Publications by authors named "Marina Vignoli"

19 Publications

  • Page 1 of 1

Case Report: Signal Transducer and Activator of Transcription 3 Gain-of-Function and Spectrin Deficiency: A Life-Threatening Case of Severe Hemolytic Anemia.

Front Immunol 2020 15;11:620046. Epub 2021 Jan 15.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy.

gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.
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http://dx.doi.org/10.3389/fimmu.2020.620046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843414PMC
July 2021

Preliminary Study on β3-Adrenoreceptor as Predictor Marker of Relapse in Ewing Sarcoma Patients.

Biomedicines 2020 Oct 13;8(10). Epub 2020 Oct 13.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, 50139 Florence, Italy.

Ewing sarcoma (EWS) is a paediatric aggressive malignant tumour of bones and soft tissues. Multidisciplinary chemotherapies, surgical resection, and radiation represent the only strategies counteracting the disease, however spreading and relapse of disease still remain a clinical issue. Circulating tumour cells (CTCs) are an important feature of EWS but the prognostic significance has not been, yet, clarified. CTCs have been found both in patients with localized disease and in those who recur or metastasize. The identification of markers that can detect recurrences and metastasis remains an important challenge for research. Unfortunately, even most of patients with localized cancer relapsed and the reason has not yet been fully understood. In this clinical study on EWS patients, we evaluated the expression of CD99 antigen and beta-3 adrenergic receptor (β3-AR) on CTCs and bioptic derived cells by flow cytometry. The preliminary data revealed a higher β3-AR expression on cells derived from metastatic or relapsed patients, suggesting a role for the β3-AR as a possible predictive maker of disease recurrence in both patients with metastatic and localized disease.
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http://dx.doi.org/10.3390/biomedicines8100413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600453PMC
October 2020

β3-Adrenoreceptor Blockade Reduces Hypoxic Myeloid Leukemic Cells Survival and Chemoresistance.

Int J Mol Sci 2020 Jun 12;21(12). Epub 2020 Jun 12.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, 50139 Florence, Italy.

β-adrenergic signaling is known to be involved in cancer progression; in particular, beta3-adrenoreceptor (β3-AR) is associated with different tumor conditions. Currently, there are few data concerning β3-AR in myeloid malignancies. Here, we evaluated β3-AR in myeloid leukemia cell lines and the effect of β3-AR antagonist SR59230A. In addition, we investigated the potential role of β3-AR blockade in doxorubicin resistance. Using flow cytometry, we assessed cell death in different in vitro myeloid leukemia cell lines (K562, KCL22, HEL, HL60) treated with SR59230A in hypoxia and normoxia; furthermore, we analyzed β3-AR expression. We used healthy bone marrow cells (BMCs), peripheral blood mononuclear cells (PBMCs) and cord blood as control samples. Finally, we evaluated the effect of SR59230A plus doxorubicin on K562 and K562/DOX cell lines; K562/DOX cells are resistant to doxorubicin and show P-glycoprotein (P-gp) overexpression. We found that SR59230A increased cancer cell lines apoptosis especially in hypoxia, resulting in selective activity for cancer cells; moreover, β3-AR expression was higher in malignancies, particularly under hypoxic condition. Finally, we observed that SR59230A plus doxorubicin increased doxorubicin resistance reversion mainly in hypoxia, probably acting on P-gp. Together, these data point to β3-AR as a new target and β3-AR blockade as a potential approach in myeloid leukemias.
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http://dx.doi.org/10.3390/ijms21124210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352890PMC
June 2020

β3-Adrenoreceptor Blockade Induces Stem Cells Differentiation in Melanoma Microenvironment.

Int J Mol Sci 2020 Feb 20;21(4). Epub 2020 Feb 20.

Hematology-Oncology Department, "Anna Meyer Children's Hospital", 50139 Florence, Italy.

