RESUMO
In this study, we analyzed multiple somatic mutations in 10 genes relevant in melanoma tumorigenesis and targeted therapies. Overall, 45% of the tumors showed mutations and, in particular, 33% had multiple mutations. Based on our results, we conclude that the assessment of mutation status of multiple genes, including CDKN2A, could provide a genetic profile that can be useful as a prognostic and therapeutic marker in melanocytic tumors.
Assuntos
Genes p16 , Melanoma/genética , Neoplasias Cutâneas/genética , Quinases Proteína-Quinases Ativadas por AMP , Biomarcadores Tumorais/genética , Análise Mutacional de DNA , GTP Fosfo-Hidrolases/genética , Humanos , Proteínas de Membrana/genética , Mutação de Sentido Incorreto , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
SULT1A1, a member of sulfotransferase superfamily, is a drug and hormone metabolizing enzyme involved in the metabolism of a variety of potential mammary carcinogens of endogenous and exogenous origin. Interestingly, the metabolic activity of SULT1A1 can be affected by variations in gene copy number. Male Breast Cancer (MBC) is a rare disease and less investigated disease compared to female BC (FBC). As in FBC, the concurrent effects of genetic risk factors, particularly BRCA2 mutations, increased exposure to estrogens and environmental carcinogens play a relevant role in MBC. By quantitative real-time PCR with TaqMan probes, we investigated the presence of SULT1A1 gene copy number variations (CNVs) in a series of 72 MBCs. SULT1A1 gene deletion was observed in 10 of the 72 MBCs (13.9%). In a multivariate analysis association between BRCA2 mutation and SULT1A1 gene deletion emerged (p = 0.0005). Based on the evidence that the level of SULT1A1 enzyme activity is correlated with CNV, our data suggest that in male breast tumors SULT1A1 activity may be decreased. Thus, it can be hypothesized that in a proportion of MBCs, particularly in BRCA2-associated MBCs, the level of estrogens and environmental carcinogens exposure might be increased suggesting a link between gene and environmental exposure in the pathogenesis of MBC.
Assuntos
Arilsulfotransferase/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/genética , Exposição Ambiental , Deleção de Genes , Predisposição Genética para Doença , Neoplasias da Mama Masculina/patologia , Feminino , Humanos , MasculinoRESUMO
Recently, the number of studies on male breast cancer (MBC) has been increasing. However, as MBC is a rare disease there are difficulties to undertake studies to identify specific MBC subgroups. At present, it is still largely unknown whether BRCA-related breast cancer (BC) in men may display specific characteristics as it is for BRCA-related BC in women. To investigate the clinical-pathologic features of MBC in association with BRCA mutations we established a collaborative Italian Multicenter Study on MBC with the aim to recruit a large series of MBCs. A total of 382 MBCs, including 50 BRCA carriers, were collected from ten Italian Investigation Centres covering the whole country. In MBC patients, BRCA2 mutations were associated with family history of breast/ovarian cancer (p<0.0001), personal history of other cancers (p=0.044) and contralateral BC (p=0.001). BRCA2-associated MBCs presented with high tumor grade (p=0.001), PR-(p=0.026) and HER2+ (p=0.001) status. In a multivariate logistic model BRCA2 mutations showed positive association with personal history of other cancers (OR 11.42, 95% CI 1.79-73.08) and high tumor grade (OR 4.93, 95% CI 1.02-23.88) and inverse association with PR+ status (OR 0.19, 95% CI 0.04-0.92). Based on immunohistochemical (IHC) profile, four molecular subtypes of MBC were identified. Luminal A was the most common subtype (67.7%), luminal B was observed in 26.5% of the cases and HER2 positive and triple negative were represented by 2.1% and 3.7% of tumors, respectively. Intriguingly, we found that both luminal B and HER2 positive subtypes were associated with high tumor grade (p=0.003 and 0.006, respectively) and with BRCA2 mutations (p=0.016 and 0.001, respectively). In conclusion, our findings indicate that BRCA2-related MBCs represent a subgroup of tumors with a peculiar phenotype characterized by aggressive behavior. The identification of a BRCA2-associated phenotype might define a subset of MBC patients eligible for personalized clinical management.
