Exploring the genomic landscape of hepatobiliary cancers to establish a novel molecular subtype classification.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 562-562
Author(s):  
Anthony Joseph Scholer ◽  
Mary Garland-Kledzik ◽  
Debopyria Ghosh ◽  
Juan Santamaria-Barria ◽  
Adam Khader ◽  
...  
Keyword(s):  
Information Exchange ◽  
Molecular Subtype ◽  
Gene Mutations ◽  
Missense Variant ◽  
Multidimensional Analysis ◽  
Upstream Gene ◽  
Subtype Classification ◽  
Hepatobiliary Cancer ◽  
Genomic Landscape ◽  
Molecular Phenotypes

562 Background: The current understanding of the genomic landscape of hepatobiliary cancer (HBC) is limited. Recent genomic and epigenomic studies have demonstrated that various cancers of different tissue origins can have similar molecular phenotypes. Therefore, the aim of this study is to evaluate the genomic alterations of HBCs as a first step towards creating a novel molecular subtype classification. Methods: A multidimensional analysis of next-generation sequencing for the genomic landscape of HBCs was conducted using mutational data from the AACR-Genomics Evidence Neoplasia Information Exchange database (v. 5.0). From 61 gene mutation platforms, we found 42 genes common to all HBC cases. Associations between histomolecular characteristics of HBCs (hepatocellular (HCC), cholangiocarcinoma (CCA), and gallbladder carcinoma (GBC)) with gene mutations (classified by COSMIC CENSUS) were analyzed using Pearson’s χ2 test. Results: A total of 1,017 alterations were identified in 61 genes (516 missense variant, 157 gene amplifications, 101 inactivating mutations, 106 truncating mutations, 84 upstream gene variants, 37 gene homozygous deletions, 16 gene rearrangements) in 329 patients: 115 (35%) CCA, 87 (26.4%) GBC, and 127 (38.6%) HCC. The majority 77.8% (256) of tumors harbored at least two mutations and 38.9% (128) had at least one alteration, with GBC having a higher average number of alterations (3.28) than HCC (3.23) and CCA (2.49) However, HCCs had the higher maximum number of alterations compared to CCA and GBC (p < 0.05). The ten genes most frequently altered across all the HBCs were TP53, TERT, CTNNB1, KRAS, ARID1A, CDKN2A, IDH1, PIK3CA, MYC, and SMAD4 with disparities in the distribution of genes altered repeatedly observed (p < 0.001). IDH1 mutations were associated with CCA, CTNNB1 and TERT mutations with HCC, and TP53 mutations with both HCC and GBC. Conclusions: HBC subtypes appear to have unique mutational landscapes, but also significant overlap of genetic signatures. Therefore, further exploratory genetic and epigenomic research is needed to develop a histomolecular classification algorithm that can be used for prognostic and therapeutic stratification of these cancers.

scholarly journals Mice Carrying a Schizophrenia-associated Mutation of the Arhgap10 Gene Are Vulnerable to the Effects of Methamphetamine Treatment on Cognitive Function: Association With Morphological Abnormalities in Striatal Neurons 

2020 ◽  
Author(s):  
Kazuhiro Hada ◽  
Bolati Wulaer ◽  
Taku Nagai ◽  
Norimichi Itoh ◽  
Masahito Sawahata ◽  
...  
Keyword(s):  
Rho Gtpase ◽  
Genetic Model ◽  
Gene Mutations ◽  
Missense Variant ◽  
Japanese Patients ◽  
Copy Number Variations ◽  
Spine Density ◽  
Striatal Neurons ◽  
Expression Levels ◽  
Significant Impairment

