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1.
Article in English | MEDLINE | ID: mdl-32518610

ABSTRACT

PURPOSE: In order to further understand genetically predisposing factors of gastric cancer, a retrospective study on 107 patients with gastric cancer was conducted. The family history of cancer cases was registered, in search of associations between gastric cancer and other cancer types. MATERIALS AND METHODS: Within Stockholm County in Sweden, all patients previously diagnosed with gastric cancer and still alive were invited to participate in the study. Patients were asked to complete a questionnaire about their gastric cancer diagnosis and if any cancers had occurred in their family. A blood sample for DNA extraction was collected. The proportions of different cancer types in the relatives of the patients were compared to the general Swedish population in 1970 and 2010. RESULTS: Among first- and second-degree relatives to the index patients with gastric cancer, the frequency of uterine cancer as well as gastric cancer was significantly overrepresented compared to the general population in Sweden. The frequency of breast cancer was significantly lower. CONCLUSIONS: There seems to be an increased risk of both gastric cancer and uterine cancer in the families of gastric cancer survivors, indicating a possible hereditary connection between these two cancer types.

2.
Nat Genet ; 48(11): 1359-1369, 2016 11.
Article in English | MEDLINE | ID: mdl-27668656

ABSTRACT

TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of the genes with the highest expression in the developing human neocortex, but its functions remained unknown. Here we identify TSHZ3 as the critical region for a syndrome associated with heterozygous deletions at 19q12-q13.11, which includes autism spectrum disorder (ASD). In Tshz3-null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs), and the human orthologs of these genes are strongly associated with ASD. Furthermore, mice heterozygous for Tshz3 show functional changes at synapses established by CPNs and exhibit core ASD-like behavioral abnormalities. These findings highlight essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly defined TSHZ3 deletion syndrome.


Subject(s)
Autism Spectrum Disorder/genetics , Homeodomain Proteins/genetics , Neocortex/pathology , Neurons/pathology , Transcription Factors/genetics , Animals , Autism Spectrum Disorder/pathology , Chromosome Deletion , Chromosomes, Human, Pair 19 , Female , Gene Deletion , Gene Expression Regulation, Developmental , Haploinsufficiency , Heterozygote , Humans , Male , Mice , Mice, Inbred CBA , Neocortex/embryology , Neurogenesis/genetics , Synapses/genetics
3.
Leuk Lymphoma ; 57(9): 2161-70, 2016 09.
Article in English | MEDLINE | ID: mdl-27090575

ABSTRACT

To identify copy number alterations (CNAs) in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL), array comparative genomic hybridization was performed on 50 cases; detected CNAs were validated in a cohort of 191 cases analyzed by single nucleotide polymorphism arrays. Apart from CNAs involving leukemia-associated genes, recurrent deletions targeting genes not previously implicated in BCP ALL, e.g. INIP, IRF1 and PDE4B, were identified. Deletions of the DNA repair gene INIP were exclusively found in cases with t(12;21), and deletions of SH2B3 were associated with intrachromosomal amplification of chromosome 21 (p < 0.001). A majority of BTLA deletions (7/11; 64%) affected samples with gain of 21q chromosome material, suggesting that BTLA deletions are associated with both germline and somatic gain of chromosome 21. In cases without known risk-associated cytogenetic markers, CNAs associated with adverse prognosis were identified in 50% (10/20), indicating that a majority of these cases could be assigned to distinct genetic subtypes.


Subject(s)
Gene Deletion , Gene Dosage , Gene Expression Regulation, Neoplastic , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Adolescent , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Transformation, Neoplastic/genetics , Child , Child, Preschool , Chromosome Aberrations , Comparative Genomic Hybridization , Computational Biology/methods , DNA Copy Number Variations , Disease Progression , Epigenesis, Genetic , Female , Gene Expression Profiling , Humans , Infant , Infant, Newborn , Male , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Recurrence
4.
J Cell Mol Med ; 16(1): 129-41, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21342435