Although there is an increasing evidence that cancer stem cell (CSC) niches in the tumor microenvironment (TME) plays a crucial role in sustaining solid tumors progression, several molecular players involved in this regulation still remain unknown. The role of β-adrenergic signaling in enhancing tumor growth through β2-adrenoreceptors (β2-ARs) has been confirmed in different cancer models, but the role played by the β3-adrenergic receptor (β3-AR) has recently emerged. Previous studies showed that β3-AR promotes cancer growth through the activation of different stromal cells in the TME, and leads to melanoma malignancy progression through inflammation, angiogenesis, and immunotolerance. Here we show that in B16 melanoma-bearing mice, the pharmacological β3-AR blockade is able to reduce the expression of CSC markers, and to induce a differentiated phenotype of hematopoietic subpopulations in TME. In particular, cytofluorimetric analysis (FACS) of the tumor mass shows that β3-AR antagonist SR59230A promotes hematopoietic differentiation as indicated by increased ratios of lymphoid/hematopoietic stem cells (HSCs) and of myeloid progenitor cells/HSCs, and increases the number of Ter119 and natural killer (NK) precursor cells, and of granulocyte precursors, indicating active hematopoiesis within the tumor tissue. Moreover, pharmacological antagonism of β3-AR induces mesenchymal stem cell (MSC) differentiation into adipocytes subtracting a potential renewal of the stem compartment by these cells. Here we demonstrate that β3-AR blockade in the TME by inducing the differentiation of different stromal cells at the expense of stemness traits could possibly have a favorable effect on the control of melanoma progression.
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http://dx.doi.org/10.3390/ijms21041420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073111PMC
February 2020

Spotlight on ROS and 3-Adrenoreceptors Fighting in Cancer Cells.

Oxid Med Cell Longev 2019 14;2019:6346529. Epub 2019 Dec 14.

Oncohematology Unit, Department of Pediatric Oncology, A. Meyer Children's University Hospital, Florence 50139, Italy.

The role of ROS and RNS is a long-standing debate in cancer. Increasing the concentration of ROS reaching the toxic threshold can be an effective strategy for the reduction of tumor cell viability. On the other hand, cancer cells, by maintaining intracellular ROS concentration at an intermediate level called "mild oxidative stress," promote the activation of signaling that favors tumor progression by increasing cell viability and dangerous tumor phenotype. Many chemotherapeutic treatments induce cell death by rising intracellular ROS concentration. The persistent drug stimulation leads tumor cells to simulate a process called hormesis by which cancer cells exhibit a biphasic response to exposure to drugs used. After a first strong response to a low dose of chemotherapeutic agent, cancer cells start to decrease the response even if high doses of drugs were used. In this framework, 3-adrenoreceptors (3-ARs) fit with an emerging antioxidant role in cancer. 3-ARs are involved in tumor proliferation, angiogenesis, metastasis, and immune tolerance. Its inhibition, by the selective 3-ARs antagonist (SR59230A), leads cancer cells to increase ROS concentration thus inducing cell death and to decrease NO levels thus inhibiting angiogenesis. In this review, we report an overview on reactive oxygen biology in cancer cells focusing on 3-ARs as new players in the antioxidant pathway.
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http://dx.doi.org/10.1155/2019/6346529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942895PMC
June 2020

β3-Adrenoreceptor Activity Limits Apigenin Efficacy in Ewing Sarcoma Cells: A Dual Approach to Prevent Cell Survival.

Int J Mol Sci 2019 Apr 30;20(9). Epub 2019 Apr 30.

Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, 50139 Florence, Italy.

Ewing Sarcoma (ES) is an aggressive paediatric tumour where oxidative stress and antioxidants play a central role in cancer therapy response. Inhibiting antioxidants expression, while at the same time elevating intracellular reactive oxygen species (ROS) levels, have been proposed as a valid strategy to overcome ES cancer progression. Flavonoid intake can affect free radical and nutritional status in children receiving cancer treatment, but it is not clear if it can arrest cancer progression. In particular, apigenin may enhance the effect of cytotoxic chemotherapy by inducing cell growth arrest, apoptosis, and by altering the redox state of the cells. Little is known about the use of apigenin in paediatric cancer. Recently, β3-adrenergic receptor (β3-AR) antagonism has been proposed as a possible strategy in cancer therapy for its ability to induce apoptosis by increasing intracellular levels of ROS. In this study we show that apigenin induces cell death in ES cells by modulating apoptosis, but not increasing ROS content. Since ES cells are susceptible to an increased oxidative stress to reduce cell viability, here we demonstrate that administration of β3-ARs antagonist, SR59230A, improves the apigenin effect on cell death, identifying β3-AR as a potential discriminating factor that could address the use of apigenin in ES.
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http://dx.doi.org/10.3390/ijms20092149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540192PMC
April 2019

CD25 deficiency: A new conformational mutation prevents the receptor expression on cell surface.

