scholarly journals Fetal Megalencephaly with Cortical Dysplasia at 18 Gestational Weeks Related to Paternal UPD Mosaicism with PTEN Mutation

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 358
Author(s):  
Ritsuko Kimata Pooh ◽  
Megumi Machida ◽  
Issei Imoto ◽  
Eri Noel Arai ◽  
Hiroyasu Ohashi ◽  
...  
Keyword(s):  
Pregnancy Termination ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Gene Mutations ◽  
Suppressor Gene ◽  
Cortical Dysplasia ◽  
Pten Gene ◽  
Phosphatase And Tensin Homolog ◽  
Pten Mutation ◽  
Tensin Homolog

The phosphatase and tensin homolog (PTEN) gene is a tumor-suppressor gene located on 10q22-23. Since the introduction of molecular genetics in prenatal diagnostics, various birth defects associated with gene mutations have been diagnosed. However, no reports on fetal cases related to PTEN mutation have been found, so far. We encountered a rare case of fetal PTEN mutation. Fetal macrocephaly was noted at 16 weeks. At 18 and 20 weeks, neurosonography revealed megalencephaly with an asymmetrical structure and multifocal polygyria. The head circumference (HC) was +6.2 SD at 18 weeks and +8.1 SD at 20 weeks. The parents opted for pregnancy termination, and the male fetus was delivered at 21 weeks, with HC +9.3 SD. Single-nucleotide polymorphism (SNP) array for amniotic cells showed paternal uniparental disomy (UPD) 10q mosaicism, and the mosaic ratio was calculated as 56% from B-allele frequency. Exome sequencing revealed the pathogenic PTEN mutation with mosaicism. The heterozygous PTEN mutation may not cause early manifestations from the fetal period, and an abnormal phenotype may appear after birth. This may be the reason why fetal defects associated with PTEN mutation are not detected. Since this case had homozygous and heterozygous mutations, survival was possible, exhibiting an incredibly huge head with cortical dysplasia from early pregnancy.

scholarly journals Cowden syndrome and Lhermitte - Duclos disease: A case report and review of the literature

2021 ◽  
Vol 2 (4) ◽  
Author(s):  
Chun Peng Goh ◽  
◽  
Bingcheng Wu ◽  
Ting Ting Feng ◽  
Ning Chou ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Clinical History ◽  
Suppressor Gene ◽  
Cowden Syndrome ◽  
Tumour Suppressor Gene ◽  
Cerebellar Lesion ◽  
Pten Gene ◽  
Multisystem Disease ◽  
Tensin Homolog ◽  
Almost All

Cowden syndrome (CS) is a rare, autosomal dominant, multisystem disease related to the mutation of Phosphatase and tensin homolog (PTEN) tumour suppressor gene. It is characterized by the occurrence of multiple hamartomas, mucocutaneous lesions, and is associated with a high risk of malignancies. Lhermitte–Duclos Disease (LDD), or dysplastic cerebellar gangliocytoma, is a rare hamartomatous lesion of the cerebellar cortex with a unique “Tiger Stripe” appearance on Magnetic Resonance Imaging (MRI). Since 1991, LDD has been considered pathognomonic and part of CS. In addition, as almost all adult onset LDD cases were associated with PTEN gene mutations, LDD and CS are both included in PTEN Harmartoma Tumour Syndrome (PHTS). In this article, we report a 48-year-old female patient, who presented with a right cerebellar lesion resulting in hydrocephalus. The histology of the cerebellar lesion confirmed the diagnosis of LDD, and her clinical history is highly suggestive of CS. Due to the high incidence of multisystemic malignancies and other disease, it is important for clinicians to be aware of the association between LDD and CS. Affected patients should be evaluated carefully and screened for cancers accordingly, so as to allow early diagnosis and treatment.

