Paediatric diffuse leptomeningeal tumor with glial and neuronal differentiation harbouring chromosome 1p/19q co-deletion and H3.3 K27M mutation: unusual molecular profile and its therapeutic implications

2018 ◽  
Vol 35 (3) ◽  
pp. 186-191 ◽  
Author(s):  
Aruna Nambirajan ◽  
Vaishali Suri ◽  
Sweta Kedia ◽  
Keshav Goyal ◽  
Prit Benny Malgulwar ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Molecular Profile ◽  
Therapeutic Implications ◽  
Chromosome 1P ◽  
K27m Mutation ◽  
Leptomeningeal Tumor

scholarly journals Epigenetic reprogramming and chromatin accessibility in pediatric diffuse intrinsic pontine gliomas: a neural developmental disease

2019 ◽  
Vol 22 (2) ◽  
pp. 195-206 ◽  
Author(s):  
Flor M Mendez ◽  
Felipe J Núñez ◽  
Maria B Garcia-Fabiani ◽  
Santiago Haase ◽  
Stephen Carney ◽  
...  
Keyword(s):  
Histone Variants ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Chromatin Accessibility ◽  
Therapeutic Implications ◽  
Polycomb Repressive Complex 2 ◽  
K27m Mutation ◽  
Histone 3 ◽  
Epigenetic Programming ◽  
Genes Encoding ◽  
Diffuse Intrinsic Pontine Gliomas

Abstract Diffuse intrinsic pontine glioma (DIPG) is a rare but deadly pediatric brainstem tumor. To date, there is no effective therapy for DIPG. Transcriptomic analyses have revealed DIPGs have a distinct profile from other pediatric high-grade gliomas occurring in the cerebral hemispheres. These unique genomic characteristics coupled with the younger median age group suggest that DIPG has a developmental origin. The most frequent mutation in DIPG is a lysine to methionine (K27M) mutation that occurs on H3F3A and HIST1H3B/C, genes encoding histone variants. The K27M mutation disrupts methylation by polycomb repressive complex 2 on histone H3 at lysine 27, leading to global hypomethylation. Histone 3 lysine 27 trimethylation is an important developmental regulator controlling gene expression. This review discusses the developmental and epigenetic mechanisms driving disease progression in DIPG, as well as the profound therapeutic implications of epigenetic programming.

scholarly journals The emerging role of molecular pathology in directing the systemic treatment of endometrial cancer

2021 ◽  
Vol 13 ◽  
pp. 175883592110359
Author(s):  
Amy Jamieson ◽  
Tjalling Bosse ◽  
Jessica N. McAlpine
Keyword(s):  
Endometrial Cancer ◽  
Molecular Subtypes ◽  
Treatment Decision ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Molecular Profile ◽  
Therapeutic Implications ◽  
Treatment Decision Making ◽  
Exciting Time ◽  
Classification Tool

Following the discovery of the four molecular subtypes of endometrial cancer (EC) by The Cancer Genome Atlas (TCGA) in 2013, subsequent studies used surrogate markers to develop and validate a clinically relevant EC classification tool to recapitulate TCGA subtypes. Molecular classification combines focused sequencing ( POLE) and immunohistochemistry (mismatch repair and p53 proteins) to assign patients with EC to one of four molecular subtypes: POLEmut, MMRd, p53abn and NSMP (no specific molecular profile). Unlike histopathological evaluation, the molecular subtyping of EC offers an objective and reproducible classification system that has been shown to have prognostic value and therapeutic implications. It is an exciting time in EC care where we have moved beyond treatment based on histomorphology alone, and molecular classification will now finally allow assessment of treatment efficacy within biologically similar tumours. It is now recommended that molecular classification should be considered for all ECs, and should be performed routinely in all high grade tumours. It is also recommended to incorporate molecular classification into standard pathology reporting and treatment decision-making algorithms. In this review, we will discuss how the molecular classification of EC can be used to guide both conventional and targeted therapy in this new molecular era.

