Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project

Background: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. Design and methods. Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer dev

Melanocortin-1 Receptor, Skin Cancer and Phenotypic Characteristics (M-SKIP) Project: Study Design and Methods for Pooling Results of Genetic Epidemiological Studies

Background: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. Design and methods: Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling. Discussion: Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields

Migratory Activity of Circulating Mononuclear Cells Is Associated With Cardiovascular Mortality in Type 2 Diabetic Patients With Critical Limb Ischemia.

OBJECTIVE Prediction of clinical outcome in diabetic patients with critical limb ischemia (CLI) is unsatisfactory. This prospective study investigates if the abundance and migratory activity of a subpopulation of circulating mononuclear cells, namely, CD45dimCD34posCXCR4posKDRpos cells, predict major amputation and cardiovascular death in type 2 diabetic patients undergoing percutaneous transluminal angioplasty for CLI. RESEARCH DESIGN AND METHODS A consecutive series of 119 type 2 diabetic patients with CLI was enrolled. CD45dimCD34posCXCR4posKDRpos cells were assessed by flow cytometry upon isolation and also after spontaneous or stromal cell-derived factor 1a2directed migration in an in vitro assay. The association between basal cell counts and migratory activity and the risk Q:3 of an event at 18-month follow-up was evaluated in a multivariable regression analysis. RESULTS Time-to-event analysis of amputation (n = 13) showed no association with the candidate predictors. Sixteen cardiovascular deaths occurred during 18 months of follow-up. Abundance of CD45dimCD34posCXCR4posKDRpos cells was not associated with cardiovascular mortality. Interestingly, in vitro migration of CD45dim CD34posCXCR4posKDRpos cells was higher in patients with cardiovascular death compared with event-free subjects (percentage of migrated cells median value and interquartile range, 0.03 (0.02–0.07) vs. 0.01 (0.01–0.03); P = 0.0095).Multivariable regression model analysis showed that cell migration forecasts cardiovascular mortality independently of other validated predictors, such as age, diagnosed coronary artery disease, serum C-reactive protein, and estimated glomerular filtration rate. In this model, doubling of migrated cell counts increases the cardiovascular death hazard by 100% (P < 0.0001). CONCLUSIONS The new predictor could aid in the identification of high-risk patients with type 2 diabetes requiring special diagnostic and therapeutic care after revascularization

Overexpression of the LSAMP and TUSC7 genes in acute myeloid leukemia following microdeletion/duplication of chromosome 3

The 3q13.31 microdeletion syndrome is characterized by developmental delay, postnatal growth above the mean, characteristic facial features, and abnormal male genitalia. Moreover, a frequent deletion in the 3q13.31 chromosome region has been identified in patients who are affected by osteosarcomas. Among the genes located within the deleted region, the involvement of the limbic system associated membrane protein gene (LSAMP), together with a non-coding RNA tumor suppressor candidate 7 gene (TUSC7), has been suggested. We describe the case of an adult acute myeloid leukemia (AML) patient with a novel chromosomal rearrangement characterized by a 3q13.31 microdeletion and an extra copy of the 3q13.31-q29 chromosomal region translocated to the long arm of the Y chromosome. This karyotypic aberration seems to cause LSAMP and TUSC7 gene expression dysregulation. In conclusion, we report the first case of LSAMP and TUSC7 gene overexpression, possibly due to a position effect in an AML patient bearing a 3q13.31 cryptic deletion

Heterogeneous prognostic impact of derivative chromosome 9 deletions in chronic myelogenous leukemia

Derivative chromosome 9 deletions are seen in 10% to 15% of patients with chronic myelogenous leukemia and have been associated with a poor prognosis; however, no studies have been performed in the context of a randomized clinical trial. We developed a DNA-based deletion screen and investigated 339 chronic phase patients treated with interferon-alpha as first-line therapy in 3 controlled German studies with a median observation time of 7 years. Deletions were detected in pretreatment DNA of 59 of 339 (17%) patients. Of these, 21 spanned the ABL/BCR junction and 38 were centromeric (n = 20) or telomeric (n = 18) of the breakpoint. There was no significant difference in overall survival between deleted and nondeleted patients. Patients with breakpoint-spanning deletions had poorer survival compared with patients without deletions (4.7 versus 7.8 years; P = .003), but this was not significant when censored at allogeneic stem cell transplantation (n = 129) or imatinib (n = 62) treatment in the first chronic phase (P = .078). Unexpectedly, deletions that did not span the breakpoint were associated with improved survival compared with cases without deletions (P = .001). Multiple Cox regression analysis indicated that deletion status (P = .007), age (P = .018), and spleen enlargement (P &lt; .001) were significant independent indicators of survival and confirmed that only deletions spanning the ABL/BCR breakpoint were associated with an adverse prognosis (P = .039)