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diseases-risk-factors 4

H00001

Cancer

Acute lymphocytic leukemia (ALL) is a clonal stem cell malignancy of excessive lymphoblast proliferation. It is now understood that ALL and lymphoblastic lymphoma are the same disease entities at the morphologic and immunophenotypic levels and classified as either B- and T-cell lymphoblastic leukemia/lymphoma (B-ALL and T-ALL). In the case of B-ALL, numerous reports have demonstrated that recurring genetic abnormalities are associated with sufficiently unique clinical, immunophenotypic, and/or prognostic features so that they can be considered as distinct entities. The most common rearrangements observed in B-ALL are the t(12;21) (p13;q22) rearrangement resulting in expression of the ETV6-RUNX1 fusion (TEL-AML1); the t(1;19) (q23;p13) translocation that results in expression of the TCF3 (E2A) fusion partner, (also known as TCF3) TFPT-PBX1 fusion (E2A-PBX); the t(9;22) (q34;q11.2) "Philadelphia" chromosome resulting in expression of the BCR-ABL1 fusion; and rearrangements of MLL (also known as KMT2A) at 11q23 to a diverse array of fusion partners. If none of these specific genetic abnormalities are found, the designation of "B lymphoblastic leukemia/lymphoma, not otherwise specified," is appropriate.

H00002

Cancer

Acute lymphocytic leukemia (ALL) is a clonal stem cell malignancy of excessive lymphoblast proliferation. It is now understood that ALL and lymphoblastic lymphoma are the same disease entities at the morphologic and immunophenotypic levels and classified as either B- and T-cell lymphoblastic leukemia/lymphoma (B-ALL and T-ALL). T-ALL comprises 15% of paediatric and 25% of adult ALL cases. T cell transformation is a multi-step process in which different genetic alterations cooperate to alter the normal mechanisms that control cell growth, proliferation, survival, and differentiation during thymocyte development. In this context, constitutive activation of NOTCH1 signaling is the most prominent oncogenic pathway in T cell transformation. In addition, T-ALLs characteristically show the translocation and aberrant expression of transcription factor oncogenes. These oncogenic transcription factors include T-cell leukaemia homeobox protein 1 (TLX1 also known as HOX11), TLX3 (HOX11L2), LYL1, TAL1 and MLL.

H00003

Cancer

Acute myeloid leukemia (AML) is a disease that is characterized by uncontrolled proliferation of clonal neoplastic cells and accumulation in the bone marrow of blasts with an impaired differentiation program. AML accounts for approximately 80% of all adult leukemias and remains the most common cause of leukemia death. Two major types of genetic events have been described that are crucial for leukemic transformation. A proposed necessary first event is disordered cell growth and upregulation of cell survival genes. The most common of these activating events were observed in the RTK Flt3, in N-Ras and K-Ras, in Kit, and sporadically in other RTKs. Alterations in myeloid transcription factors governing hematopoietic differentiation provide second necessary event for leukemogenesis. Transcription factor fusion proteins such as PML-RARalpha (in Acute promyelocytic leukemia, a subtype of AML), AML-ETO or PLZF-RARalpha block myeloid cell differentiation by repressing target genes. In other cases, the transcription factors themselves are mutated.

H00004

Cancer

H00005

Cancer

H00006

Cancer

H00007

Cancer

H00008

Cancer

H00009

Cancer

H00010

Cancer

H00011

Cancer

H00012

Cancer

H00013

Cancer

H00014

Cancer

H00015

Cancer

H00016

Cancer

Oral cancer refers to a subgroup of head and neck malignancies that develop at the lips, tongue, salivary glands, gingiva, floor of the mouth, oropharynx, buccal surfaces and other intra-oral locations, according to the International Classification of Diseases. Nevertheless, the term is synonymous to squamous cell carcinoma (SCC) of oral mucosal origin that accounts for more than 90% of all malignant presentations at the aforementioned anatomical sites. Worldwide, oral SCC (OSCC) is the sixth most common cancer; more than 300,000 new cases are diagnosed each year. The development of OSCC is a multistep process requiring the accumulation of multiple genetic alterations, influenced by a patient's genetic predisposition as well as by environmental influences, including tobacco, alcohol, chronic inflammation, and viral infection. The genetic changes include activation of the epidermal growth factor receptor (EGFR), alterations of tumor suppressors p53 and p16, and cyclin D1 overexpression.