Spliceosome GENE MUTATIONS ARE Also PRESENT In the Diverse Mutational Spectrum of CHRONIC Myelomonocytic LEUKEMIA

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1402-1402
Author(s):  
Hideki Makishima ◽  
Anna M Jankowska ◽  
Valeria Visconte ◽  
Ramon V. Tiu ◽  
Kathryn M Guinta ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Gene Mutations ◽  
P53 Mutation ◽  
Chronic Myelomonocytic Leukemia ◽  
Homozygous Mutation ◽  
Myelomonocytic Leukemia

Abstract Abstract 1402 Chronic myelomonocytic leukemia (CMML) is characterized by monocytic proliferation, cytomorphologic dysplasia and frequent progression to acute myelogeneous leukemia (AML). The molecular basis of CMML is poorly defined, although somatic mutations in a number of genes have recently been identified in a proportion of patients (epigenetic regulatory genes, spliceosomal genes, apoptosis genes, growth signal transducers and others). We performed a comprehensive analysis of molecular lesions, including somatic mutations detected by sequencing and chromosomal abnormalities investigated by metaphase and SNP-array karyotyping. We have selected a cohort of 72 patients (36 CMML1, 16 CMML2 and 20 sAML evolved from CMML). Our mutational screen performed in stages (as new mutations were discovered by our and other groups) and currently reveals mutations in UTX in 8%, DNMT3A in 9%, CBL in 14%, IDH1/2 in 4%, KRAS in 2.7%, NRAS in 4.1%, JAK2 in 1%, TET2 in 48%, ASXL1 in 43%, EZH2 in 5.5%, RUNX1 37%. Based on the discovery of various spliceosomal mutations in myeloid malignancies, novel mutations were also found in CMML, in U2AF1 in 12%, SF3B1 in 14%, SFRS19 in 6 % of cases tested. Chromosomal defects were detected in 60% of patients. In particular, a high frequency of somatic uniparental disomy (sUPD) were identified 71% of patients with abnormal cytogenetics, including UPD1p (N=3), UPD7q (N=8), UPD4q (N=6), UPD2p (N=2), UPD17q (N=2), UPD11q (N=5), UPDX (N=1), UPD21q (N=2). Some of the detected mutations were homozygous through their association with sUPD as for example for 3 EZH2, 1 UTX, 6 TET2, 2 DNMT3A, 5 CBL, 1 NRAS, 1 U2AF1 mutations. Furthermore, UPD17p implies that a P53 mutation is also present in this case as previously LOH17p was shown to be invariably associated with P53 mutations. Similarly, 2 cases of UPD17q imply that homozygous mutation of SRSF2, which is one of the Serine/arginine-rich splicing factor, may be present in this location and the mutation analysis is ongoing. In over 90% of >1 mutation was found but many patients harbored multiple mutations with frequent combinations of TET2/CBL or TET2/ASXL1 as well as RUNX1 and U2AF1 serving as examples. There was an accumulation of mutations from sAML, CMML2 and CMML1 suggesting stepwise accumulation of lesions. In serial studies, some of the mutations were present at the inception (e.g., TET2, ASXL1 and DNMT3A) in some cases originally heterozygous mutations were also while other can occur in the course of disease (e.g. CBL). RAS and DNMT3A mutations were associated with a higher blasts count. In sum, combined analysis of molecular lesions in CMML reveals that similar phenotype may be a result of diverse mutations associated with seemingly unrelated pathways and that clinical phenotype may be a result of a combination of mutations which accumulate as the disease progresses. Survival analyses will require large cohorts to account for various confounding factors including the presence of multiple chromosomal abnormalities and mutations in one patient, however currently EZH2, DNMT3 and CBL mutations appear to convey less favorable prognosis. Disclosures: No relevant conflicts of interest to declare.

Translational significance of a newly identified hepatocellular carcinoma tumor suppressor gene on chromosome 8p.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15097-e15097
Author(s):  
Han Chong Toh ◽  
Francis Enane ◽  
Marissa Teo ◽  
Hideki Makishima ◽  
JoAnna Ng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Biological Significance ◽  
Suppressor Gene ◽  
Cell Cycle Exit ◽  
Malignant Liver