Clin Immunol 2019 04 8;201:15-19. Epub 2019 Feb 8.

Department of "NEUROFARBA", Section of Child's Health, University of Florence, Italy; Department of Haematology-Oncology "Anna Meyer" Children's Hospital, Florence, Italy. Electronic address:

CD25 deficiency is a very rare autosomal recessive disorder that shows a clinical phenotype highly overlapping IPEX syndrome with an increased susceptibility to viral, bacterial, and fungal infections. It is due to mutations in the IL2Rα gene that codes for the α subunit of the IL2 receptor complex. Here we report the characterization of a novel IL2Rα gene mutation leading to a severe protein conformational alteration that abrogates its cell surface expression in a child presenting with early-onset IPEX-like disorder. Cytofluorimetric analysis revealed the total absence of CD25 cell surface expression and addressed IL2Rα molecular investigation. The early clinical and molecular diagnosis of CD25 deficiency in this patient promptly led to hematopoietic stem cell transplantation (HSCT), allowing complete resolution of the symptoms and definitive cure of the disease.
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http://dx.doi.org/10.1016/j.clim.2019.02.003DOI Listing
April 2019

3-Adrenoreceptors Control Mitochondrial Dormancy in Melanoma and Embryonic Stem Cells.

Oxid Med Cell Longev 2018 13;2018:6816508. Epub 2018 Nov 13.

Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, A. Meyer Children's University Hospital, Florence, Italy.

The early phases of embryonic development and cancer share similar strategies to improve their survival in an inhospitable environment: both proliferate in a hypoxic and catecholamine-rich context, increasing aerobic glycolysis. Recent studies show that 3-adrenergic receptor (3-AR) is involved in tumor progression, playing an important role in metastasis. Among -adrenergic receptors, 3-AR is the last identified member of this family, and it is involved in cancer cell survival and induction of stromal reactivity in the tumor microenvironment. 3-AR is well known as a strong activator of uncoupling protein 1 (UCP1) in brown fat tissue. Interestingly, 3-AR is strongly expressed in early embryo development and in many cancer tissues. Induction of uncoupling protein 2 (UCP2) has been related to cancer metabolic switch, leading to accelerated glycolysis and reduced mitochondrial activity. In this study, for the first time, we demonstrate that 3-AR is able to promote this metabolic shift in both cancer and embryonic stem cells, inducing specific glycolytic cytoplasmic enzymes and a sort of mitochondrial dormancy through the induction of UCP2. The 3-AR/UCP2 axis induces a strong reduction of mitochondrial activity by reducing ATP synthesis and mitochondrial reactive oxygen species (mtROS) content. These effects are reverted by SR59230A, the specific 3-AR antagonist, causing an increase in mtROS. The increased level of mtROS is neutralized by a strong antioxidant activity in embryonic stem cells, but not in cancer stem cells, where it causes a dramatic reduction in tumor cell viability. These results lead to the possibility of a selective antitumor therapeutic use of SR59230A. Notably, we demonstrate the presence of 3-AR within the mitochondrial membrane in both cell lines, leading to the control of mitochondrial dormancy.
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http://dx.doi.org/10.1155/2018/6816508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258109PMC
January 2019

Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome.

Front Immunol 2018 1;9:2411. Epub 2018 Nov 1.

Seattle Children's Research Institute, University of Washington, Seattle, WA, United States.

Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the gene. In addition, there has been an increasing number of patients with wild-type gene and, in some cases, mutations in other immune regulatory genes. To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of mutation-positive (IPEX patients) with those from mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of "Primary Immune Deficiency (PID-related) genes." Forty-four distinct variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.
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http://dx.doi.org/10.3389/fimmu.2018.02411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223101PMC
October 2019

Timely follow-up of a GATA2 deficiency patient allows successful treatment.

J Allergy Clin Immunol 2016 11 29;138(5):1480-1483.e4. Epub 2016 Jul 29.

Department of "NEUROFARBA," Section of Child's Health, University of Florence, Florence, Italy; Hematology-Oncology Department, "Anna Meyer Children's Hospital," Florence, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2016.06.004DOI Listing
November 2016

Gut immune reconstitution in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome after hematopoietic stem cell transplantation.

J Allergy Clin Immunol 2015 Jan 25;135(1):260-2. Epub 2014 Oct 25.