H00017

Cancer

H00018

Cancer

H00019

Cancer

H00020

Cancer

Colorectal cancer (CRC) is the second largest cause of cancer-related deaths in Western countries. CRC arises from the colorectal epithelium as a result of the accumulation of genetic alterations in defined oncogenes and tumour suppressor genes (TSG). Two major mechanisms of genomic instability have been identified in sporadic CRC progression. The first, known as chromosomal instability (CIN), results from a series of genetic changes that involve the activation of oncogenes such as K-ras and inactivation of TSG such as p53, DCC/Smad4, and APC. The second, known as microsatellite instability (MSI), results from inactivation of the DNA mismatch repair genes MLH1 and/or MSH2 by hypermethylation of their promoter, and secondary mutation of genes with coding microsatellites, such as transforming growth factor receptor II (TGF-RII) and BAX. Hereditary syndromes have germline mutations in specific genes (mutation in the tumour suppressor gene APC on chromosome 5q in FAP, mutated DNA mismatch repair genes in HNPCC).

H00021

Cancer

H00022

Cancer

H00023

Cancer

H00024

Cancer

Prostate cancer constitutes a major health problem in Western countries. It is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths. The identification of key molecular alterations in prostate-cancer cells implicates carcinogen defenses (GSTP1), growth-factor-signaling pathways (NKX3.1, PTEN, and p27), and androgens (AR) as critical determinants of the phenotype of prostate-cancer cells. Glutathione S-transferases (GSTP1) are detoxifying enzymes. Cells of prostatic intraepithelial neoplasia, devoid of GSTP1, undergo genomic damage mediated by carcinogens. NKX3.1, PTEN, and p27 regulate the growth and survival of prostate cells in the normal prostate. Inadequate levels of PTEN and NKX3.1 lead to a reduction in p27 levels and to increased proliferation and decreased apoptosis. Androgen receptor (AR) is a transcription factor that is normally activated by its androgen ligand. During androgen withdrawal therapy, the AR signal transduction pathway also could be activated by amplification of the AR gene, by AR gene mutations, or by altered activity of AR coactivators. Through these mechanisms, tumor cells lead to the emergence of androgen-independent prostate cancer.

H00025

Cancer

H00026

Cancer

H00027

Cancer

H00028

Cancer

H00029

Cancer

H00030

Cancer

H00031

Cancer

H00032

Cancer

Thyroid cancer is the most common endocrine malignancy and accounts for the majority of endocrine cancer- related deaths each year. More than 95% of thyroid carcinomas are derived from follicular cells. Their behavior varies from the indolent growing, well-differentiated papillary and follicular carcinomas (PTC and FTC, respectively) to the extremely aggressive undifferentiated carcinoma (UC). Somatic rearrangements of RET and TRK are almost exclusively found in PTC and may be found in early stages. The most distinctive molecular features of FTC are the prominence of aneuploidy and the high prevalence of RAS mutations and PAX8-PPAR{gamma} rearrangements. p53 seems to play a crucial role in the dedifferentiation process of thyroid carcinoma.

H00033

Cancer

H00034

Cancer

H00035

Cancer

H00036

Cancer

H00037

Cancer

Rhabdomyosarcomas (RMSs) are soft tissue sarcomas that are one of the most common neoplasms in children and adolescents. RMSs are presumed to be associated with the skeletal muscle lineage, although those tumors can be present in organs histologically lacking skeletal muscle, like prostate, urinary bladder or gallbladder. RMS is divided into two major subtypes: embryonal (ERMS) and alveolar (ARMS). Alveolar rhabdomyosarcoma (ARMS) is a pediatric sarcoma that typically occurs in older children predominantly arising in the trunk and extremities, and exhibits a worse prognosis than other types of RMSs. ARMS is associated with 2;13 or 1;13 chromosomal translocations, which generate PAX3-FOXO1A and PAX7-FOXO1A fusion products, respectively. These translocations result in altered expression, function, and subcellular localization of the fusion products relative to the wild-type proteins, and ultimately contribute to oncogenic behavior by modifying growth, differentiation, and apoptosis pathways.

H00038

Cancer

Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. Melanoma arises from the malignant transformation of pigment-producing cells, melanocytes. The only known environmental risk factor is exposure to ultraviolet (UV) light and in people with fair skin the risk is greatly increased. Melanoma pathogenesis is also driven by genetic factors. Oncogenic NRAS mutations activate both effector pathways Raf-MEK-ERK and PI3K-Akt. The Raf-MEK-ERK pathway may also be activated via mutations in the BRAF gene. The PI3K-Akt pathway may be activated through loss or mutation of the inhibitory tumor suppressor gene PTEN. These mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Melanoma development has been shown to be strongly associated with inactivation of the p16INK4a/cyclin dependent kinases 4 and 6/retinoblastoma protein (p16INK4a/CDK4,6/pRb) and p14ARF/human double minute 2/p53 (p14ARF/HMD2/p53) tumor suppressor pathways. MITF and TP53 are implicated in further melanoma progression.

