scholarly journals The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia

2015 ◽  
Vol 173 (4) ◽  
pp. 435-440 ◽  
Author(s):  
Ricardo Correa ◽  
Mihail Zilbermint ◽  
Annabel Berthon ◽  
Stephanie Espiard ◽  
Maria Batsis ◽  
...  
Keyword(s):  
Germline Mutation ◽  
Genetic Variance ◽  
Somatic Mutations ◽  
Adrenal Glands ◽  
Suppressor Gene ◽  
Single Patient ◽  
Rare Type ◽  
Somatic Variant ◽  
Site Variation ◽  
Sanger Method

ObjectivePrimary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing's syndrome (CS) that results in increased cortisol production and bilateral enlargement of the adrenal glands. Recent work showed that the disease may be caused by germline and somatic mutations in the ARMC5 gene, a likely tumor suppressor gene (TSG). We investigated 20 different adrenal nodules from one patient with PMAH for ARMC5 somatic sequence changes.DesignAll of the nodules were obtained from a single patient who underwent bilateral adrenalectomy. DNA was extracted by standard protocol and the ARMC5 sequence was determined by the Sanger method.ResultsSixteen of 20 adrenocortical nodules harbored, in addition to what appeared to be the germline mutation, a second somatic variant. The p.Trp476* sequence change was present in all 20 nodules, as well as in normal tissue from the adrenal capsule, identifying it as the germline defect; each of the 16 other variants were found in different nodules: six were frame shift, four were missense, three were nonsense, and one was a splice site variation. Allelic losses were confirmed in two of the nodules.ConclusionThis is the most genetic variance of the ARMC5 gene ever described in a single patient with PMAH: each of 16 adrenocortical nodules had a second new, ‘private,’ and – in most cases – completely inactivating ARMC5 defect, in addition to the germline mutation. The data support the notion that ARMC5 is a TSG that needs a second, somatic hit, to mediate tumorigenesis leading to polyclonal nodularity; however, the driver of this extensive genetic variance of the second ARMC5 allele in adrenocortical tissue in the context of a germline defect and PMAH remains a mystery.

scholarly journals Comprehensive integrative profiling of upper tract urothelial carcinomas

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xiaoping Su ◽  
Xiaofan Lu ◽  
Sehrish Khan Bazai ◽  
Eva Compérat ◽  
Roger Mouawad ◽  
...  
Keyword(s):  
Patient Outcome ◽  
Somatic Mutations ◽  
Suppressor Gene ◽  
Epigenetic Alterations ◽  
Upper Tract ◽  
Urothelial Carcinomas ◽  
Immune Alterations ◽  
Invasive Status ◽  
Muscle Invasive ◽  
First Time

Abstract Background Crosstalk between genetic, epigenetic, and immune alterations in upper tract urothelial carcinomas and their role in shaping muscle invasiveness and patient outcome are poorly understood. Results We perform an integrative genome- and methylome-wide profiling of diverse non-muscle-invasive and muscle-invasive upper tract urothelial carcinomas. In addition to mutations of FGFR3 and KDM6A, we identify ZFP36L1 as a novel, significantly mutated tumor suppressor gene. Overall, mutations of ZFP36 family genes (ZFP36, ZFP36L1, and ZFP36L2) are identified in 26.7% of cases, which display a high mutational load. Unsupervised DNA methylation subtype classification identifies two epi-clusters associated with distinct muscle-invasive status and patient outcome, namely, EpiC-low and EpiC-high. While the former is hypomethylated, immune-depleted, and enriched for FGFR3-mutated, the latter is hypermethylated, immune-infiltrated, and tightly associated with somatic mutations of SWI/SNF genes. Conclusions Our study delineates for the first time the key role for convergence between genetic and epigenetic alterations in shaping clinicopathological and immune upper tract urothelial carcinoma features.

scholarly journals Accuracy of Ranking Individuals in Field Tests of Different Designs: A Computer Simulation

2006 ◽  
Vol 55 (1-6) ◽  
pp. 70-77 ◽  
Author(s):  
Chang-Yi Xie ◽  
Y.-B. Fu ◽  
A. D. Yanchuk
Keyword(s):  
Computer Simulation ◽  
Genetic Variance ◽  
Block Design ◽  
Additive Genetic Variance ◽  
Field Tests ◽  
Incomplete Block ◽  
Single Tree ◽  
Incomplete Block Design ◽  
Variation Patterns ◽  
Site Variation

Abstract A computer simulation was conducted to investigate the accuracy of ranking individual trees in field tests of different designs. A test population that consists of 900 trees from 45 full-sib families generated by three 6-parent disconnected half-diallels was considered. One incomplete block design with single-tree plots and four complete block designs with 1, 2, 4, and 10-tree row plots were examined. Various narrow-sense heritabilities, site variation patterns (patch sizes and gradient slopes), and two levels of dominant to additive genetic variance ratios (0 and 0.30) were evaluated. Results indicate that the accuracy of ranking depends more on the heritability of the trait and less on the magnitude of the dominant genetic variance, site variation patterns, and field designs. With patchy site variation, differences in ranking accuracy were observed for different designs, but became smaller with higher heritabilities. Impact of environmental gradient on the accuracy of individual ranking was negligible. Incomplete block design with single-tree plots (ICB1) provided the most accurate ranking when heritability was low while complete block design with 2-tree plots (RCB2) appeared to be the best when heritability was high. Large row plot designs were among the least effective in all the simulated scenarios. For traits with medium heritabilities, the statistical efficiencies of ICB1 and RCB with 1 and 2-tree plots are comparable.

