Development of classical Hodgkin’s lymphoma in an adult with biallelic STXBP2 mutations

Experimental model systems have delineated an important role for cytotoxic lymphocytes in the immunosurveillance of cancer. In humans, perforin-deficiency has been associated with occurrence of hematologic malignancies. Here, we describe an Epstein-Barr virus-positive classical Hodgkin's lymphoma in a patient harboring biallelic mutations in STXBP2, a gene required for exocytosis of perforin-containing lytic granules and associated with familial hemophagocytic lymphohistocytosis. Cytotoxic T lymphocytes were found infiltrating the tumor, and a high frequency of Epstein-Barr virus-specific cytotoxic T lymphocytes were detected in peripheral blood. However, lytic granule exocytosis and cytotoxicity by cytotoxic T lymphocytes, as well as natural killer cells, were severely impaired in the patient. Thus, the data suggest a link between defective lymphocyte exocytosis and development of lymphoma in STXBP2-deficient patients. Therefore, with regards to treatment of familial hemophagocytic lymphohistocytosis patients with mutations in genes required for lymphocyte exocytosis, it is important to consider both the risks of hemophagocytic lymphohistocytosis and malignancy.Swedish Research CouncilSwedish Cancer FoundationSwedish Children’s Cancer FoundationHistiocytosis AssociationClas Groschinsky’s Memorial FundJeanssons FoundationÅke Olsson Foundation for Hematological ResearchÅke Wiberg FoundationKarolinska Institute Research FoundationStockholm County Council (ALF project)Publishe

Genes with Relevance for Early to Late Progression of Colon Carcinoma Based on Combined Genomic and Transcriptomic Information from the Same Patients

Background: Genetic and epigenetic alterations in colorectal cancer are numerous. However, it is difficult to judge whether such changes are primary or secondary to the appearance and progression of tumors. Therefore, the aim of the present study was to identify altered DNA regions with significant covariation to transcription alterations along colon cancer progression. Methods: Tumor and normal colon tissue were obtained at primary operations from 24 patients selected by chance. DNA, RNA and microRNAs were extracted from the same biopsy material in all individuals and analyzed by oligo-nucleotide array-based comparative genomic hybridization (CGH), mRNA- and microRNA oligo-arrays. Statistical analyses were performed to assess statistical interactions (correlations, co-variations) between DNA copy number changes and significant alterations in gene and microRNA expression using appropriate parametric and non-parametric statistics. Results: Main DNA alterations were located on chromosome 7, 8, 13 and 20. Tumor DNA copy number gain increased with tumor progression, significantly related to increased gene expression. Copy number loss was not observed in Dukes A tumors. There was no significant relationship between expressed genes and tumor progression across Dukes A–D tumors; and no relationship between tumor stage and the number of microRNAs with significantly altered expression. Interaction analyses identified overall 41 genes, which discriminated early Dukes A plus B tumors from late Dukes C plus D tumor; 28 of these genes remained with correlations between genomic and transcriptomic alterations in Dukes C plus D tumors and 17 in Dukes D. One microRNA (microR-663) showed interactions with DNA alterations in all Dukes A-D tumors. Conclusions: Our modeling confirms that colon cancer progression is related to genomic instability and altered gene expression. How- ever, early invasive tumor growth seemed rather related to transcriptomic alterations, where changes in microRNA may be an early phenomenon, and less to DNA copy number changes

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Heritability of cortisol production and metabolism throughout adolescence: a twin study