H00039

Cancer

H00040

Cancer

H00041

Cancer

H00042

Cancer

H00043

Cancer

H00044

Cancer

H00045

Cancer

H00046

Cancer

H00047

Cancer

H00048

Cancer

H00049

Cancer

H00050

Cancer

H00051

Cancer

H00052

Cancer

H00053

Cancer

H00054

Cancer

H00055

Cancer

H00056

Neurodegenerative disease

H00057

Neurodegenerative disease

H00058

Neurodegenerative disease

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive degeneration of motor neurons in the brain and spinal cord. In 90% of patients, ALS is sporadic, with no clear genetic linkage. On the other hand, the remaining 10% of cases show familial inheritance, with mutations in SOD1, TDP43(TARDBP), FUS, or C9orf72 genes being the most frequent causes. In spite of such difference, familial ALS and sporadic ALS have similarities in their pathological features. Proposed disease mechanisms contributing to motor neuron degeneration in ALS are: impaired proteostasis, aberrant RNA processing, mitochondrial disfunction and oxidative stress, microglia activation, and axonal dysfunction.

H00059

Neurodegenerative disease

H00060

Neurodegenerative disease

H00061

Neurodegenerative disease

H00062

Neurodegenerative disease

H00063

Neurodegenerative disease

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of progressive neurodegenerative diseases characterised by loss of balance and motor coordination due to the primary dysfunction of the cerebellum. Compelling evidence points to major aetiological roles for transcriptional dysregulation, protein aggregation and clearance, autophagy, the ubiquitin-proteasome system, alterations of calcium homeostasis, mitochondria defects, toxic RNA gain-of-function mechanisms and eventual cell death with apoptotic features of neurons during SCA disease progression.

H00064

Neurodegenerative disease; Primary immunodeficiency

H00065

Neurodegenerative disease

H00066

Neurodegenerative disease

H00067

Neurodegenerative disease

H00068

Nervous system disease; Congenital disorder of metabolism

H00069

Congenital disorder of metabolism

Glycogen storage disease (GSD) is an autosomal recessive (all types except IXa and IXd) or X-linked (types IXa and IXd) disorder with symptoms ranging from weakness to growth abnormalities. GSD is caused by a defect in an enzyme gene or a transporter gene involved in glycogen metabolism; types I, VII, and XI for processing of glucose, types II-VI and IX for processing of glycogen, and type 0 for glycogen synthesis. Pompe disease (type II) is a lysosomal storage disease.

H00070

Congenital disorder of metabolism

Galactosemia (GALAC) is an autosomal recessive disorder caused by a defect in one of the enzyme genes for galactose metabolism. Newborns with the enzyme deficiency cannot properly metabolize milk sugar. Without treatment, toxic metabolites can cause severe growth problems including cataracts.

H00071

Congenital disorder of metabolism

H00072

Congenital disorder of metabolism

Pyruvate dehydrogenase complex deficiency is an autosomal or X-linked recessive disorder caused by deficient enzyme activity in the pyruvate dehydrogenase complex, resulting in deficiency of acetyl CoA and reduced synthesis of acetylcholine. This deficiency in newborns may lead to brain malformations. The PDH complex comprises three catalytic subunits, PDH (E1), dihydrolipoamide acetyltransferase (E2) and dihydrolipoamide dehydrogenase (E3), and two regulatory subunits, E1 kinase and phospho-E1-phosphatase, together with a sixth component, E3-binding protein, which is believed to play a role in the attachment of E3 to the E2 core.

H00073

Inherited metabolic disease

H00074

Inherited metabolic disease; Neurodegenerative disease

H00075

Neurodegenerative disease; Congenital disorder of metabolism; Peroxisomal disease

H00076

Neurodegenerative disease

H00077

Neurodegenerative disease

H00078

Neurodegenerative disease

Frontotemporal lobar degeneration (FTLD) is a heterogeneous syndrome with the common feature being a relatively selective degeneration of the frontal and temporal lobes. Multiple genes have been implicated in FTLD including microtubule associate protein tau (MAPT), progranulin (PGRN),Valosin-containing protein (VCP) and chromatin modifying protein 2B (CHMP2B). MAPT mutations are associated with tau pathology. Mutations in progranulin and valosin are associated with TDP-43 inclusions. The CHMP2B mutations are associated with ubiquitin-positive pathology.

