RESUMO
BACKGROUND AND OBJECTIVES: Malignant sweat gland tumors are rare, with the most common being eccrine porocarcinoma (EP). Approximately 18% of benign eccrine poroma (EPO) transit to EP. Previous research has provided first insights into the mutational landscape of EP. However, only few studies have performed gene expression analyses. This leaves a gap in the understanding of EP biology and potential drivers of malignant transformation from EPO to EP. METHODS: Transcriptome profiling of 23 samples of primary EP and normal skin (NS). Findings from the EP samples were then tested in 17 samples of EPO. RESULTS: Transcriptome profiling revealed diversity in gene expression and indicated biologically heterogeneous sub-entities as well as widespread gene downregulation in EP. Downregulated genes included CD74, NDGR1, SRRM2, CDC42, ANXA2, KFL9 and NOP53. Expression levels of CD74, NDGR1, SRRM2, ANXA2, and NOP53 showed a stepwise-reduction in expression from NS via EPO to EP, thus supporting the hypothesis that EPO represents a transitional state in EP development. CONCLUSIONS: We demonstrated that EP is molecularly complex and that evolutionary trajectories correspond to tumor initiation and progression. Our results provide further evidence implicating the p53 axis and the EGFR pathway. Larger samples are warranted to confirm our findings.
Assuntos
Porocarcinoma Écrino , Perfilação da Expressão Gênica , Neoplasias das Glândulas Sudoríparas , Humanos , Porocarcinoma Écrino/genética , Porocarcinoma Écrino/patologia , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias das Glândulas Sudoríparas/patologia , Neoplasias das Glândulas Sudoríparas/metabolismo , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Feminino , Masculino , Transformação Celular Neoplásica/genética , Regulação Neoplásica da Expressão Gênica , Idoso , Pessoa de Meia-IdadeRESUMO
Lynch syndrome (LS), Lynch-like syndrome (LLS) and familial colorectal cancer type X (FCCX) are different entities of familial cancer predisposition leading to an increased risk of colorectal cancer (CRC). The aim of this prospective study was to characterise and to compare the risks for adenoma and CRC in these three risk groups. Data was taken from the registry of the German Consortium for Familial Intestinal Cancer. Patients were prospectively followed up in an intensified colonoscopic surveillance programme that included annual examinations. Cumulative risks for adenoma and CRC were calculated separately for LS, LLS and FCCX, and then for males and females. Multivariate Cox regression was used to analyse the independent contributions of risk group, mismatch repair gene (within LS), sex and previous adenoma. The study population comprised 1448 individuals (103 FCCX, 481 LLS and 864 LS). The risks were similar for colorectal adenomas, but different for first and metachronous CRC between the three risk groups. CRC risk was highest in LS, followed by LLS and lowest in FCCX. Male sex and a prevalent adenoma in the index colonoscopy were associated with a higher risk for incident adenoma and CRC. In patients with LS, CRC risks were particularly higher in female MSH2 than MLH1 carriers. Our study may support the development of risk-adapted surveillance policies in LS, LLS and FCCX.
Assuntos
Adenoma/patologia , Biomarcadores Tumorais/genética , Neoplasias Colorretais Hereditárias sem Polipose/classificação , Neoplasias Colorretais Hereditárias sem Polipose/complicações , Neoplasias Colorretais/patologia , Adenoma/etiologia , Adenoma/metabolismo , Adulto , Idoso , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/genética , Proteína 2 Homóloga a MutS/genética , Mutação , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
Ververi-Brady syndrome (VBS, # 617982) is a rare developmental disorder, and loss-of-function variants in QRICH1 were implicated in its etiology. Furthermore, a recognizable phenotype was proposed comprising delayed speech, learning difficulties and dysmorphic signs. Here, we present four unrelated individuals with one known nonsense variant (c.1954C > T; p.[Arg652*]) and three novel de novo QRICH1 variants, respectively. These included two frameshift mutations (c.832_833del; p.(Ser278Leufs*25), c.1812_1813delTG; p.(Glu605Glyfs*25)) and interestingly one missense mutation (c.2207G > A; p.[Ser736Asn]), expanding the mutational spectrum. Enlargement of the cohort by these four individuals contributes to the delineation of the VBS phenotype and suggests expressive speech delay, moderate motor delay, learning difficulties/mild ID, mild microcephaly, short stature and notable social behavior deficits as clinical hallmarks. In addition, one patient presented with nephroblastoma. The possible involvement of QRICH1 in pediatric cancer assumes careful surveillance a key priority for outcome of these patients. Further research and enlargement of cohorts are warranted to learn about the genetic architecture and the phenotypic spectrum in more detail.