Assuntos
Neoplasias da Mama Masculina/genética , Carcinoma Ductal de Mama/genética , Genes BRCA1 , Genes BRCA2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama Masculina/patologia , Carcinoma Ductal de Mama/patologia , Análise Mutacional de DNA , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Breast cancer (BC) in men is rare compared with BC in women, but its incidence is increasing along with attention toward this uncommon disease. Although with some differences, male and female BC share similar genetic predisposition factors, including BRCA1/2, CHEK2, and PALB2 mutations. As other BRCA1/2 functionally related DNA repair genes, such as CHEK2 and PALB2, BRIP1 is considered a moderate-penetrance BC susceptibility gene. At present, the role of BRIP1 on BC susceptibility in men is unknown. In this study, we aimed to assess whether BRIP1 variants may contribute to male BC (MBC) risk, by screening 97 MBC cases, all negative for BRCA1/2, CHEK2, and PALB2 mutations, selected from a population-based series of 126 MBCs from Central Italy. A total of five BRIP1 germ-line sequence alterations, three coding, and two non-coding variants, were detected in our series. The two non-coding variants IVS4-28G > A and 3'UTR 4049C > T were classified as neutral by in silico analysis. Of the three coding variants, one was a silent variant (E879E) and two resulted in amino acid substitution (R264W and P919S) showing a putative pathogenic role by in silico analysis. However, further analysis of tumor-associated loss of heterozygosity and the frequency of variant alleles, tested in 203 male population controls, suggested a neutral effect for both of these variants. Overall, our results indicate that BRIP1 variants may not play a relevant role in MBC predisposition.
Assuntos
Neoplasias da Mama Masculina/genética , Proteínas de Ligação a DNA/genética , RNA Helicases/genética , Regiões 3' não Traduzidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Neoplasias da Mama Masculina/epidemiologia , Estudos de Casos e Controles , Análise Mutacional de DNA , Éxons , Proteínas de Grupos de Complementação da Anemia de Fanconi , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Íntrons , Itália/epidemiologia , Perda de Heterozigosidade , Masculino , Pessoa de Meia-Idade , Mutação de Sentido IncorretoRESUMO
BACKGROUND: Germline mutations in the BRCA1 and BRCA2 tumour-suppressor genes predispose to early-onset breast and ovarian cancer. Although both genes display a highly heterogeneous mutation spectrum, a number of alterations recur in some populations. Only a limited number of founder mutations have been identified in the Italian population so far. OBJECTIVE: To investigate the spectrum of BRCA1/BRCA2 mutations in a set of families originary from the Central-Eastern part of Tuscany and to ascertain the presence of founder effects. We also wanted to approximate the age of the most frequent BRCA1 founder mutation. RESULTS: Overall, four distinct BRCA1 mutations accounted for a large fraction (72.7%) of BRCA1-attributable hereditary breast/ovarian cancer in families originary from this area. We identified common haplotypes for two newly recognised recurrent BRCA1 mutations, c.3228_3229delAG and c.3285delA. The c.3228_3229delAG mutation was estimated to have originated about 129 generations ago. Interestingly, male breast cancer cases were present in 3 out of 11 families with the c.3228_3229delAG mutation. CONCLUSIONS: The observation that a high proportion of families with BRCA1 alterations from Central-Eastern Tuscany harbours a limited number of founder mutations can have significant impact on clinical management of at risk subjects from this area. In addition, the identification of a large set of families carrying an identical mutation that predisposes to breast and ovarian cancer provides unique opportunities to study the effect of other genetic and environmental factors on penetrance and disease phenotype.
