an equal ratio of the alleles. Of interest, another patient had an asymmetric allele ratio (4:1) of the copy number of the wild-type allele, compared with that of the mutant allele. These findings were further verified using quantitative assays. An allele-specific methylation assay demonstrated a random methylation pattern in the FSCN2 gene. The copy numbers of the FSNC2 gene and of each allele in the mutant samples were quantified. The findings excluded the possibility that allelic CNV was associated with RP, suggesting that the c.72delG variant is not the primary cause of RP. It is not likely that the FSCN2 gene is imprinted differentially. The real-time PCR-based genotyping method developed in this study is useful for investigations of allelic asymmetries within genomic regions with CNVs.