ABSTRACT

The syntaxin 11 (STX11) gene is mutated in a proportion of patients with familial haemophagocytic lymphohistiocytosis (FHL) and exocytosis of cytotoxic granules is impaired in STX11-deficient NK cells. However, the subcellular localization, regulation of expression and molecular function of STX11 in NK cells and other cytotoxic lymphocytes remain unknown. Here we demonstrate that STX11 expression is strictly controlled by several mechanisms in a cell-type-specific manner and that the enzymatic activity of the proteasome is required for STX11 expression in NK cells. In resting NKL cells, STX11 was localized in the cation-dependent mannose-6-phosphate receptor (CD-M6PR)-containing compartment, which was clearly distinct from cytotoxic granules or Rab27a-expressing vesicles. These subcellular structures appeared to fuse at the contact area with NK-sensitive target cells as demonstrated by partial colocalization of STX11 with perforin and Rab27a. Although STX11-deficent allo-specific cytotoxic T-lymphocytes efficiently lysed target cells and released cytotoxic granules, they exhibited a significantly lower extent of spontaneous association of perforin with Rab27a as compared with STX11-expressing T cells. Thus, our results suggest that STX11 promotes the fusion of Rab27a-expressing vesicles with cytotoxic granules and reveal an additional level of complexity in the spatial/temporal segregation of subcellular structures participating in the process of granule-mediated cytotoxicity.


Subject(s)
Cytoplasmic Granules/metabolism , Immunological Synapses/immunology , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Qa-SNARE Proteins/metabolism , Cell Line , Humans , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/physiopathology , Perforin/metabolism , Proteasome Endopeptidase Complex/metabolism , Qa-SNARE Proteins/genetics , Subcellular Fractions/metabolism , T-Lymphocytes, Cytotoxic/immunology , rab GTP-Binding Proteins/genetics , rab GTP-Binding Proteins/metabolism , rab27 GTP-Binding Proteins
5.
Pediatr Blood Cancer ; 54(4): 563-72, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19953648

ABSTRACT

BACKGROUND: Griscelli syndrome type 2 (GS2) is an autosomal-recessive immunodeficiency caused by mutations in RAB27A, clinically characterized by partial albinism and haemophagocytic lymphohistocytosis (HLH). We evaluated the frequency of RAB27A mutations in 21 unrelated patients with haemophagocytic syndromes without mutations in familial HLH (FHL) causing genes or an established diagnosis of GS2. In addition, we report three patients with known GS2. Moreover, neurological involvement and RAB27A mutations in previously published patients with genetically verified GS2 are reviewed. PROCEDURE: Mutation analysis of RAB27A was performed by direct DNA sequencing. NK cell activity was evaluated and microscopy of the hair was performed to confirm the diagnosis. RESULTS: RAB27A mutations were found in 1 of the 21 families. This Swedish family had three affected children with heterozygous compound mutations consisting of a novel splice error mutation, [c.239G>C], and a nonsense mutation, [c.550C>T], p.R184X. The three additional children all carried homozygous RAB27A mutations, one of which is a novel splice error mutation, [c.240-2A>C]. Of note, five of the six patients displayed neurological symptoms, while three out of six patients displayed NK cell activity within normal reference values, albeit low. A literature review revealed that 67% of GS2 patients have been reported with neurological manifestations. CONCLUSIONS: Identification of RAB27A mutations can facilitate prompt diagnosis and treatment, and aid genetic counselling and prenatal diagnosis. Since five of six patients studied herein initially were diagnosed as having FHL, we conclude that the diagnosis of GS2 may be overlooked, particularly in fair-haired patients with haemophagocytic syndromes.


Subject(s)
Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , rab GTP-Binding Proteins/genetics , Abnormalities, Multiple/genetics , Adolescent , Albinism/genetics , Child , DNA Mutational Analysis , Female , Hair/ultrastructure , Humans , Infant , Killer Cells, Natural/immunology , Male , Microscopy, Electron, Transmission , Mutation , Pedigree , rab27 GTP-Binding Proteins
7.
Pediatr Blood Cancer ; 52(4): 527-9, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19058215

ABSTRACT

A patient with previously unrecognized X-linked chronic granulomatous disease (X-CGD) died of multi-organ failure, secondary to ongoing infection and hemophagocytic lymphohistiocytosis (HLH). Post mortem histological investigations were compatible with X-CGD, and a CYBB gene mutation was confirmed. No homozygous mutations in the genes encoding perforin (PRF1), MUNC 13-4 or syntaxin-11 (STX11) were found; however, there was a heterozygous alteration c.1471G>A in the PRF1 gene causing a p.Asp491Asn substitution. Although this substitution has not been reported to cause primary or secondary HLH, we speculate that it may have made the patient more susceptible for HLH under the circumstances of ongoing infection associated with X-CGD.