Diagnostic utility and prognostic performance of a 92-gene cancer classifier to molecularly profile periampullary adenocarcinomas.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 197-197 ◽  
Author(s):  
Michael J. Overman ◽  
Huamin Wang ◽  
Catherine A. Schnabel ◽  
Jeff Anderson ◽  
Mark G. Erlander ◽  
...  
Keyword(s):  
Molecular Classification ◽  
Good Prognosis ◽  
Molecular Profile ◽  
Molecular Testing ◽  
Diagnostic Utility ◽  
Prognostic Performance ◽  
Therapeutic Implications ◽  
Rna Profiling ◽  
Gene Assay

197 Background: Due to the small anatomic size, multiplicity of epitheliums, and suboptimal diagnostics determining the site of origin of periampullary adenocarcinomas (PAA) is a challenge. We investigated the ability of a 92-gene RT-PCR assay (CancerTYPE ID) to categorize PAA and to prognostically stratify ampullary adenocarcinomas. Methods: 45 PAA patients who underwent pancreaticoduodenectomies were included; samples were histopathologically verified for tumor subtype determination (pancreatic, extrahepatic biliary, ampullary, or duodenal). Blinded FFPE tumor sections underwent molecular testing and were compared for concordance to histopathological tumor types and prognostic performance. 28 of these samples had previously undergone whole-genome RNA profiling (Overman et al. GI ASCO 2011 a161). Results: Molecular classification of 43 (96%) evaluable samples (13 ampullary, 10 pancreatic, 10 biliary, 10 duodenal) showed 91% concordance: ampullary [5 intestinal (int), 7 pancreaticobiliary (pb)], pancreatic [10 pb], duodenal [3 int, 7 gastroesophageal (ge)], biliary [7 pb]. The 92-gene assay was prognostic with a median OS of 70 m for ge/int cases vs. 32 m for pb cases, P=0.05. Discordant classifications were ge for 1 ampullary and 2 biliary samples, and ovary for 1 biliary case. Previous unsupervised RNA hierarchical clustering of all 13 ampullary cases had identified two prognostic groups (a good-prognosis int-like and a poor-prognosis pb-like), which were identical to the 92-gene classification for 12 cases (5 int and 7 pb). These two ampullary subgroups were prognostic with median OS of 63 vs. 24 m, P=0.07, respectively. Conclusions: The 92-gene assay demonstrated diagnostic utility for molecular site-of-origin classification of PAA. These results support exploration of this approach for the management of metastatic PAA (in which pathologic review of a primary resection specimen is not an option). Molecular classification of ampullary adenocarcinomas into intestinal and pancreaticobiliary subgroups is prognostically relevant; these and the gastric-like molecular profile of duodenal adenocarcinomas may have therapeutic implications.

Landscape of somatic DNA damage repair (DDR) gene mutations in genitourinary cancer in China.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17516-e17516
Author(s):  
Kaiwei Yang ◽  
Qi Tang ◽  
Yue Mi ◽  
Wei Yu ◽  
Yi Song ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Cell Cancer ◽  
Gene Mutations ◽  
Molecular Profile ◽  
Plasma Samples ◽  
Therapeutic Implications ◽  
Genitourinary Cancer ◽  
Mutation Burden ◽  
Unknown Significance ◽  
Comprehensive Genomic Profiling

e17516 Background: DDR gene alterations(GAs) are prevalent in cancer and play key roles in tumorigenesis, progression and therapeutic response. However, the molecular profile of DDR in genitourinary cancer is still lacking in Asian. In this study, we assessed DDR GAs for better understanding therapeutic implications. Methods: Patients(pts) diagnosed with genitourinary cancer were enrolled. Tumors and plasma samples were collected for next-generation sequencing with Acornmed panel(2.0 Mbp) containing 808 cancer-related genes, including 34 DDR genes(Jonathan, et al.). OncoKB and COSMIC were used to identify GAs status including deleterious, unknown significance, and wild type(wt). Results: A total of 140 pts were enrolled with 56 pts of prostate cancer(PC), 55 pts of renal cell cancer(RCC) and 29 pts of urothelial cancer(UC). Metastatic diseases were accounted for 33.5%. A total of 127 tumor tissues and 109 baseline plasma samples were collected, including 96 matched tissue/plasma samples. A total of 109 pts(77.9%) harbored at least one GA in DDR pathway. UC carried the most DDR GAs(93.1 %), followed by PC(75%) and RCC(72.7%). After stratifying GA status, the most commonly deleterious GAs were ATM(n = 5); FANCA(n = 4); ERCC2, BRCA1, ATR, CHEK2(n = 2 each); MSH6, ERCC4, BRCA2, PALB2(n = 1 each).Tumor mutation burden(TMB) was significantly different among pts with deleterious, unknown significance and wt in PC(Mean: 17.8 vs 9.065 vs 4.468; p = 0.0003). Notably, DDR GAs were more likely to present in pts with metastatic disease(80.95% vs 62.50%), deleterious DDR GAs as well(14.29% vs 8.33%). Conclusions: DDR pathways are frequently altered in genitourinary cancer, especially UC in China. DDR GAs were significantly associated with higher TMB in PC. A higher prevalence was identified in metastatic disease. Comprehensive genomic profiling of DDR GAs highlights the clinical and therapeutic implication. Further exploration of the deleterious nature and alterations of unknown significance are required. [Table: see text]

