Interactions between variation in candidate genes and environmental factors in the etiology of schizophrenia and bipolar disorder : a systematic review

Schizophrenia and bipolar disorder (BD) are complex and multidimensional disorders with high heritability rates. The contribution of genetic factors to the etiology of these disorders is increasingly being recognized as the action of multiple risk variants with small effect sizes, which might explain only a minor part of susceptibility. On the other site, numerous environmental factors have been found to play an important role in their causality. Therefore, in recent years, several studies focused on gene × environment interactions that are believed to bridge the gap between genetic underpinnings and environmental insults. In this article, we performed a systematic review of studies investigating gene × environment interactions in BD and schizophrenia spectrum phenotypes. In the majority of studies from this field, interacting effects of variation in genes encoding catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF), and FK506-binding protein 5 (FKBP5) have been explored. Almost consistently, these studies revealed that polymorphisms in COMT, BDNF, and FKBP5 genes might interact with early life stress and cannabis abuse or dependence, influencing various outcomes of schizophrenia spectrum disorders and BD. Other interactions still require further replication in larger clinical and non-clinical samples. In addition, future studies should address the direction of causality and potential mechanisms of the relationship between gene × environment interactions and various categories of outcomes in schizophrenia and BD

Uncommon constellation of multiglandular deficiency with 2 mutations in AIRE gene in an 18-year-old girl — 12 years of observation

Zespoły autoimmunologicznej niewydolności wielogruczołowej (APS) składają się z różnych zaburzeń, zarówno endokrynnych, jak i nieendokrynnych. Zespoły te są złożone i występują z różnymi objawami. Wczesne wykrycie zaburzeń może zapobiec wielu poważnym skutkom klinicznym, które są zazwyczaj wynikiem opóźnionego rozpoznania. W pracy przedstawiono przypadek pacjentki, której objawy kliniczne przemawiają za zespołem autoimmunologicznej niewydolności wielogruczołowej. W ciągu 12 lat obserwacji i leczenia, autoimmunologiczne tło, z wyjątkiem stwierdzenia podwyższonego miana przeciwciał przeciw peroksydazie i przeciw tyreoglobulinie, nie zostało potwierdzone, podobnie jak krytyczna mutacja w genie AIRE. U pacjentki zidentyfikowano 5 polimorfizmów i 2 mutacje w eksonie 1 genu AIRE. (Endokrynol Pol 2014; 65 (6): 514–518)Autoimmune polyglandular syndromes (APS) consist of a variety of endocrine and non-endocrine disorders. The syndromes are complex and their occurrence in life does not follow any pattern. Early detection of such disorders may prevent many serious clinical consequences which are usually a result of delayed diagnosis. We present the case of a female patient whose clinical symptoms very strongly suggested APS, however neither autoimmune background except elevated anti-thyroid peroxidase and anti-thyroglobulin antibodies of multiglandular deficiency, nor critical mutations in the AIRE gene have been confirmed or detected, yet we identified five polymorphisms and two mutations in exon1 of gene AIRE during 12 years of observation and treatment. (Endokrynol Pol 2014; 65 (6): 514–518

Rapid-FISH – fast and reliable method of detecting common numerical chromosomal aberrations in prenatal diagnosis

Abstract Objective: In recent years, new possibilities of prenatal diagnosis have opened up, due to the development of techniques which guarantee shorter time of obtaining results. One of those methods, called Rapid-FISH (rapid fluorescence in situ hybridization), for detecting numerical aberrations of chromosomes 13, 18, 21, X and Y without culturing, enables to have the results in 2-5 days. The time necessary to obtain fetal karyotype result with the usage of the classical cytogenetic methods is about 2-3 weeks and depends mainly on the culture growth rate. Design: The aim of the study was to evaluate the effectiveness of the Rapid-FISH technique in detecting numerical chromosome aberrations of 13, 21, 18, X and Y in amniocytes’ nuclei from amniotic fluid. Materials and Methods: Rapid-FISH and cytogenetic analysis has been performed for 161 pregnancies in the Department of Genetics at Wroclaw Medical University during years 2005 and 2006. The FISH was performed using AneuVysion kit (Vysis), according to a standard protocol. Results: All normal and abnormal results were confirmed by classical cytogenetic method (GTG banding and karyotyping). Additional chromosomal aberrations, not possible to be detected in FISH, were observed in case of two patients with normal results from FISH analysis. Conclusions: Rapid-FISH is a reliable and fast method for detecting numerical chromosomal aberrations in prenatal diagnosis and should be implemented as a routine diagnostic procedure in pregnancies with high risk of fetal aneuploidy (of chromosomes 13, 18, 21, X i Y)

The First Evidence of Cryptosporidium meleagridis Infection in a Colon Adenocarcinoma From an Immunocompetent Patient