Subject(s)
Granulomatous Disease, Chronic/complications , Granulomatous Disease, Chronic/genetics , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/genetics , Pore Forming Cytotoxic Proteins/genetics , Child, Preschool , Fatal Outcome , Female , Granulomatous Disease, Chronic/physiopathology , Humans , Lymphohistiocytosis, Hemophagocytic/physiopathology , Male , Membrane Glycoproteins/genetics , NADPH Oxidase 2 , NADPH Oxidases/genetics , Pedigree , Perforin , Polymorphism, Genetic
8.
Br J Haematol ; 143(1): 75-83, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18710388

ABSTRACT

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare autosomal recessive lethal condition characterized by fever, cytopenia, hepatosplenomegaly and hemophagocytosis. The hallmark of FHL is defect apoptosis triggering and lymphocyte cellular cytotoxicity. Thus far three disease-causing genes (PRF1, UNC13D, STX11) have been identified. We performed a genotype-phenotype study in a large, multi-ethnic cohort of 76 FHL patients originating from 65 unrelated families. Biallelic mutations in PRF1, UNC13D and STX11 were demonstrated in 13/74 (18%), 6/61 (10%) and 14/70 (20%) patients, respectively. In 27/60 (45%) patients analyzed for all three genes, no molecular diagnosis was established. STX11 mutations were most common in Turkish families (7/28, 25%), whereas in Middle East families, PRF1 mutations were most frequent (6/13, 46%). No biallelic mutation was identified in most families of Nordic origin (13/14, 93%). Patients carrying PRF1 mutations had higher risk of early onset (age <6 months) compared to patients carrying STX11 mutations [adjusted odds ratio 8.23 (95% confidence interval [CI] = 1.20-56.40), P = 0.032]. Moreover, patients without identified mutations had increased risk of pathological cerebrospinal fluid (CSF) at diagnosis compared to patients with STX11 mutations [adjusted odds ratio 26.37 (CI = 1.90-366.82), P = 0.015]. These results indicate that the disease-causing mutations in FHL have different phenotypes with regard to ethnic origin, age at onset, and pathological CSF at diagnosis.


Subject(s)
Lymphohistiocytosis, Hemophagocytic/genetics , Membrane Proteins/genetics , Mutation , Pore Forming Cytotoxic Proteins/genetics , Qa-SNARE Proteins/genetics , Age of Onset , Child, Preschool , Cohort Studies , Female , Genotype , Humans , Infant , Infant, Newborn , Logistic Models , Lymphohistiocytosis, Hemophagocytic/cerebrospinal fluid , Lymphohistiocytosis, Hemophagocytic/ethnology , Male , Odds Ratio , Oman/ethnology , Perforin , Phenotype , Risk Assessment/methods , Sweden/ethnology , Turkey/ethnology
9.
Pediatr Blood Cancer ; 50(5): 1067-9, 2008 May.
Article in English | MEDLINE | ID: mdl-18000860

ABSTRACT

In the present study, DNA sequencing of the genes SRGN, ARF6, AP3B1, and SH2D1A was performed in a well defined cohort of 18 families with familial hemophagocytic lymphohistiocytosis (FHL). A heterozygous nucleotide change (C > T) in the 3'untranslated region of the SRGN gene and a monoallelic 3-base pair deletion (c.2409_2411delGAA) in exon 21 of the AP3B1 gene were observed in two different families. Additionally, two novel polymorphisms, one in intron 17 of AP3B1 and another in intron 2 of SH2D1A were identified. We conclude that mutations in SRGN, ARF6, and AP3B1 are not likely to be common in patients fulfilling the FHL criteria.