scholarly journals Functional Neuronal Differentiation of Injury-Induced Muscle-Derived Stem Cell-Like Cells with Therapeutic Implications

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Kinga Vojnits ◽  
Haiying Pan ◽  
Xiaojing Dai ◽  
Hao Sun ◽  
Qingchun Tong ◽  
...  
Keyword(s):  
Stem Cell ◽  
Neuronal Differentiation ◽  
Therapeutic Implications

scholarly journals BMP2 promotes differentiation of nitrergic and catecholaminergic enteric neurons through a Smad1-dependent pathway

2010 ◽  
Vol 298 (3) ◽  
pp. G375-G383 ◽  
Author(s):  
Mallappa Anitha ◽  
Nikrad Shahnavaz ◽  
Emad Qayed ◽  
Irene Joseph ◽  
Gudrun Gossrau ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Substance P ◽  
Cell Line ◽  
Neuronal Differentiation ◽  
Transforming Growth Factor ◽  
Neuronal Cell ◽  
Cholinergic Neurons ◽  
Enteric Neurons ◽  
Neuronal Markers ◽  
Therapeutic Implications

The bone morphogenetic protein (BMP) family is a class of transforming growth factor (TGF-β) superfamily molecules that have been implicated in neuronal differentiation. We studied the effects of BMP2 and glial cell line-derived neurotrophic factor (GDNF) on inducing differentiation of enteric neurons and the signal transduction pathways involved. Studies were performed using a novel murine fetal enteric neuronal cell line (IM-FEN) and primary enteric neurons. Enteric neurons were cultured in the presence of vehicle, GDNF (100 ng/ml), BMP2 (10 ng/ml), or both (GDNF + BMP2), and differentiation was assessed by neurite length, markers of neuronal differentiation (neurofilament medium polypeptide and β-III-tubulin), and neurotransmitter expression [neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS), tyrosine hydroxylase (TH), choline acetyltransferase (ChAT) and Substance P]. BMP2 increased the differentiation of enteric neurons compared with vehicle and GDNF-treated neurons ( P < 0.001). BMP2 increased the expression of the mature neuronal markers ( P < 0.05). BMP2 promoted differentiation of NPY-, nNOS-, and TH-expressing neurons ( P < 0.001) but had no effect on the expression of cholinergic neurons (ChAT, Substance P). Neurons cultured in the presence of BMP2 have higher numbers of TH-expressing neurons after exposure to 1-methyl 4-phenylpyridinium (MPP+) compared with those cultured with MPP+alone ( P < 0.01). The Smad signal transduction pathway has been implicated in TGF-β signaling. BMP2 induced phosphorylation of Smad1, and the effects of BMP2 on differentiation of enteric neurons were significantly reduced in the presence of Smad1 siRNA, implicating the role of Smad1 in BMP2-induced differentiation. The effects of BMP2 on catecholaminergic neurons may have therapeutic implications in gastrointestinal motility disturbances.

Diagnostic utility and prognostic performance of a 92-gene cancer classifier to molecularly profile periampullary adenocarcinomas (PAA).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4133-4133
Author(s):  
Michael J. Overman ◽  
Huamin Wang ◽  
Catherine A. Schnabel ◽  
Jeffrey Anderson ◽  
Mark G. Erlander ◽  
...  
Keyword(s):  
Molecular Classification ◽  
Good Prognosis ◽  
Molecular Profile ◽  
Molecular Testing ◽  
Diagnostic Utility ◽  
Prognostic Performance ◽  
Therapeutic Implications ◽  
Gene Assay ◽  
Ffpe Tumor