Objectives: The potential linkage between Cryptosporidium spp. infection and colorectal human cancer was suggested by limited reports showing higher prevalence of C. parvum and C. hominis in patients with colon cancer. Here we conducted research concerning presence of Cryptosporidium spp. in malignant tissue collected from patients with colorectal cancer.Methods: Cancerous colon tissue samples collected from 145 non-HIV infected patients with colorectal cancer were screened for Cryptosporidium spp. by immunofluorescence antibody test and genus-specific nested polymerase chain reaction followed by sequencing.Results: Screened pathogen was found in cancerous tissue originating from immunocompetent man with colon adenocarcinoma. Genotyping revealed presence of Cryptosporidium meleagridis. The presence of Cryptosporidium life cycle stages (oocysts and endogenous stages) in colon carcinoma tissue was confirmed by genus-specific FITC-labeling.Conclusions: Herein, we report on a C. meleagridis infection of a colon adenocarcinoma in an immunocompetent patient. This is the first report of C. meleagridis infection in the human colon and first evidence of active development of this species in cancer tissue

Wytyczne dla laboratoriów genetyki nowotworów litych

Niniejsze wytyczne skierowane są do laboratoriów wykonujących diagnostyczne badania genetyczne technikami biologii molekularnej i cytogenetyki molekularnej (FISH) w zakresie genetyki nowotworów litych zarówno w obszarze zaburzeń genetycznych dziedzicznych, jak i nabytych. Diagnostyczne badanie genetyczne jest wykonywane w celu identyfikacji zaburzeń w DNA komórek człowieka. Przestrzeganie niniejszych zasad ma na celu zapewnienie wysokiego poziomu usług medycznych świadczonych przez laboratoria

Transcriptomic Profiling for the Autophagy Pathway in Colorectal Cancer

The role of autophagy in colorectal cancer (CRC) pathogenesis appears to be crucial. Autophagy acts both as a tumor suppressor, by removing redundant cellular material, and a tumor-promoting factor, by providing access to components necessary for growth, metabolism, and proliferation. To date, little is known about the expression of genes that play a basal role in the autophagy in CRC. In this study, we aimed to compare the expression levels of 46 genes involved in the autophagy pathway between tumor-adjacent and tumor tissue, employing large RNA sequencing (RNA-seq) and microarray datasets. Additionally, we verified our results using data on 38 CRC cell lines. Gene set enrichment analysis revealed a significant deregulation of autophagy-related gene sets in CRC. The unsupervised clustering of tumors using the mRNA levels of autophagy-related genes revealed the existence of two major clusters: microsatellite instability (MSI)-enriched and -depleted. In cluster 1 (MSI-depleted), ATG9B and LAMP1 genes were the most prominently expressed, whereas cluster 2 (MSI-enriched) was characterized by DRAM1 upregulation. CRC cell lines were also clustered according to MSI-enriched/-depleted subgroups. The moderate deregulation of autophagy-related genes in cancer tissue, as compared to adjacent tissue, suggests a prominent field cancerization or early disruption of autophagy. Genes differentiating these clusters are promising candidates for CRC targeting therapy worthy of further investigation

Major Histocompatibility Complex Genes as Therapeutic Opportunity for Immune Cold Molecular Cancer Subtypes

Current immunotherapies are effective only in a subset of patients, likely due to several factors including defects in tumor cell antigen presentation, decreased response to immune effectors, and molecular heterogeneity of cancers. Recent molecular classifications enable the categorization of many tumor types. However, deregulation of major histocompatibility complex (MHC) gene expression is poorly characterized in the context of molecular cancer subtypes. To suppress the confounding effect of immune infiltrates on expression patterns of immunoregulators, we identified and removed genes with strong correlation to estimated immune compartment levels in each tumor type. Next, we reanalyzed a total of 13 TCGA cancer types encompassing 5651 tumors and 485 normal adjacent tissues by performing unsupervised clustering of 14 MHC genes. Subsequently, resultant clusters were statistically compared in terms of expression of other immune-related genes. Three MHC expression clusters were discovered by unsupervised clustering. We identified concordantly decreased expression of MHC genes (MHC-low) in 26 out of 55 molecular subtypes. Consequently, our study underlines the urgent need for designing strategies to enhance tumor MHC expression that could improve immune cold tumor rejection by cytotoxic T lymphocytes

Personalised medical management of patients with melanoma (part 1)