H00079

Immune system disease

Asthma is a complex syndrome with many clinical phenotypes in both adults and children. Its major characteristics include a variable degree of airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Inhaled allergens encounter antigen presenting cells (APC) that line the airway. Upon recognition of the antigen and activation by APC, naive T cells differentiate into TH2 cells. Activated TH2 stimulate the formation of IgE by B cells. IgE molecules bind to IgE receptors located on mast cells. The crosslinking of mast-cell-bound IgE by allergens leads to the release of biologically active mediators (histamine, leukotrienes) by means of degranulation and, so, to the immediate symptoms of allergy. Mast cells also release chemotactic factors that contribute to the recruitment of inflammatory cells, particularly eosinophils, whose proliferation and differentiation from bone marrow progenitors is promoted by IL-5. The activation of eosinophils leads to release of toxic granules and oxygen free radicals that lead to tissue damage and promote the development of chronic inflammation.

H00080

Immune system disease

H00081

Immune system disease

H00082

Immune system disease

H00083

Immune system disease

H00084

Immune system disease

H00085

Immune system disease

There are three major categories of antibody deficiencies: (a) defects in early B cell development, (b) hyper-IgM syndromes (also called class switch recombination defects), and (c) common variable immunodeficiency (CVID). Category (a) consists of agammaglobulinaemias (AGM). Defects in early B cell development are characterized by the onset of recurrent bacterial infections in the first 5 years of life, profound hypogammaglobulinemia, markedly reduced or absent B cells in the peripheral circulation, and (in the bone marrow) a severe block in B cell differentiation before the production of surface immunoglobulin-positive B cells. Mutations in Btk, the gene responsible for X-linked agammaglobulinemia (XLA), account for approximately 85% of affected patients. Approximately half of the remaining patients have mutations in genes encoding components of the pre-B cell receptor (pre-BCR) or BCR, including mu heavy chain (IGHM); the signal transduction molecules Ig-alpha (CD79A) and Ig-beta (CD79B); and lambda 5 (IGLL1), which forms the surrogate light chain with Vpre-B. A small number of patients with defects in BLNK, a scaffold protein that assembles signal transduction molecules activated by cross-linking of the BCR, have been reported.

H00086

Immune system disease

H00087

Immune system disease

H00088

Immune system disease

H00089

Primary immunodeficiency

H00090

Primary immunodeficiency

H00091

Primary immunodeficiency

H00092

Primary immunodeficiency

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of monogenic disorders that result in early-onset severe infections by a range of pathogens (such as bacteria, viruses and fungi). Typically, patients with SCID have a severe defect in T-cell differentiation, along with direct or indirect impairment of B-cell development and function. Adenosine deaminase (ADA) deficiency accounts for about half of the autosomal recessive forms of SCIDs. It is one of the most severe immunodeficiencies and is associated with severe depletion of B cells, T cells, and NK cells. V(D)J- recombination deficiency caused by defects in recombinase-activating gene 1 (RAG1), RAG2 and Artemis (DCLRE1C) leads to a T-B-SCID phenotype that is characterized by an arrest of B- and T-cell maturation at the stage of pro-B and pre-T cells, respectively, whereas natural killer (NK)-cell maturation is not affected. V(D)J recombination generates the diversity of B- and T-cell primary immune repertoires.

H00093

Primary immunodeficiency

The term combined immunodeficiency (CID) is used to distinguish patients with low, but not absent, T-cell function from those with severe CID (SCID) characterized by profound deficiencies of T- and B-cell (and sometimes NK- cell) function. Hyper-IgM syndrome (HIM) represents a group of distinct entities characterized by defective normal or elevated IgM in the presence of diminished IgG and IgA levels. The genetic anomaly in X-linked hyper-IgM syndrome has been mapped to Xq26, and resides in mutations of the CD40 ligand gene. ZAP-70 deficiency is inherited in an autosomal recessive manner. Recurrent and opportunistic infections occur within the first year of life. The mutations in genes responsible for CRAC channel function, ORAI1 and STIM1, cause the defect in Ca2+ influx.