Institute of Cellular Medicine, University of Newcastle, Newcastle upon Tyne, United Kingdom; Department of Pediatric Immunology, Great North Children's Hospital, Newcastle upon Tyne, United Kingdom.

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http://dx.doi.org/10.1016/j.jaci.2014.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4282727PMC
January 2015

Langerhans cell histiocytosis in IPEX syndrome: possible role for natural regulatory T cells?

Pediatr Allergy Immunol 2014 Oct 16;25(6):601-3. Epub 2014 Mar 16.

Department of Pediatric Gastroenterology, Konya Training and Research Hospital, Konya, Turkey.

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http://dx.doi.org/10.1111/pai.12219DOI Listing
October 2014

CACP syndrome: identification of five novel mutations and of the first case of UPD in the largest European cohort.

Eur J Hum Genet 2014 Feb 12;22(2):197-201. Epub 2013 Jun 12.

Department of 'NEUROFARBA', Section of Child's Health, University of Florence and Anna Meyer Children's Hospital, Florence, Italy.

Camptodactyly-Arthropathy-Coxa vara-Pericarditis (CACP) syndrome is a rare autosomal recessive disorder caused by mutations in PRG4 gene that encodes for proteoglycan 4, a mucin-like glycoprotein that is the major lubricant for joints and tendon surfaces. The molecular studies reported so far have described the identification of 15 mutations associated with this syndrome and the majority of them were found in families of Arabian origin. Here we report the molecular investigation of the largest European cohort that comprises 13 patients, and allowed the identification of 5 novel mutations and of the first case of CACP syndrome resulting from uniparental disomy of chromosome 1.
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http://dx.doi.org/10.1038/ejhg.2013.123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895642PMC
February 2014

Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity.

Clin Immunol 2013 Mar 24;146(3):248-61. Epub 2013 Jan 24.

San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.

Cell-surface CD25 expression is critical for maintaining immune function and homeostasis. As in few reported cases, CD25 deficiency manifests with severe autoimmune enteritis and viral infections. To dissect the underlying immunological mechanisms driving these symptoms, we analyzed the regulatory and effector T cell functions in a CD25 deficient patient harboring a novel IL2RA mutation. Pronounced lymphoproliferation, mainly of the CD8(+) T cells, was detected together with an increase in T cell activation markers and elevated serum cytokines. However, Ag-specific responses were impaired in vivo and in vitro. Activated CD8(+)STAT5(+) T cells with lytic potential infiltrated the skin, even though FOXP3(+) Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets. Thus, the complex pathogenesis of CD25 deficiency provides invaluable insight into the role of IL2/IL-2RA-dependent regulation in autoimmunity and inflammatory diseases.
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http://dx.doi.org/10.1016/j.clim.2013.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594590PMC
March 2013

Thymidylate synthase expression and genotype have no major impact on the clinical outcome of colorectal cancer patients treated with 5-fluorouracil.

Pharmacol Res 2011 Sep 23;64(3):242-8. Epub 2011 Apr 23.

Fondazione Farmacogenomica Fiorgen, Sesto Fiorentino, Italy; Dipartimento di Fisiopatologia Clinica, Sezione di Genetica Medica, Università di Firenze, Firenze, Italy.

Background And Objectives: Thymidylate synthase (TS) expression levels appear to be related to response to 5-fluorouracil-(5-FU)-based chemotherapy in colorectal cancer (CRC) patients. Three polymorphisms have been proposed as modulators of TS expression: a tandemly repeated sequence (2R/3R) in the 5' UTR, a SNP (G>C) within the 3R allele and a 6bp deletion in the 3' UTR. To evaluate the influence of TS expression and polymorphisms on clinical outcome of 5-FU-treated patients we performed a comprehensive genetic analysis on 63 CRC patients.

Methods: TS expression levels were analyzed in normal and tumor tissues. TS coding sequence and UTR polymorphisms were investigated on DNA from normal tissue. LOH analysis was performed to determine tumor genotype.

Results: A difference in disease-free survival (DFS), although not statistically significant, was observed between high and low mRNA expression levels: patients with low levels showed longer DFS. The 2R2R genotype showed significantly lower expression than the 3R3R and 2R3R genotypes in normal tissue. No other TS polymorphism was associated with mRNA expression or clinical outcome.