Assuntos
Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Adolescente , Criança , Pré-Escolar , Códon sem Sentido/genética , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/patologia , Exoma/genética , Feminino , Mutação da Fase de Leitura/genética , Genótipo , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Mutação com Perda de Função/genética , Masculino , Mutação de Sentido Incorreto/genética , FenótipoRESUMO
INTRODUCTION: Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3â% of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). One in 300 individuals of the general population are considered to be mutation carriers (300â000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46â% till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers. METHODS: The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany. RESULTS: A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13â%. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8â%. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10â% of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years. CONCLUSION: LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/patologia , Reparo de Erro de Pareamento de DNA , Endoscopia do Sistema Digestório/métodos , Guias de Prática Clínica como Assunto , Comportamento de Redução do Risco , Neoplasias Colorretais , Neoplasias Colorretais Hereditárias sem Polipose/genética , Alemanha , Humanos , Vigilância da População , Fatores de TempoAssuntos
Porocarcinoma Écrino , Perfilação da Expressão Gênica , Neoplasias das Glândulas Sudoríparas , Humanos , Porocarcinoma Écrino/genética , Porocarcinoma Écrino/patologia , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias das Glândulas Sudoríparas/patologia , Transcriptoma/genética , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Feminino , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Masculino , Regulação Neoplásica da Expressão Gênica , Pessoa de Meia-IdadeRESUMO
Pattern hair loss is the most common form of hair loss in both women and men. Male pattern hair loss, also termed male androgenetic alopecia (M-AGA), is an androgen-dependent trait that is predominantly genetically determined. Androgen-mediated mechanisms are probably involved in female pattern hair loss (FPHL) in some women but the evidence is less strong than in M-AGA; other non-androgenic pathways, including environmental influences, may contribute to the aetiology. Genome-wide association studies have identified several genetic loci for M-AGA and have provided better insight into the underlying biology. However, the role of heritable factors in Female Pattern Hair Loss (FPHL) is largely unknown. Recently published studies have been restricted to candidate gene approaches and could not clearly identify any susceptibility locus/gene for FPHL but suggest that the aetiology differs substantially from that of M-AGA. Hypotheses about possible pathomechanisms of FPHL as well as the results of the genetic studies performed to date are summarized.
Assuntos
Alopecia/etiologia , Alopecia/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Alopecia/epidemiologia , Androgênios/metabolismo , Apoptose , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Inflamação , Ferro/química , Fenótipo , Prevalência , Prostaglandinas/metabolismo , Transdução de Sinais , Esteroides/metabolismo , Estudos em Gêmeos como Assunto , Vitamina D/químicaRESUMO
Alopecia areata (AA) is a common hair loss disorder of autoimmune aetiology, which often results in pronounced psychological distress. Understanding of the pathophysiology of AA is increasing, due in part to recent genetic findings implicating common variants at several genetic loci. To date, no study has investigated the contribution of copy number variants (CNVs) to AA, a prominent class of genomic variants involved in other autoimmune disorders. Here, we report a genomewide- and a candidate gene-focused CNV analysis performed in a cohort of 585 patients with AA and 1340 controls of Central European origin. A nominally significant association with AA was found for CNVs in the following five chromosomal regions: 4q35.2, 6q16.3, 9p23, 16p12.1 and 20p12.1. The most promising finding was a 342.5-kb associated region in 6q16.3 (duplications in 4/585 patients; 0/1340 controls). The duplications spanned the genes MCHR2 and MCHR2-AS1, implicated in melanin-concentrating hormone (MCH) signalling. These genes have not been implicated in previous studies of AA pathogenesis. However, previous research has shown that MCHR2 affects the scale colour of barfin flounder fish via the induction of melanin aggregation. AA preferentially affects pigmented hairs, and the hair of patients with AA frequently shows a change in colour when it regrows following an acute episode of AA. This might indicate a relationship between AA, pigmentation and MCH signalling. In conclusion, the present results provide suggestive evidence for the involvement of duplications in MCHR2 in AA pathogenesis.
