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Shi J.,U.S. National Institutes of Health | Yang X.R.,U.S. National Institutes of Health | Ballew B.,U.S. National Institutes of Health | Rotunno M.,U.S. National Institutes of Health | And 59 more authors.
Nature Genetics | Year: 2014

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations. © 2014 Nature America, Inc. All rights reserved.

Iles M.M.,St James's Hospital | Law M.H.,Queensland Institute of Medical Research | Stacey S.N.,DeCODE Genetics Inc. | Han J.,Harvard University | And 101 more authors.
Nature Genetics | Year: 2013

We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10 -12, per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.

Amadori D.,Cancer Institute Of Romagna Irst | Silvestrini R.,Cancer Institute Of Romagna Irst | De Lena M.,Italian National Cancer Institute | Boccardo F.,University of Genoa | And 15 more authors.
Breast Cancer Research and Treatment | Year: 2011

Adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) have proven highly effective in rapidly proliferating breast cancer (RPBC). It has also been seen that sequential administration of doxorubicin and CMF is superior to their alternation, especially in indolent tumors. In a phase III study, we evaluated whether adjuvant epirubicin (E) followed by CMF is superior to the inverse sequence in RPBC. Patients with node-negative or 1-3 node-positive RPBC (Thymidine Labeling Index > 3% or histological grade 3 or S-phase > 10% or Ki67 > 20%) were randomized to receive E (100 mg/m2 i.v. d1, q21 days for 4 cycles) followed by CMF (600, 40, 600 mg/m2 i.v. d1 and 8, q28 days for 4 cycles) (E → CMF) or CMF followed by E (CMF → E) or CMF for 6 cycles. From November 1997 to December 2004, 1066 patients were enrolled: E → CMF 440, CMF → E 438, and CMF 188. At a median follow-up of 69 months, 5-year OS was 91% (95% CI 88-94) for E → CMF and 93% (95% CI 90-95) for CMF → E, with adjusted hazard ratio of 0.88 (95% CI 0.58-1.35), and DFS was 80% in both arms, with adjusted hazard ratio of 0.99 (95% CI 0.73-1.33, Cox model). Adverse events were similar, apart from a higher rate of neutropenia in the CMF → E arm. No important differences in clinical outcome were observed between the two different sequences, making both a valid option in early breast cancer. Further molecular characterization of the tumors might help to identify subgroups achieving higher benefit from either sequence. © 2010 Springer Science+Business Media, LLC.

Barrett J.H.,St James's Hospital | Iles M.M.,St James's Hospital | Harland M.,St James's Hospital | Taylor J.C.,St James's Hospital | And 78 more authors.
Nature Genetics | Year: 2011

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10 -5 and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10 -3: an SNP in ATM (rs1801516, overall P = 3.4 × 10 -9), an SNP in MX2 (rs45430, P = 2.9 × 10 -9) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10 -10). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10 -7 under a fixed-effects model and P = 1.2 × 10 -3 under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series. © 2011 Nature America, Inc. All rights reserved.

Yang X.R.,U.S. National Institutes of Health | Brown K.,U.S. National Institutes of Health | Landi M.T.,U.S. National Institutes of Health | Ghiorzo P.,University of Genoa | And 13 more authors.
Pigment Cell and Melanoma Research | Year: 2012

Copy number variations (CNVs) have been shown to contribute substantially to disease susceptibility in several inherited diseases including cancer. We conducted a genome-wide search for CNVs in blood-derived DNA from 79 individuals (62 melanoma patients and 17 spouse controls) of 30 high-risk melanoma-prone families without known segregating mutations using genome-wide comparative genomic hybridization (CGH) tiling arrays. We identified a duplicated region on chromosome 4q13 in germline DNA of all melanoma patients in a melanoma-prone family with three affected siblings. We confirmed the duplication using quantitative PCR and a custom-made CGH array design spanning the 4q13 region. The duplicated region contains 10 genes, most of which encode CXC chemokines. Among them, CXCL1 (melanoma growth-stimulating activity α) and IL8 (interleukin 8) have been shown to stimulate melanoma growth in vitro and in vivo. Our data suggest that the alteration of CXC chemokine genes may confer susceptibility to melanoma. Published 2012. This article is a US Government work and is in the public domain in the USA.

Demenais F.,French Institute of Health and Medical Research | Demenais F.,University Paris Diderot | Mohamdi H.,French Institute of Health and Medical Research | Mohamdi H.,University Paris Diderot | And 42 more authors.
Journal of the National Cancer Institute | Year: 2010

Background Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited. Methods We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided. Results Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10-6 ≤ P ≤. 0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10-8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤. 04), hair color (.006 ≤ P ≤. 06), and number of nevi (6.9 × 10-6 ≤ P ≤. 02). Conclusions Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings. © 2010 The Author.