CONTEXT: Inter-individual differences in cortisol production and metabolism emerge with age and may be explained by genetic factors. OBJECTIVE: To estimate the relative contributions of genetic and environmental factors to inter-individual differences in cortisol production and metabolism throughout adolescence. DESIGN: Prospective follow-up study of twins. SETTING: Nationwide register. PARTICIPANTS: 218 mono- and dizygotic twins (N = 109 pairs) born between 1995 amd 1996, recruited from the Netherlands Twin Register. Cortisol metabolites were determined in 213, 169, and 160 urine samples at the ages of 9, 12, and 17, respectively. MAIN OUTCOME MEASURES: The total contribution of genetic factors (broad-sense heritability) and shared and unshared environmental influences to inter-individual differences in cortisol production and activities of 5α-reductase, 5β-reductase, and 11β-hydroxysteroid dehydrogenases and cytochrome P450 3A4. RESULTS: For cortisol production rate at the ages of 9, 12, and 17, broad-sense heritability was estimated as 42%, 30%, and 0%, respectively, and the remainder of the variance was explained by unshared environmental factors. For cortisol metabolism indices, the following heritability was observed: for the A-ring reductases (5α-and 5β-reductases), broad-sense heritability increased with age (to >50%), while for the other indices (renal 11β-HSD2, global 11β-HSD, and CYP3A4), the contribution of genetic factors was highest (68%, 18%, and 67%, respectively) at age 12. CONCLUSIONS: The contribution of genetic factors to inter-individual differences in cortisol production decreased between 12 and 17y, indicative of a predominant role of individual circumstances. For cortisol metabolism, distinct patterns of genetic and environmental influences were observed, with heritability that either increased with age or peaked at age 12y

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Prognostic and epidemiological factors in childhood leukemia : studies of p53 and MDM2 expression and of space-time clustering

Although cure rates in acute childhood leukaemias have improved it remains a challenge to understand how molecular aberrations influence the prognosis of leukaemia and thus the choice of optimal therapy. Some studies have suggested that dysfunction of the tumour suppressor gene p53 or the oncogene MDM2 could indicate disease progression in children with leukaemia. While these studies mainly have described uncommon pretranslational aberrations we examined p53 and MDM2 protein overexpression by immunohistochemical techniques in an unselected group of ALL children in the first study. As MDM2 overexpression was observed in high risk patients, in a second study we examined twenty-nine bone marrow samples in children with active, prognostically unfavourable and relapsed leukaemia. p53 protein was expressed in 12 patients and MDM2 in 17 patients. To put this in perspective, we investigated p53/MDM2 expression at diagnosis in 31 children who had maintained a long-term remission of ALL. Of these patients only 4 cases expressed p53, while 8 of 15 ALL-patients in relapse did (p=0.01). Four of these cases also expressed MDM2, while 10 of 15 relapsed ALLs did (p=0.0007). MDM2 and p53 expression was also seen in a higher proportion in the original diagnostic bone marrows of the relapse patients than in children with subsequent long term remission. In conclusion these observations support the hypothesis that p53 and MDM2 are overexpressed in more aggressive leukaemias. Prospective studies are needed to investigate whether p53/MDM2 alterations at relapse represent secondary changes appearing during disease, or when present at diagnosis, if they are indicators of a poor outcome. Clustering of family cases of neoplasia could be a key to the genetic and environmental factors leading to cancer. By linking the Medical Birth Registry to the Cancer Registry in Sweden we conducted a nation-wide study including 2354 mothers whose children had had cancer, to assess whether these mothers had an increased risk of cancer compared with the general population. Our main findings revealed no general association between childhood cancer and cancer risks among mothers. These registries were also used to study space-time clustering in childhood lymphatic leukaemias. If the etiological agent is infectious and the induction of leukaemia takes place perinatally, space-time clustering would be related to the time of birth rather than the time of diagnosis. We studied 645 recorded cases of childhood acute lymphoblastic leukaemia in Sweden 1973-1996, by using the close pair method of Knox. There was a significant excess of case-pairs close in date and place of birth in the 5-15 year age group. The group was expanded to 1020 recorded cases of childhood ALL and 293 cases of non-Hodgkin's lymphoma between 1973 -1996. A significant excess of case-pairs (p=0.01) was observed close in date and place of birth in the 4-14 year age group with ALL, but not when the cases of ALL and the non-Hodgkin's lymphomas were combined. Although only a small proportion of the cases is involved in the clusters, in conjunction with other data these results indicate that childhood leukaemia can occur in clusters and strengthen the hypothesis that perinatal infections may be involved in a process leading to ALL