Subject(s)
ADP-Ribosylation Factors/genetics , Adaptor Protein Complex 3/genetics , Adaptor Protein Complex beta Subunits/genetics , Intracellular Signaling Peptides and Proteins/genetics , Lymphohistiocytosis, Hemophagocytic/genetics , Polymorphism, Genetic/genetics , Proteoglycans/genetics , Vesicular Transport Proteins/genetics , 3' Untranslated Regions/genetics , ADP-Ribosylation Factor 6 , Child , Child, Preschool , Cohort Studies , DNA Mutational Analysis , Exons/genetics , Female , Humans , Infant , Male , Mutation/genetics , Signaling Lymphocytic Activation Molecule Associated Protein
10.
Acta Paediatr ; 96(11): 1703-6, 2007 Nov.
Article in English | MEDLINE | ID: mdl-17888050

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition with high mortality. We report an extremely premature girl, born in the 24th gestational week (BW 732 g), that during her second month developed a severe HLH subsequent to a Serratia marcescens septicemia, with hepatosplenomegaly, cytopenias, hyperbilirubinemia (mostly conjugated, total bilirubin 916 mumol/L), hypertriglyceridemia, hypofibrinogenemia, hyperferritinemia (21266 mug/L), and elevated sIL-2 receptor levels. Genetic analysis revealed no PRF1, STX11 or UNC13D gene mutations. Treatment was provided according to the HLH-2004 protocol with etoposide, dexamethasone, and immunoglobulin, but no cyclosporin because of immature kidneys. She recovered fully from the HLH but developed a severe retinopathy as well as green teeth secondary to the hyperbilirubinemia. We conclude that secondary, bacteria-associated HLH can develop in premature infants, and that HLH can be treated with cytotoxic therapy also in premature infants. It is important to be aware of HLH in premature infants, since it is treatable.


Subject(s)
Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Sepsis/diagnosis , Sepsis/drug therapy , Serratia Infections/diagnosis , Serratia Infections/drug therapy , Adrenal Cortex Hormones/administration & dosage , Cytotoxins/administration & dosage , Cytotoxins/therapeutic use , Dexamethasone/administration & dosage , Drug Therapy, Combination , Etoposide/administration & dosage , Female , Humans , Hyperbilirubinemia/diagnosis , Immunoglobulins/administration & dosage , Infant, Extremely Low Birth Weight , Infant, Newborn , Infant, Premature , Lymphohistiocytosis, Hemophagocytic/microbiology , Retinopathy of Prematurity , Sepsis/complications , Sepsis/microbiology , Serratia Infections/complications , Serratia marcescens
11.
Blood ; 110(6): 1906-15, 2007 Sep 15.
Article in English | MEDLINE | ID: mdl-17525286

ABSTRACT

Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsislike illness with cytopenia, hepatosplenomegaly, and deficient lymphocyte cytotoxicity. Disease-causing mutations have been identified in genes encoding perforin (PRF1/FHL2), Munc13-4 (UNC13D/FHL3), and syntaxin-11 (STX11/FHL4). In contrast to mutations leading to loss of perforin and Munc13-4 function, it is unclear how syntaxin-11 loss-of-function mutations contribute to disease. We show here that freshly isolated, resting natural killer (NK) cells and CD8(+) T cells express syntaxin-11. In infants, NK cells are the predominant perforin-containing cell type. NK cells from FHL4 patients fail to degranulate when encountering susceptible target cells. Unexpectedly, IL-2 stimulation partially restores degranulation and cytotoxicity by NK cells, which could explain the less severe disease progression observed in FHL4 patients, compared with FHL2 and FHL3 patients. Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may facilitate diagnosis, and that these new insights may offer novel therapeutic possibilities.


Subject(s)
Gene Expression Regulation , Killer Cells, Natural/cytology , Lymphocytes/cytology , Lymphohistiocytosis, Hemophagocytic/genetics , Qa-SNARE Proteins/genetics , Adult , Blotting, Western , Cell Proliferation , Child, Preschool , Cytokines/metabolism , Female , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Infant , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Killer Cells, Natural/metabolism , LIM Domain Proteins , LIM-Homeodomain Proteins , Lymphocyte Subsets , Lymphocytes/metabolism , Lymphohistiocytosis, Hemophagocytic/metabolism , Lymphohistiocytosis, Hemophagocytic/pathology , Male , Membrane Glycoproteins/genetics , Membrane Glycoproteins/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Muscle Proteins/genetics , Muscle Proteins/metabolism , Mutation/genetics , Perforin , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/metabolism , Qa-SNARE Proteins/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/genetics , Transcription Factors/metabolism
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