Conclusions: The results obtained in this pilot study indicate that the number of 5' UTR repeats is the major genetic determinant of TS expression. The lack of association with other polymorphisms might be partially explained by the existence of linkage disequilibrium in the TS gene. Our data support the growing evidence that TS control may require multiple mechanisms acting in close coordination with one another and suggest that TS genotyping alone in tumor samples is not sufficient to accurately predict response to 5-FU.
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http://dx.doi.org/10.1016/j.phrs.2011.04.006DOI Listing
September 2011

Genomic rearrangements of the CDKN2A locus are infrequent in Italian malignant melanoma families without evidence of CDKN2A/CDK4 point mutations.

Melanoma Res 2008 Dec;18(6):431-7

Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy.

Predisposition to familial cutaneous malignant melanoma has been associated with mutations in the CDKN2A and CDK4 genes. However, only a small subgroup of melanoma pedigrees harbour CDKN2A or CDK4 germline mutations. It is possible that other types of CDKN2A rearrangements, not detectable by routine PCR-based approaches, are involved in a fraction of melanoma cases negative for point sequence changes. In order to gain insights on the possible role of CDKN2A large deletions or duplications in melanoma susceptibility in the Italian population, we screened a series of 124 cutaneous malignant melanoma families referred to five national medical/cancer genetics centres. All probands were negative for point mutations in CDKN2A and CDK4. All samples were tested by MLPA (multiplex ligation-dependent probe amplification), and the results were confirmed by real-time quantitative PCR in a subset of 53 cases. No genomic rearrangements were detected in this series, one of the largest so far investigated. These data suggest that large deletions/duplications in the CDKN2A locus are infrequently involved in the development of familial melanoma in the Italian population. Based on these results, routine search for these rearrangements in CDKN2A- and CDK4-mutation negative melanoma families is not warranted, although it would be reasonable to pursue it in selected cases with very strong family history and/or showing linkage to 9p21.
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http://dx.doi.org/10.1097/CMR.0b013e328319412fDOI Listing
December 2008

High-resolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer.

Am J Clin Pathol 2008 Aug;130(2):247-53

Clinical Biochemistry, Department of Clinical Physiopathology, University of Florence, Florence, Italy.

High-resolution melting analysis (HRMA) provides a valid approach to efficiently detect DNA genetic and somatic mutations. In this study, HRMA was used for the screening of 116 colorectal cancers (CRCs) to detect hot-spot mutations in the KRAS and BRAF oncogenes. Mutational hot spots on the PIK3CA gene, exons 9 and 20, were also screened. Direct sequencing was used to confirm and characterize HRMA results. HRMA revealed abnormal melting profiles in 65 CRCs (56.0%), 16 of them harboring mutations in 2 different genes simultaneously. The frequency of mutations was 17.2% for PIK3CA (11.2% in exon 9 and 6.0% in exon 20), 43.1% for KRAS exon 2, and 9.5% in exon 15 of the BRAF gene. We found a significant association between PIK3CA and KRAS mutations (P = .008), whereas KRAS and BRAF mutations were mutually exclusive (P = .001). This report describes a novel approach for the detection of PIK3CA somatic mutations by HRMA.
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http://dx.doi.org/10.1309/LWDY1AXHXUULNVHQDOI Listing
August 2008

The p.G23S CDKN2A founder mutation in high-risk melanoma families from Central Italy.

Melanoma Res 2007 Dec;17(6):387-92

Section of Medical Genetics, Department of Clinical Pathophysiology, University of Florence, Italy.

We have investigated the frequency and spectrum of CDKN2A/CDK4 mutations in 23 cutaneous melanoma families from Central Italy (Tuscany). Three distinct mutations were identified in five families. One mutation, p.G23S, was present in three families. Several lines of evidence indicate that p.G23S is a pathogenic mutation: it is located in the functionally important first ankyrinic domain of p16, it was not detected in a sample of 100 control individuals, and it was present in all tested affected individuals from the three families. Haplotype analysis showed a common ancestral origin of the p.G23S mutation. Our data show that the p.G23S mutation is an important cause of hereditary melanoma in Tuscany.
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http://dx.doi.org/10.1097/CMR.0b013e3282f1d328DOI Listing
December 2007

Triple synchronous cutaneous melanoma: a clinical, dermoscopic, and genetic case study.

Dermatol Surg 2007 Apr;33(4):488-91

Department of Dermatology, Medical Genetics Unit, University of Florence, Florence, Italy.

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http://dx.doi.org/10.1111/j.1524-4725.2007.33098.xDOI Listing
April 2007
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