e15097 Background: After deletion of 17p that removes the tumor suppressor gene (TSG) TP53, deletion of 8p is the next most common chromosome abnormality in hepatocellular carcinoma (HCC). However, 8p TSG are insufficiently defined. Methods: Integrated genomic analysis of HCC and non-malignant liver obtained at therapeutic segmentectomy from the same patients. Results: A minimally deleted region on 8p was identified by SNP array. This incorporated GATA4. Therefore, GATA4 was Sanger sequenced in paired HCC/non-malignant liver: recurrent somatic non-synonymous missense mutations were identified in exon 4 (V267M n=5) or exon 6 (S357T n=6, R362N n=2, T366R n=2). Biallelic abnormalities were deletion and mutation (n=6) or mutation and uniparental disomy (n=4), with mutation or deletion of at least one GATA4 allele in 29/47 (62%) of HCC cases. The other GATA4 exons were mutation free. Although missense mutation is not intrinsically expected to decrease GATA4 expression, GATA4 mRNA was significantly decreased in cases with mutation as well as deletion (p<0.01) compared to non-malignant liver or wild-type GATA4 HCC. GATA4 drives liver differentiation, and the biological significance of GATA4 deficiency was demonstrated by significant enrichment (49%) for liver differentiation genes (p<1.2exp-124, Benjamini corrected) amongst genes with decreased expression in HCC compared to non-malignant liver. From an oncogenesis perspective, the most important of these hepatocyte genes (e.g., HNF4A, CEBPD) antagonize MYC to terminate proliferation: GATA4 introduction (expression vector) into HCC cells containing mutated or deleted GATA4 (HepG2 and PLC respectively) restored HNF4A and CEBPD expression, suppressed MYC protein, upregulated p27/CDKN1B that mediates cell cycle exit by maturation and significantly decreased HCC proliferation without apoptosis. In objectively quantified immunohistochemical analyses (ImageIQ), HCC cases with GATA4 mutation/deletion had significantly increased MYC protein (p<0.05). Conclusions: 8p deletion/GATA4 mutation in HCC suppresses cell cycle exit by maturation, thus complementing 17p deletion that suppresses cell cycle exit by apoptosis.

scholarly journals Expression of Phosphatase and Tensin Homolog (PTEN) gene at mRNA level in equine endometrium

2015 ◽  
Vol 31 (1) ◽  
pp. 51-51
Author(s):  
Gonca Sen ◽  
Mustafa Hitit ◽  
Caglayan Ozel ◽  
Aydin Guzeloglu ◽  
Seyit Ali Kayis ◽  
...  
Keyword(s):  
Mrna Level ◽  
Pten Gene ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog

Molecular Diversity Detected by Whole Exome Sequencing in Chronic Myelomonocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 310-310
Author(s):  
Basel Rouphail ◽  
Kenichi Yoshida ◽  
Holleh D Husseinzadeh ◽  
Edward P Evans ◽  
Satoru Miyano ◽  
...  
Keyword(s):  
Research Funding ◽  
Germ Line ◽  
Target Therapy ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Gene Mutations ◽  
Molecular Pathogenesis ◽  
Common Mutation ◽  
Mutational Status ◽  
Recurrent Mutations