4133 Background: Due to the small anatomic size, multiplicity of epitheliums, and suboptimal diagnostics determining the site of origin of PAA is a challenge. We investigated the ability of a 92-gene RT-PCR assay (CancerTYPE ID) to categorize PAA and to prognostically stratify ampullary adenocarcinomas. Methods: 171 PAA patients who underwent pancreaticoduodenectomies were included; samples were histopathologically verified for tumor subtype determination: pancreatic (PAN), extrahepatic biliary (EB), ampullary (AMP), or duodenal (DOUD). Blinded FFPE tumor sections underwent molecular testing. Analytical sets were an initial 45 PAA set evaluating concordance to histopathological tumor types and prognostic performance, and a second set of 126 AMP and DOUD adenocarcinoma for validation of prognostic performance. Results: Of the initial 45 patient cohort, molecular classification of 43 (96%) evaluable samples (13 AMP, 10 PAN, 10 EB, 10 DOUD) showed 91% concordance: AMP [5 intestinal (int), 7 pancreaticobiliary (pb)], PAN [10 pb], DOUD [3 int, 7 gastroesophageal (ge)], EB [7 pb]. The 92-gene assay was prognostic with a median OS of 70 m for ge/int cases vs. 32 m for pb cases, P=0.05. Discordant classifications were ge for 1 AMP and 2 EB samples, and ovary for 1 EB case. Previous unsupervised RNA hierarchical clustering (Overman GI ASCO 2011 a161) of all 13 AMP cases had identified two prognostic groups (a good-prognosis int-like and a poor-prognosis pb-like), which were identical to the 92-gene classification for 12 of the 13 cases. Conclusions: In the initial cohort of 45 patients, the 92-gene assay demonstrated diagnostic utility for molecular site-of-origin classification of PAA; evaluation of the remaining 126 ampullary and duodenal cases will be presented. Results support exploration of this approach for the management of metastatic PAA (in which pathologic review of a primary resection specimen is not an option). Molecular classification of ampullary adenocarcinomas into intestinal and pancreaticobiliary subgroups is prognostically relevant; these and the gastric-like molecular profile of duodenal adenocarcinomas may have therapeutic implications.

scholarly journals Sinonasal mucosal melanoma: Molecular profile and therapeutic implications from a series of 32 cases

Head & Neck ◽  
2012 ◽  
Vol 35 (8) ◽  
pp. 1066-1077 ◽  
Author(s):  
Mario Turri-Zanoni ◽  
Daniela Medicina ◽  
Davide Lombardi ◽  
Marco Ungari ◽  
Piera Balzarini ◽  
...  
Keyword(s):  
Mucosal Melanoma ◽  
Molecular Profile ◽  
Therapeutic Implications

scholarly journals Genomic Profiling of Two Histologically Distinct Rare Urothelial Cancers in a Clinical Setting to Identify Potential Therapeutic Options for Treatment and Management of Disease

2018 ◽  
Vol 11 (1) ◽  
pp. 196-205 ◽  
Author(s):  
Andrew N. Hesse ◽  
William Fabricius ◽  
Christian A. Thomas ◽  
Ramesh Gaindh ◽  
Robert Christman ◽  
...  
Keyword(s):  
Cell Cycle Control ◽  
Copy Number Variants ◽  
Neuroendocrine Differentiation ◽  
Molecular Profile ◽  
Single Nucleotide Variants ◽  
Therapeutic Implications ◽  
Molecular Stratification ◽  
Proposed Model ◽  
Poorly Differentiated

Molecular profiling of urothelial cancers for therapeutic and prognostic potential has been very limited due to the absence of cancer-specific targeted therapies. We describe here 2 clinical cases with a histological diagnosis of an invasive sarcomatoid and a poorly differentiated carcinoma favoring urothelial with some neuroendocrine differentiation, two of the rarer types of urothelial cancers, which were evaluated for mutations in 212 genes for single-nucleotide variants and copy-number variants and 53 genes for fusions associated with solid tumors. In both cases, we identified variants in 2 genes, ARID1A and CDKN2A, indicative of the role of dysregulation of chromatin remodeling and cell cycle control as being common features of bladder cancer, consistent with the proposed model of tumorigenesis in these rare, highly aggressive pathological subtypes. The presence of a KRAS mutation in the poorly differentiated cancer and a TP53 mutation in the sarcomatoid tumor is indicative of a distinctive profile and adds a potential layer of molecular stratification to these rarer histological subtypes. We present a comparative analysis of the histological, clinical, and molecular profile of both cases and discuss the potential to delineate these tumors at the molecular level keeping in mind the possible therapeutic implications.

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