scholarly journals Aristolochic Acid and Immunotherapy for Urothelial Carcinoma: Directions for unmet Needs

2019 ◽  
Vol 20 (13) ◽  
pp. 3162 ◽  
Author(s):  
Huang-Yu Yang ◽  
Chih-Chao Yang ◽  
Chao-Yi Wu ◽  
Li-Jen Wang ◽  
Kun-Lin Lu
Keyword(s):  
Urothelial Carcinoma ◽  
Somatic Mutations ◽  
Aristolochic Acid ◽  
Suppressor Gene ◽  
Immune Checkpoint Blockade ◽  
Current State ◽  
Close Relationship ◽  
Tp53 Tumor Suppressor Gene ◽  
Treatment Responses ◽  
Carcinoma Of The Bladder

Urothelial carcinoma of the bladder (UCB) and upper tracts (UTUC) used to share management with similar principles. However, their genetic and epigenetic differences along with different responses to immunotherapy were recently identified, which are reminiscent of their distinct etiologies. Different from the variety of environmental factors relating to UCB, UTUC is best known for its close relationship with exposure to aristolochic acid (AA). AA is believed to cause its carcinogenicity through forming DNA adducts of deoxyadenosine-aristolactam, as well as A:T → T:A transversions in the TP53 tumor suppressor gene. Since recent findings suggested that cancers with higher somatic mutations are associated with better treatment responses upon immune checkpoint blockade, UTUC and AA-related biomarkers reasonably serve as good candidates, as well as a potential prognostic predictor for the flourishing immunotherapy. This review covers the current state of the literature on the clinical response of UTUC and UCB receiving immunotherapy and points out directions for refinement regarding patient selection.

Abstract 2201: Involvement of somatic mutations in silencing cystatin E/M tumor suppressor gene in breast cancer

2011 ◽  
Author(s):  
Natarajan Venkatesan ◽  
Shawnt P. Issakhanian ◽  
Charles G. Ginther ◽  
Dennis J. Slamon ◽  
Eri S. Srivatsan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Somatic Mutations ◽  
Suppressor Gene

scholarly journals Aldosterone-Producing Cell Clusters in Normal and Pathological States

2017 ◽  
Vol 49 (12) ◽  
pp. 951-956 ◽  
Author(s):  
Kei Omata ◽  
Scott Tomlins ◽  
William Rainey
Keyword(s):  
Somatic Mutations ◽  
Adrenal Glands ◽  
Normal Subjects ◽  
Cardiovascular Complications ◽  
Cell Clusters ◽  
Key Factor ◽  
Aldosterone Producing Adenoma ◽  
Next Generation Sequencing Ngs ◽  
Small Clusters ◽  
Generation Sequencing

AbstractPrimary aldosteronism (PA) significantly increases the risk of cardiovascular complications, and early diagnosis and targeted treatment based on its pathophysiology is warranted. Next-generation sequencing (NGS) has revealed recurrent somatic mutations in aldosterone-driving genes in aldosterone-producing adenoma (APA). By applying CYP11B2 (aldosterone synthase) immunohistochemistry and NGS to adrenal glands from normal subjects and PA patients, we and others have shown that CYP11B2-positive cells make small clusters, termed aldosterone-producing cell clusters (APCC), beneath the adrenal capsule, and that APCC harbor somatic mutations in genes mutated in APA. We have shown that APCC are increased in CT-negative PA adrenals, while others showed potential progression from APCC to micro APA through mutations. These results suggest that APCC are a key factor for understanding the origin of PA, and further investigation on the relation between APCC and PA is highly needed.

Detection of a germline mutation and somatic homozygous loss of the von Hippel-Lindau tumor-suppressor gene in a family with a de novo mutation

1996 ◽  
Vol 97 (6) ◽  
pp. 770-776 ◽  
Author(s):  
H.-J. H. Decker ◽  
Christine Neuhaus ◽  
Anna Jauch ◽  
M. Speicher ◽  
T. Ried ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Germline Mutation ◽  
De Novo ◽  
Suppressor Gene ◽  
De Novo Mutation ◽  
Von Hippel Lindau

scholarly journals TNscope: Accurate Detection of Somatic Mutations with Haplotype-based Variant Candidate Detection and Machine Learning Filtering

2018 ◽  
Author(s):  
Donald Freed ◽  
Renke Pan ◽  
Rafael Aldana
Keyword(s):  
Machine Learning ◽  
Normal Tissue ◽  
Structural Variation ◽  
Somatic Mutations ◽  
Variant Calling ◽  
Somatic Variant ◽  
Accurate Detection ◽  
Machine Learning Model ◽  
Early Engineering ◽  
Somatic Mutation Calling

AbstractDetection of somatic mutations in tumor samples is important in the clinic, where treatment decisions are increasingly based upon molecular diagnostics. However, accurate detection of these mutations is difficult, due in part to intra-tumor heterogeneity, contamination of the tumor sample with normal tissue and pervasive structural variation. Here, we describe Sentieon TNscope, a haplotype-based somatic variant caller with increased accuracy relative to existing methods. An early engineering version of TNscope was used in our submission to the most recent ICGC-DREAM Somatic Mutation calling challenge. In that challenge, TNscope is the leader in accuracy for SNVs, indels and SVs. To further improve variant calling accuracy, we combined the improvements in the variant caller with machine learning. We benchmarked TNscope using in-silico mixtures of well-characterized Genome in a Bottle (GIAB) samples. TNscope displays higher accuracy than the other benchmarked tools and the accuracy is substantially improved by the machine learning model.

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