W ostatnich latach obserwuje się dynamiczny wzrost zachorowań na czerniaki, szczególnie w grupie osób młodych oraz w wieku średnim, dlatego wyleczalność chorych staje się priorytetem również w odniesieniu do czynników ekonomicznych. Czerniaki pod względem zmian genetycznych należą do grupy nowotworów o bardzo dużej heterogenności. Najczęściej stwierdzane zmiany genetyczne dotyczą dwóch ścieżek przekazywania sygnałów, są to: ścieżka aktywowana mitogenami (MAPK) oraz ścieżka sygnałowa kinazy 3-fosfatydyloinozytolu (PI3K). Identyfikacja charakterystycznych zmian molekularnych w tkance nowotworowej pozwala na optymalizację i indywidualizację terapii z zastosowaniem rekomendowanych leków a tym samym przyczynia się do ograniczenia skutków ubocznych leczenia oraz poprawy jakości życia chorych. Obecnie standardem postępowania w leczeniu pacjentów z czerniakiem skóry, bok postępowania chirurgicznego i klasycznej, coraz rzadziej stosowanej chemio-/radioterapii, jest wdrażanie leczenia ukierunkowanego na zmiany molekularne obecne w tkance guza oraz immunoterapia polegająca na aktywowaniu układu immunologicznego.In recent years, a dynamic increase has been observed in occurrence of melanomas, especially in young and middle-aged patients. This is the reason why curing these patients has become a priority also in the economic context. Melanomas belong to a group of neoplasms of very high genetic heterogeneity. The most common genetic alterations concern two signalling pathways: mitogen-activated pathway (MAPK) and phosphoinositide 3-kinase (PI3K) pathway. Identification of the characteristic molecular changes in the neoplastic tissue allows optimisation and individualisation of the therapy. Thus, it contributes to an increase in successful cancer treatment, reduction of treatment side effects and to improvement of the patients’ quality of life. Currently, the standard management of skin melanoma patients involves – along with surgical treatment and classical chemo/radiotherapy which is now less frequently used – also introduction of targeted therapy focused on molecular changes within the tumour tissue as well as immunotherapy which relies on activating the immune system

Dysplazja czołowo-przynasadowa (zespół Gorlina i Cohena) jako przykład rzadkiej choroby układu kostnego sprzężonej z chromosomem X – opis kliniczny dwóch przypadków o późnym rozpoznaniu

Dysplazja czołowo-przynasadowa, zwana zespołem Gorlina i Cohena, jest zespołem chorobowym dziedziczonym w sprzężeniu z płcią w sposób dominujący, uwarunkowanym mutacją w genie FLNA (Xq28). Mutacje w genie FLNA odpowiedzialne są za kilka dobrze określonych klinicznie chorób o bardzo heterogennych objawach (plejotropizm). Zespół Gorlina i Cohena charakteryzuje się licznymi zmianami kostnymi w obrębie czaszki oraz przynasad kości długich, osteoporozą, deformacją klatki piersiowej i mostka, spłaszczeniem kręgów, ograniczeniem ruchomości w stawach łokciowych i nadgarstkowych, skoliozą, charakterystyczną dysmorfią twarzoczaszki, stóp i dłoni, a także niepełnosprawnością intelektualną, niedosłuchem, problemami okulistycznymi oraz przyspieszoną erozją szkliwa zębów, a co za tym idzie – szybką utratą zębów stałych. U osób dorosłych ujawniają się zaburzenia kardiologicz‑ ne i układu moczowego. W pracy przedstawiono opis kliniczny dwóch pacjentów z późno rozpoznaną i potwier‑ dzoną w badaniu molekularnym dysplazją czołowo-przynasadową, jak również obraz kliniczny choroby i jej prze‑ bieg na podstawie przeglądu literatury. U pacjenta nr 1 wykazano patogenną mutację punktową w eksonie 45. genu FLNA – 7267C>T, powodującą zmianę proliny na serynę w pozycji 2423 łańcucha aminokwasowego białka; u pacjenta nr 2 wykazano mutację w pozycji c.745G->T, prowadzącą do zmiany sekwencji białka (p.Asp249Tyr). W obu przypadkach stwierdzono nosicielstwo mutacji u matek pacjentów (status heterozygotyczny). U matek nie zaobserwowano żadnych objawów klinicznych dysplazji czołowo-przynasadowej

Personalised medical management of patients with melanoma (part 2)

In recent years, a dynamic increase has been observed in occurrence of melanomas, especially in young and middle-aged patients. This is the reason why curing these patients has become a priority also in the economic context. Melanomas belong to a group of neoplasms of very high genetic heterogeneity. The most common genetic alterations concern two signalling pathways: mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathway. Identification of the characteristic molecular changes in the neoplastic tissue allows optimisation and individualisation of the therapy. Thus, it contributes to an increase in successful cancer treatment, reduction of treatment side effects and to improvement of the patients’ quality of life. Currently, the standard management of skin melanoma patients involves – along with surgical treatment and classical chemo/radiotherapy which is now less frequently used – also introduction of targeted therapy focused on molecular changes within the tumour tissue as well as immunotherapy which relies on activating the immune system