Assuntos
Neoplasias da Mama Masculina/genética , Neoplasias da Mama/genética , Efeito Fundador , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Genes BRCA1 , Haplótipos , Humanos , Itália , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUND: Male breast cancer (MBC) is a rare and scarcely investigated disease. The strongest genetic risk factor for MBC is represented by inherited BRCA2 mutations, whereas the association between MBC and BRCA1 mutations is less clear. MBC appears to be biologically similar to breast cancer in females, however the phenotypic characteristics of BRCA1/2-related MBCs are not yet well elucidated. OBJECTIVE: To investigate the genetic and phenotypic characteristics of MBC in a large and well-characterized population-based series of 108 MBCs from Tuscany (Central Italy) and to evaluate associations between BRCA1/BRCA2 mutation status and clinical-pathological features including breast/ovarian cancer first-degree family history, tumor histology and grade, proliferative activity, estrogen/progesterone receptors (ER/PR) and epidermal growth factor receptor 2 (HER2) expression. Results BRCA1/BRCA2 mutations were identified in ten MBCs, in particular, two cases (1.9%) carried BRCA1 and eight cases (7.4%) carried BRCA2 mutations. The same BRCA1 mutation (3347delAG) was detected in two unrelated MBC cases. Three novel BRCA2 pathogenic mutations were found. Statistically significant associations emerged between BRCA2-related tumors and absence of PR expression (P = 0.008), HER2 over-expression (P = 0.002) and high tumor grade (P = 0.005). Conclusions Here, we (i) reported that in our population about 9% of MBC cases are accounted for by BRCA1/BRCA2 mutations; (ii) enlarged the BRCA2 mutational spectrum and (iii) characterized a specific phenotype associated with BRCA2-related MBCs suggestive of aggressive behavior. Overall, our results may have important implications on clinical management for this rare disease.
Assuntos
Adenocarcinoma Mucinoso/genética , Neoplasias da Mama Masculina/genética , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/genética , Carcinoma Papilar/genética , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa/genética , Adenocarcinoma Mucinoso/epidemiologia , Adulto , Idoso , Neoplasias da Mama Masculina/epidemiologia , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Lobular/epidemiologia , Carcinoma Papilar/epidemiologia , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Haplótipos/genética , Humanos , Técnicas Imunoenzimáticas , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
BACKGROUND: Male breast cancer (MBC) is a rare disease and little is known about its aetiology. Germ-line mutations of BRCA2 and, at lower frequency, of BRCA1 are implicated in a relatively small proportion of MBC cases. Common polymorphic variants in BRCA1 and BRCA2 genes may represent breast cancer (BC) susceptibility alleles and could be associated with a modestly increased risk of MBC at population level. Considering the relevant role of BRCA2 in MBC, we investigated whether the BRCA2 N372H variant, representing the only common non-synonymous polymorphism in BRCA2, might modulate the risk of BC in male populations. METHODS: A case-control study was performed comparing a population-based series of 99 MBC cases, characterized for BRCA1 and BRCA2 mutations, with 261 male population controls, all residing in Tuscany, Central Italy. All MBC cases and controls were genotyped for the BRCA2 N372H allele by TaqMan allelic discrimination assays. To evaluate the genotype specific risk of the BRCA2 N372H variant, MBC carriers of germ-line BRCA1/2 mutations were excluded from the analyses. RESULTS: No association emerged in univariate and age-adjusted analyses. Age-specific analyses suggested an increased risk for the HH homozygous genotype in subjects younger than 60 years. A statistically significant interaction emerged between this genotype and age (p = 0.032). When analyses were restricted to MBC cases enrolled in the first 4 years following diagnosis, a recessive model showed a significantly increased risk of MBC in HH subjects younger than 60 years (OR = 5.63; 95% CI = 1.70;18.61). CONCLUSION: Overall, our findings, although based on a relatively small series, suggest that the BRCA2 HH homozygous genotype might be positively associated with an increased risk of MBC in men younger than 60 years.