Assuntos
Alopecia em Áreas/genética , Variações do Número de Cópias de DNA , Estudo de Associação Genômica Ampla , Receptores Acoplados a Proteínas G/genética , Receptores do Hormônio Hipofisário/genética , Adulto , Bélgica , Mapeamento Cromossômico , Estudos de Coortes , Europa (Continente) , Feminino , Genótipo , Alemanha , Humanos , Hormônios Hipotalâmicos/metabolismo , Masculino , Melaninas/metabolismo , Países Baixos , Pigmentação , Hormônios Hipofisários/metabolismo , Polimorfismo de Nucleotídeo Único , Transdução de SinaisAssuntos
Proteínas Mitocondriais/deficiência , Hipotonia Muscular/etiologia , Síndromes Miastênicas Congênitas/diagnóstico , Serina Endopeptidases/deficiência , Endoscopia Gastrointestinal , Gastrostomia , Humanos , Proteínas Mitocondriais/genética , Transtornos Motores , Mutação , Síndromes Miastênicas Congênitas/genética , Fenótipo , Serina Endopeptidases/genéticaRESUMO
Purpose The aim was to develop evidence-based recommendations where possible. The guideline presents the medical principles and scientific evidence for indications, counselling of affected persons, performing terminations, the choice of method, and the care and monitoring of a terminated pregnancy up until week 12 + 0 of gestation p.âc. Methods In accordance with the requirements for an S2k-guideline, the contents of the guideline were drafted following a systematic search of the literature by a representative interdisciplinary group of experts. Guideline authors held several formal meetings under the auspices of the German Society for Gynaecology and Obstetrics (DGGG) during which the contents of the guideline were finalised and agreed upon. Recommendations The guideline provides recommendations on the surgical termination of pregnancy and follow-up care after termination of pregnancy.
RESUMO
Purpose The aim was to develop evidence-based recommendations where possible. The guideline presents the medical principles and scientific evidence for indications, the counselling of affected women, performing terminations, the choice of method, and the care and monitoring of a terminated pregnancy up until week 12 + 0 of gestation p.âc. Methods In accordance with the requirements for S2k-guidelines, the contents of the guideline were drafted following a systematic search of the literature by a representative interdisciplinary group of experts. Guideline authors held several formal meetings under the auspices of the German Society for Gynaecology and Obstetrics (DGGG) during which the contents of the guideline were finalised and agreed upon. Recommendations A total of 61 recommendations are provided, covering care structures, provision of information and counselling to support decision-making, the measures to be taken before terminating the pregnancy, and medical termination of the pregnancy.
RESUMO
Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a rare X-linked, oculocutaneous human disorder. Here, we assign the IFAP locus to the 5.4 Mb region between DXS989 and DXS8019 on Xp22.11-p22.13 and provide evidence that missense mutations exchanging highly conserved amino acids of membrane-bound transcription factor protease, site 2 (MBTPS2) are associated with this phenotype. MBTPS2, a membrane-embedded zinc metalloprotease, activates signaling proteins involved in sterol control of transcription and ER stress response. Wild-type MBTPS2 was able to complement the protease deficiency in Chinese hamster M19 cells as shown by induction of an SRE-regulated reporter gene in transient transfection experiments and by growth of stably transfected cells in media devoid of cholesterol and lipids. These functions were impaired in five mutations as detected in unrelated patients. The degree of diminished activity correlated with clinical severity as noted in male patients. Our findings indicate that the phenotypic expression of IFAP syndrome is quantitatively related to a reduced function of a key cellular regulatory system affecting cholesterol homeostasis and ability to cope with ER stress.
Assuntos
Alopecia/enzimologia , Alopecia/genética , Ictiose Ligada ao Cromossomo X/enzimologia , Ictiose Ligada ao Cromossomo X/genética , Metaloendopeptidases/deficiência , Metaloendopeptidases/genética , Fotofobia/enzimologia , Fotofobia/genética , Alopecia/congênito , Substituição de Aminoácidos , Animais , Células CHO , Estudos de Casos e Controles , Colesterol/metabolismo , Cromossomos Humanos X/genética , Cricetinae , Cricetulus , Retículo Endoplasmático/metabolismo , Feminino , Teste de Complementação Genética , Homeostase , Humanos , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Linhagem , Fenótipo , Estresse Fisiológico , Síndrome , TransfecçãoRESUMO
Female pattern hair loss (FPHL) is a common disorder with a complex mode of inheritance. Although understanding of its etiopathogenesis is incomplete, an interaction between genetic and hormonal factors is assumed to be important. The involvement of an androgen-dependent pathway and sex steroid hormones is the most likely hypothesis. We therefore selected a total of 21 variants from the steroid-5-alpha-reductase isoforms SRD5A1 and SRD5A2, the sex steroid hormone receptors ESR1, ESR2 (oestrogen receptor) and PGR (progesterone receptor) and genotyped these in a case-control sample of 198 patients (145 UK; 53 German patients) and 329 controls (179 UK; 150 German). None of these variants showed any significant association, either in the overall UK and German samples or in the subgroup analyses. In summary, the present results, while based on a limited selection of gene variants, do not point to the involvement of SRD5A1, SRD5A2, ESR1, ESR2 or PGR in FPHL.
Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Alopecia/genética , Variação Genética/genética , Proteínas de Membrana/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Alelos , Alopecia/etnologia , Estudos de Casos e Controles , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Alemanha , Humanos , Reino UnidoAssuntos
Alopecia em Áreas/genética , Pai , Mães , Linhagem , Alopecia em Áreas/diagnóstico , Alopecia em Áreas/epidemiologia , Alopecia em Áreas/imunologia , Europa (Continente)/epidemiologia , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Masculino , Fenótipo , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Malignant sweat gland tumours are rare, with the most common form being Eccrine porocarcinoma (EP). To investigate the mutational landscape of EP, we performed whole-exome sequencing (WES) on 14 formalin-fixed paraffin-embedded samples of matched primary EP and healthy surrounding tissue. Mutational profiling revealed a high overall median mutation rate. This was attributed to signatures of mutational processes related to ultraviolet (UV) exposure, APOBEC enzyme dysregulation, and defective homologous double-strand break repair. All of these processes cause genomic instability and are implicated in carcinogenesis. Recurrent driving somatic alterations were detected in the EP candidate drivers TP53, FAT2, CACNA1S, and KMT2D. The analyses also identified copy number alterations and recurrent gains and losses in several chromosomal regions including that containing BRCA2, as well as deleterious alterations in multiple HRR components. In accordance with this reduced or even a complete loss of BRCA2 protein expression was detected in 50% of the investigated EP tumours. Our results implicate crucial oncogenic driver pathways and suggest that defective homologous double-strand break repair and the p53 pathway are involved in EP aetiology. Targeting of the p53 axis and PARP inhibition, and/or immunotherapy may represent promising treatment strategies.
Assuntos
Porocarcinoma Écrino , Neoplasias das Glândulas Sudoríparas , Humanos , Mutação , Proteína Supressora de Tumor p53/genética , Sequenciamento do ExomaRESUMO
BACKGROUND: In 1925, Dr Marie Unna described a rare form of hereditary hypotrichosis in a German multigenerational family. This was later termed "Marie Unna hereditary hypotrichosis" (MUHH). MUHH is an autosomal dominant disorder that is characterized by the absence or scarcity of scalp hair, eyebrows, and eyelashes at birth; coarse and wiry hair during childhood; and progressive hair loss beginning around puberty. Causal mutations in U2HR, an inhibitory upstream open reading frame in the 5'-untranslated region of the human hairless (HR) gene, were recently identified in several unrelated MUHH families from various ethnic backgrounds. OBJECTIVE: Although there have been several clinical reports of descendants of the originally described family, the molecular cause of disease in this particular family has not been established. The aim of this study was to investigate descendants of this family and to analyze their DNA for the presence of U2HR mutations. METHODS: Descendants of the family (including one affected individual) were examined clinically. Direct sequencing of U2HR was performed. Enzymatic digestion using the restriction enzyme NcoI was performed to confirm the sequencing results. RESULTS: The index patient displayed the typical MUHH pattern of hair loss and was found to carry the disease-causing c.3G>A (p.M1I) U2HR mutation. This mutation was not detected in unaffected family members. LIMITATIONS: Only one affected family member was investigated. CONCLUSIONS: Eighty-five years after the first description of this rare form of alopecia, the disease-causing mutation in the originally reported family has been identified.
Assuntos
Mutação Puntual , Fatores de Transcrição/genética , Saúde da Família , Alemanha , Humanos , Hipotricose/congênito , Hipotricose/genética , LinhagemRESUMO
We report a family with Marie Unna hereditary hypotrichosis (MUHH) from Turkey. MUHH is a distinct form of scalp and body hair loss characterized by the absence or scarcity of scalp hair, eyebrows, and eyelashes at birth. Coarse wiry hair begins to grow during childhood. Around puberty, progressive hair loss occurs in the affected patients. Recently, mutations were identified in U2HR, an inhibitory upstream open reading frame in the 5'-untranslated region of the human hairless gene (HR) as the underlying cause of MUHH. We are presenting hair loss of eyebrows in a Turkish family comprising eight affected and seven unaffected individuals. The pedigree is compatible with autosomal dominant inheritance. Linkage and haplotype analyses confirmed linkage of this family to the MUHH locus at cytoband 8p21. By sequencing U2HR, we identified the mutation c.2T>C (M1T) in all affected family members. We concluded that there may be considerable clinical variations in MUHH, and that eyebrow loss is an important clue for accurate diagnosis.