Abstract Abstract 310 CMML is characterized by monocytic proliferation, cytomorphologic dysplasia, and frequent progression to AML. Heterogeneity in or subtlety of presentation can make diagnosis challenging. Recent advances in molecular technology set the stage for systematic study of genetic and genomic lesions associated with CMML. Initially, RAS and RUNX1 mutations were identified in CMML; subsequently, mutations in TET2, CBL, ASXL1 and EZH2 have been discovered. Most recently, recurrent mutations in various genes of the spliceosomal machinery have been added, with SRSF2 likely the most common mutation in this condition. We hypothesized that more precise analysis of molecular lesions in CMML may allow for better categorization of this condition according to molecular pathogenesis and may provide clues to target therapy of this rather refractory condition. We identified 136 patients with CMML or secondary AML (sAML) with antecedent CMML: 87 CMML-1, 20 CMML-2 and 29 post-CMML sAML. The original cohort has been expanded by an additional 53 patients since first reported. The mean follow up period was 16 months (range, 0–114). Abnormal cytogenetics were found in 50% of the cohort by both metaphase and SNP-array-based karyotyping. In a representative subset of 27 patients, we have applied whole genome sequencing (WES) for which paired tumor/germ line DNA was used. To minimize false positives and focus on the most prevalent/relevant somatic events, we implemented a rational bioanalytic filtering approach and results were aligned using Burrows-Wheeler Aligner and variants detected using the GATK pipeline (Best Practice Variant Detection from Broad Institute). We focused on somatic defects with a frequency of >5% of the cohort. For the most commonly affected genes, results were validated using an expanded panel of 18 genes in 72 additional patients and, thus, for the most relevant genes a cohort of 95 patients was studied. The most frequently mutated genes were TET2 (48%), SRSF2 (35%), ASXL1 (17%) and RUNX1 (17%), whereas CBL (13%), EZH2 (13%), UTX (8%) and U2AF1 (8%), SETPB1 (10%), and RIT1 (9%) were less frequent. We also found TP53 and RUNX1 mutations in 5% and 16% of patients, respectively. A JAK2 V617F mutation was present in one case of seemingly typical CMML. BCOR and STAG2 mutations were found in 13% and 9% of patients, respectively; KRAS/NRAS mutations were in 10%. Spliceosomal gene mutations seem to be mutually exclusive, but were frequently associated with other non-spliceosomal gene mutations examined. Within the cohort of 28 SRSF2 mutant cases, 15 had coexisting TET2 mutations, 22 had ASXL1 mutations, 7 had RUNX1 and 5 had CBL mutations. Among 10 U2AF1 mutant cases, 3, 5 and 2 had TET2, ASXL1, and RUNX1 mutations, respectively. SETBP1 mutations were present in 34% of CMML-1/2 and frequently associated with RUNX1, SRSF2, CBL (approximately 2% each) and ASXL1 (4%) mutations. Cohesin mutations were less frequent (10%) because RAD21 and SMC mutations were absent. Mutations of PTPN11 and NF1 were less frequent in adult CMML than those reported in JMML. We also identified several less-recurrent gene mutations that likely modify pathogenesis or clinical outcomes of specific cases. Serial studies performed on 6 cases showed insight into the clonal architecture, producing a series of putative ancestral and secondary events, including uniparental disomy and acquisition of KRAS/NRAS or SETPB1 mutations. Association between mutational status and overall survival (OS) was assessed using Kaplan-Meier statistics. While all permutations were tested, we highlight here only significant positive and relevant negative results. In the whole cohort, presence of CBL mutations conferred worse OS (p=.018; HR 2.44, 95%CI 1.18–4.69). Median OS was 16 months for CMML-1, 6 months for CMML-2, and 14-months for sAML. In subgroup analyses, CBL mutations were also significant worse prognostic factor in CMML-1 cohort (p=.037; HR 3.23, 95%CI 1.07–8.04). In sum, WES provides intricate information on the molecular pathogenesis of CMML and the wide mutational spectrum correlates with the clinical diversity. Expert-based analysis of the genomic data may be supplanted by unsupervised and unbiased approaches which would cluster patients based on molecular similarities. Disclosures: Maciejewski: NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Makishima:Scott Hamilton CARES Initiative: Research Funding.

scholarly journals Cowden Syndrome: report of a case and brief review of literature

2013 ◽  
Vol 88 (6 suppl 1) ◽  
pp. 52-52 ◽  
Author(s):  
Ana Carolina Souza Porto ◽  
Elisabeth Roider ◽  
Thomas Ruzicka
Keyword(s):  
Cell Cycle Progression ◽  
Cowden Syndrome ◽  
Pten Gene ◽  
Benign Tumors ◽  
Cutaneous Lesions ◽  
Phosphatase And Tensin Homolog ◽  
Tensin Homolog ◽  
Increased Risk ◽  
History Of ◽  
Risk Of Cancer

We present the case of a female patient with facial cutaneous lesions, a cobblestone-like pattern of the oral mucosa, and verruciform lesions on the hand since her youth. She reported a history of breast cancer, endometrial cancer, melanoma and multiple benign tumors and cysts. PTEN gene analysis was performed and confirmed Cowden Syndrome, a rare genodermatosis with an autosomal dominant pattern of inheritance, characterized by multiple hamartomas. The phosphatase and tensin homolog (PTEN) gene negatively regulates cell proliferation and cell cycle progression. Loss of PTEN function contributes to an increased risk of cancer. We emphasize the importance of early detection and accurate management of Cowden Syndrome.

Sign in / Sign up

Export Citation Format

Share Document