Assuntos
Neoplasias da Mama Masculina/genética , Genes BRCA2 , Predisposição Genética para Doença , Fatores Etários , Idoso , Estudos de Casos e Controles , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de RiscoRESUMO
To investigate at the population level the impact of BRCA1/BRCA2 gene alterations in male breast cancer, we analyzed a population-based series of 25 male breast cancer cases from Florence, Central Italy. We combined mutational screening with the study of germ-line allele transcript levels and of tumor-associated losses of heterozygosity. Screening by protein truncation test and single-strand conformational polymorphism assay, followed by sequencing, revealed 4 pathogenetic mutations (4 of 25 = 16%; 95% confidence interval, 5-37%), 1 in BRCA1 and 3 in BRCA2, including mutations recurring in Central Italy (BRCA1 3345delAG and BRCA2 6696delTC). The a priori probability of carrying a mutation, estimated using BRCAPRO software, showed a good agreement between expected and observed mutations (14% versus 16%). A 7-fold association between germ-line mutations and family history of breast-ovarian cancer emerged. To investigate associations between BRCA1/BRCA2 status and clinicopathological characteristics, we analyzed the histopathological and immunophenotypic parameters of the tumors. A significant association emerged between mutation carrier status and high histological grade (P = 0.02). Furthermore, one BRCA2 carrier was affected with Paget's disease, an extremely rare male breast cancer histotype. Overall, BRCA1/2 mutations were observed to be strongly associated with positive c-erbB-2 immunostaining (P = 0.004). To evaluate germ-line allele expression, we used primer extension assays targeting frequent BRCA1 and BRCA2 polymorphisms. A BRCA2 allele transcript imbalance was found in one of four heterozygotes tested, all of them negative for germ-line mutations. BRCA1 transcript imbalances were not detected in nine heterozygotes analyzed. Losses of heterozygosity at one or more of nine loci in the BRCA2 region were found in 8 of 22 tumors tested. Interestingly, a case that was negative for BRCA1/BRCA2 germ-line mutations and that had a priori mutation probability <10% showed loss of heterozygosity at all three of the intragenic BRCA2 markers analyzed, which could be related to a somatic involvement of BRCA2. No losses of heterozygosity were detected at BRCA1. In conclusion, constitutional BRCA1/BRCA2 mutations accounted for 16% of the male breast cancer cases in this area of Central Italy. The detection of a BRCA2 germ-line transcript imbalance and of a somatic loss of BRCA2 among the cases that resulted negative for germ-line mutations suggests a role of this gene more relevant than indicated by conventional mutational analysis. A distinct pattern of characteristics indicative of aggressive behavior, including high-grade and c-erbB-2 expression, was evident in tumors from germ-line BRCA2 mutation carriers. This suggests that phenotypic characteristics may contribute to the identification of hereditary BRCA2-related male breast cancers and that these tumors might share a unique molecular pathway of cancer progression.
Assuntos
Neoplasias da Mama Masculina/genética , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Perda de Heterozigosidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alelos , Proteína BRCA1/biossíntese , Proteína BRCA1/genética , Proteína BRCA2/biossíntese , Proteína BRCA2/genética , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/metabolismo , Neoplasias da Mama Masculina/patologia , Humanos , Imuno-Histoquímica , Itália/epidemiologia , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismoAssuntos
Neoplasias da Mama Masculina/epidemiologia , Proteínas Nucleares/genética , Proteínas Supressoras de Tumor/genética , Regiões 5' não Traduzidas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Proteínas Reguladoras de Apoptose , Proteína BRCA2/metabolismo , Neoplasias da Mama Masculina/genética , Análise Mutacional de DNA , Éxons/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi , Genes BRCA1 , Genes BRCA2 , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Proteínas Nucleares/química , Proteínas Nucleares/metabolismo , Penetrância , Mutação Puntual , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Supressoras de Tumor/química , Proteínas Supressoras de Tumor/metabolismoRESUMO
Fire has always been involved in human thoughts, believes and actions. For many psychological reasons fire has been considered as living power: red as the human blood, warm as the human body, clearly shines in the night. Fire worship is very common, especially in regions where terrestrial fire is believed to be the image of the heavenly fire. Fire worship has represented the base for symbolic systems involved in the cultural-anthropological evolution of populations settled close to mount Soratte. Fire cults in this region have originated in independent and long-time separated contexts, according to available knowledge. Hirpi Sorani, ancient inhabitants of mount Soratte territory, celebrated Sorano Apollo by a famous fire walking ceremony, with a likely cathartic and apotropaic meaning, as reported by ancient Roman writers. The victory of Christianity over paganism caused the decline of these religious practices. The beginning of the XIX century witnessed the establishment ofa new kind of devotion to the Virgin Mary at the mount Soratte. Today, this religious piety-linked identity has weakened due to changes in lifestyles,from an agricultural to one based on outside home employment, and has been largely shifted on cultural and anthropological bases. In conclusion, fire worship at mount Soratte has evolved because of external influences and local inhabitants have reacted by asserting their own identity.