Abstract We recently found a significant association between exonic copy-number variations in the Rho GTPase activating protein 10 (Arhgap10) gene and schizophrenia in Japanese patients. Special attention was paid to one patient carrying a missense variant (p.S490P) in exon 17, which overlapped with an exonic deletion in the other allele, because two mutations in the same gene are considered a typical genetic model of severe schizophrenia. Accordingly, we generated a mouse model (ARHGAP10NHEJ/S490P mice) carrying a missense variant and a coexisting frameshift mutation (NHEJ). We examined the spatiotemporal expression of Arhgap10 mRNA in the brain and found the highest expression levels in the striatum and nucleus accumbens (NAc), followed by the frontal cortex in adolescent mice. The expression levels of phosphorylated myosin phosphatase-targeting subunit 1 and phosphorylated p21-activated kinases in the striatum and NAc were significantly increased in ARHGAP10NHEJ/S490P mice compared with WT littermates. ARHGAP10NHEJ/S490P mice exhibited a significant increase in neuronal complexity and spine density in the striatum and NAc. There was no difference in touchscreen-based visual discrimination (VD) learning between ARHGAP10NHEJ/S490P and WT mice, but a significant impairment of VD was evident in ARHGAP10NHEJ/S490P mice but not WT mice when they were treated with methamphetamine. The number of c-Fos-positive cells was significantly increased after methamphetamine treatment in the dorsomedial striatum and NAc core of ARHGAP10NHEJ/S490P mice. Taken together, these results suggested that schizophrenia-associated Arhgap10 gene mutations result in morphological abnormality in the striatum and NAc neurons, which may be associated with vulnerability of cognition to methamphetamine treatment.

scholarly journals DNA methylation data-based molecular subtype classification and prediction in patients with gastric cancer

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Qixin Lian ◽  
Bo Wang ◽  
Lijun Fan ◽  
Junqiang Sun ◽  
Guilai Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Molecular Subtype ◽  
Methylation Data ◽  
Subtype Classification

scholarly journals Molecular Landscape of Acute Myeloid Leukemia: Prognostic and Therapeutic Implications

2020 ◽  
Vol 22 (6) ◽  
Author(s):  
Ludovica Marando ◽  
Brian J. P. Huntly
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Influence Strategies ◽  
Prognostic Information ◽  
Therapeutic Implications ◽  
Genomic Landscape ◽  
Genetic Landscape ◽  
Molecular Landscape ◽  
Acute Myeloid

Abstract Purpose of Review The field of acute myeloid leukemia (AML) has been revolutionized in recent years by the advent of high-throughput techniques, such as next-generation sequencing. In this review, we will discuss some of the recently identified mutations that have defined a new molecular landscape in this disease, as well as their prognostic, predictive, and therapeutic implications. Recent Findings Recent studies have shown how many cases of AML evolve from a premalignant period of latency characterized by the accumulation of several mutations and the emergence of one or multiple dominant clones. The pattern of co-occurring mutations and cytogenetic abnormalities at diagnosis defines risk and can determine therapeutic approaches to induce remission. Besides the genetic landscape at diagnosis, the continued presence of particular gene mutations during or after treatment carries prognostic information that should further influence strategies to maintain remission in the long term. Summary The recent progress made in AML research is a seminal example of how basic science can translate into improving clinical practice. Our ability to characterize the genomic landscape of individual patients has not only improved our ability to diagnose and prognosticate but is also bringing the promise of precision medicine to fruition in the field.

scholarly journals Consensus molecular subtype classification of colorectal adenomas

2018 ◽  
Vol 246 (3) ◽  
pp. 266-276 ◽  
Author(s):  
Malgorzata A Komor ◽  
Linda JW Bosch ◽  
Gergana Bounova ◽  
Anne S Bolijn ◽  
Pien M Delis-van Diemen ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Colorectal Adenomas ◽  
Subtype Classification ◽  
Consensus Molecular Subtype

Unusual Segregation of APP Mutations in Monogenic Alzheimer Disease

2019 ◽  
Vol 19 (2) ◽  
pp. 96-100
Author(s):  
Gioia Mastromoro ◽  
Stefano Gambardella ◽  
Enrica Marchionni ◽  
Rosa Campopiano ◽  
Alice Traversa ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Autosomal Dominant ◽  
Age Of Onset ◽  
Gene Mutations ◽  
Missense Variant ◽  
The Other ◽  
Dominant Trait ◽  
Homozygous State ◽  
Severe Clinical Picture ◽  
App Gene

APP gene mutations causing Alzheimer disease (AD) segregate in an autosomal dominant pattern. We report on a 40-year-old woman with a severe cognitive decline starting at 36 years, while her affected relatives presented symptoms onset in the 6th decade. The proband carried an APP missense variant in homozygous state (NM_000484.4: c.2032G>A; NP_000475.1: p.Asp678Asn; rs63750064) and showed a more severe clinical picture than the other AD relatives, as regards the age of onset and the rate of disease progression. This mutation behaves as a semi-dominant trait. The very rare chance of studying APP mutations in the homozygous state demonstrates they are not always dominant and other segregation models are possible.

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