H00094

Primary immunodeficiency

A number of genetically determined disorders collectively called as the chromosome breakage syndromes or DNA-repair disorders have a characteristic cytogenetic feature, chromosome instability. They are all autosomal recessive, show an increased tendency for chromosomal aberrations and to develop malignancies. Ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), and an ataxia-like disorder (ATLD), are chromosome instability disorders that are defective in the ataxia telangiectasia mutated (ATM), NBS, and Mre11 genes, respectively. These genes are critical in maintaining cellular resistance to ionizing radiation (IR), which kills largely by the production of double-strand breaks (DSBs). Bloom syndrome involves a defect in the BLM helicase, which seems to play a role in restarting DNA replication forks that are blocked at lesions, thereby promoting chromosome stability. A point mutational change in DNA ligase I was identified in a unique immunodeficient individual who suffered recurrent sinopulmonary infection leading to bronchiectasis. A non-inactivating mutational change in DNA ligase IV has also been identified in a leukaemia patient, who was dramatically over-sensitive to radiotherapy.

H00095

Immune system disease

Ectodermal dysplasia (ED) refers to a group of inherited disorders involving absence or dysplasia of the ectodermal appendages. Clinically, it is characterized by absence, abnormality, or deficient function of ectodermal derivatives, including skin, teeth, hair, eccrine glands, or nails. In the hypohidrotic/ anhidrotic form of ED (HED/EDA) the patient has no sweat glands, sparse scalp hair and rare conical teeth. Patients with EDA and immunodeficiency (EDA-ID) present some or all of these features, together with severe infectious diseases. EDA-ID principally affects boys, suggesting X-linked recessive inheritance (XL-EDA-ID). This was confirmed in 2000 and beyond with the identification of disease-causing hypomorphic mutations in NEMO, which is located on the X chromosome and encodes IKK-gamma. A novel autosomal dominant of EDA-ID, recently identified in one child, was found to be caused by a hypermorphic mutation of the gene encoding I{kappa}B{alpha}. Similar to XL-EDA-ID patients, from the age of two months he suffered from multiple and severe infections with several Gram-positive and Gram-negative bacteria, leading to chronic bronchopneumonitis and gastroenteritis, with failure to thrive.

H00096

Primary immunodeficiency

Human interleukin (IL) 1 receptor-associated kinase 4 (IRAK-4) deficiency is a primary immunodeficiency that impairs Toll/IL-1R immunity, except for the Toll-like receptor (TLR) 3- and TLR4-interferon (IFN)-a/b pathways. IRAK-4 is a kinase that plays a crucial role downstream of individual TLR and IL-1R receptors and upstream of TNF receptor-associated factor-6 (TRAF-6). Patients with IRAK-4 deficiency thus fail to produce TNF-alpha, IL-6, and IFN-gamma in response to IL-1beta and IL-18, respectively. Their blood cells also fail to produce IL-1beta, IL-6, IL-8, IL-12, and TNF-alpha upon stimulation with known TLR agonists. Despite the broad impairment at the two subsequent levels of onset (TLR) and propagation (IL-1R) of inflammation, the clinical phenotype of IRAK-4 deficiency is relatively mild. Patients present no developmental defect and a restricted spectrum of infectious diseases, mostly caused by pyogenic encapsulated bacteria, principally, but not exclusively Gram-positive. Recently, other monogenic defects of toll-like receptor signaling that cause severe immunodeficiency have been reported.

H00097

Primary immunodeficiency

H00098

Primary immunodeficiency

H00099

Primary immunodeficiency

H00100

Primary immunodeficiency

Neutropenias represents a series of potentially life-threatening disorders characterised by a reduction in circulating neutrophils. Since neutrophils play a major role in host defense against bacteria, neutropenia patients suffer from frequent episodes of opportunistic bacterial infections. Severe congenital neutropenia (SCN) is a rare neutropenia with a bone marrow maturation arrest of granulocytic differentiation. Kostmann syndrome is an autosomal recessive SCN. The characteristic maturation arrest and the lack of mature neutrophils in peripheral blood of patients with Kostmann syndrome can be explained by the deletion of an anti-apoptotic factor (HAX-1) in myeloid cells of these patients. Heterozygous mutations in the protooncogene growth factor-independent 1 (GFI1) gene are also associated with SCN. In patients with autosomal dominant cyclic neutropenia (CyN), a condition with oscillating neutrophil counts but less severe clinical symptoms, heterozygous mutations in ELA-2/ELANE were discovered. Patients with X-linked severe congenital neutropenia (SCN) have been reported with activating mutations in Wiskott-Aldrich syndrome protein (WASp) leading to a constitutively-active form of the protein, and unregulated actin polymerization.