Iafusco D.,The Second University of Naples | Massa O.,Bambino Gesu Childrens Hospital | Pasquino B.,Regional Hospital | Colombo C.,Bambino Gesu Childrens Hospital | And 14 more authors.
Acta Diabetologica | Year: 2012

Until early 2000, permanent and transient neonatal diabetes mellitus (NDM), defined as diabetes with onset within 6 weeks from birth that requires insulin therapy for at least 2 weeks, were considered exceedingly rare conditions, with a global incidence of 1:500,000-1:400,000 live births. The new definition of NDM recently adopted, that includes patients with diabetes onset within 6 months of age, has prompted studies that have set the incidence of the permanent form alone between 1:210,000 and 1:260,000 live births. Aim of the present work was to ascertain the incidence of NDM (i.e. permanent + transient form) in Italy for years 2005-2010. Patients referred to the Italian reference laboratory for NDM between years 2005 and 2010 and screened for mutations in common NDM genes (KCNJ11, ABCC8, and INS) and for uniparental isodisomy of chromosome 6 (UDP6) were reviewed. A questionnaire aimed at identifying NDM cases investigated in other laboratories was sent to 54 Italian reference centers for pediatric diabetes. Twenty-seven patients with NDM born between 2005 and 2010 were referred to the reference laboratory. In this group, a mutation of either KCNJ11, ABCC8 or INS was found in 18 patients, and a case with UDP6 was identified. Questionnaires revealed 4 additional cases with transient neonatal diabetes due to UDP6. Incidence of NDM was calculated at 1:90,000 (CI: 1:63,000-1:132,000) live births. Thus, with the definition currently in use, about 6 new cases with NDM are expected to be born in Italy each year. © 2011 The Author(s).

Calista D.,Maurizio Bufalini Hospital | Vitali P.,M Bufalini Hospital | Arcangeli F.,Maurizio Bufalini Hospital
Giornale Italiano di Dermatologia e Venereologia | Year: 2013

Aim. The purpose of this study was to investigate the disease-free time (DFT) and overall survival (OS) of patients with intermediate or high-risk cutaneous melanoma who were treated with conventional surgery alone, and to compare them with that of a second group of patients who were treated with surgery and SLN biopsy. Methods. A retrospective, single-centre study was performed at the Department of Dermatology of the "M. Bufalini" Hospital, Cesena, Italy based on data collected between January 1990 and December 2007. A total of 757 consecutive patients with stage I-II melanoma were identified: the former group (control group), treated with conventional surgery, was composed of 224 patients; the latter, treated with surgery and SLN biopsy (SLN biopsy group), was formed of 529 patients. Results. The 5-year disease free time (DFT) rate, estimated with Kaplan-Meyer, was 73.9% (95% CI: 67.5-79.2) in the control group, and 82.2% (95% CI: 78.6-85.3) in the SLN biopsy group. Although the DFT rate was significantly higher in the SLN group than in the control group in univariate analyses (P=0.004), this gain was lost in multivariate analysis (P=0.2). The 5-year overall survival (OS) rate was 88.4% (95% CI: 83.2-92.1) for the control group, and 87.9% (95% CI: 84.6-90.4) for the SLN biopsy group. Statistical comparison of specific OS was not statistically significant (P=0.93). Conclusion. On the basis of our follow-up data, we found that patients who underwent SLN biopsy technique experienced a reduction in the proportion of lymph nodal relapse, but DFT and OS were statistically equivalent between the two groups.

De Cunto A.,University of Trieste | Bensa M.,Maurizio Bufalini Hospital | Tonelli A.,E Medea Scientific Institute
Pediatric Neurology | Year: 2012

Hemiplegic migraine constitutes an unusual form, characterized by periodic attacks of migraine with a motor component (hemiplegia). Familial forms are dominantly inherited, and are attributable to mutations in genes encoding proteins involved in ion transportation, including ATP1A2, which codes for the α-2 isoform of the sodium-potassium adenosine triphosphatase, a P-type cation transport adenosine triphosphatase, and responsible for the so-called familial hemiplegic migraine type 2. We describe a 9-year-old boy affected by familial hemiplegic migraine, with a novel ATP1A2 gene mutation (c.1799T>C p.V600A) in exon 13. Long-term treatment with flunarizine resulted in a good clinical response and the prevention of further attacks. © 2012 Elsevier Ltd. All rights reserved.

PubMed | Maurizio Bufalini Hospital
Type: Journal Article | Journal: Nursing children and young people | Year: 2014

Trauma from burns and scalds in children is more common and more damaging than in adults, and may indicate abuse. The main goal of intensive care of an acute burn is to limit the extent of the systemic insult. Effective treatment of such acute physiological changes requires experienced monitoring by multidisciplinary teams, following appropriate emergency protocols at specialised burn centres in cases of major trauma. First aid involves maintaining a patent airway, supporting circulation and respiration, arresting the burning, managing pain and distress, reducing infection and considering transfer to specialist care. Advances in techniques and treatment have increased survival rates and ultimate quality of life, but education and prevention programmes are still required at all levels to reduce the incidence of burns among children.

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