Assuntos
Cultura , Religião/história , Incêndios , História do Século XIX , História do Século XX , História do Século XXI , História Antiga , História Medieval , ItáliaRESUMO
A case of a parasitic perineal monstrosity from the collection of the Pathology Museum of the University of Florence, is described on the basis of the original medical records and illustrations. The surgeon Giorgio Pellizzari (1814-1894) first reported this extraordinary case of sacrococcygeal teratoma containing a rudimentary inferior limb. Reader of Descriptive Anatomy, Pellizzari was a well-known Anatomy Dissector and Curator of the Physiological Museum of the Regio Arcispedale di Santa Maria Nuova in Florence. This report underlines the importance of studying the archive material in order to thoroughly comprehend a single museum talking object. This handling of matters will help to turn anatomical collections into a unique teaching toolfor modern medical practice and a noteworthy documentation of scientific, artistic and historical value. Through analysis of the original catalogue and investigation by means of modern scientific techniques, discovering the story behind the object becomes afeasible challenge.
Assuntos
Períneo/patologia , Região Sacrococcígea/patologia , Teratologia/história , Teratoma/história , Europa (Continente) , História do Século XV , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História Antiga , História Medieval , Itália , Períneo/cirurgia , Região Sacrococcígea/cirurgia , Teratoma/patologia , Teratoma/cirurgiaRESUMO
Mount Soratte is a limestone ridge that rises on a lonely plateau of Pliocene tuff on the right of the Tiber, about forty kilometers North of Rome. Studies related to human settlements during prehistory in this territory have been sporadic and occasional. The first evidence of prehistoric cults on mount Soratte has been found in the early Fifties when ajar, dating back to Neolithic times, was discovered in the cave of the Meri. The jar was placed in a position to be always filled of water and indicates the existence of ancient practices of worship linked to groundwater. In the Middle Ages, although caves became a step towards the Hell, dripping caves were often associated with the magical-religious and therapeutic aspects of water linked to fertility in the popular imagination. In the cave church of the Saint Romana, on the eastern slope of Mount Soratte close to Meri, there is a small marble basin near the altar and the water drips from the rock above it. This water is taken out for devotion and drunk by mothers who did not get milk from their breasts. Recently, the water of the Saint Romana would have drained as a result of an act of sacrilege, albeit unintentionally, as reported in a oral testimony. Overall, the territory of Mount Soratte is characterized by a sharp and clear karst. This causes the water, that collects on the inside, coming out in many springs all around the valley. This water is collected to supply fountains used years ago by farmers and livestock and nowadays may represent a cultural space of social life with the aim to build a strong link with the territory and a new awareness of the past and history of the countryside around Mount Soratte.
Assuntos
Cavernas , Comportamento Ritualístico , Nascentes Naturais , Religião/história , Antropologia Cultural , Cristianismo/história , Cultura , Feminino , História do Século XVII , História do Século XVIII , História do Século XIX , História Antiga , História Medieval , Humanos , Transtornos da Lactação/história , Transtornos da Lactação/psicologia , Mães/psicologiaRESUMO
Breast cancer is the most common cancer among women, accounting for about 30% of all cancers. In contrast, breast cancer is a rare disease in men, accounting for less than 1% of all cancers. Up to 10% of all breast cancers are hereditary forms, caused by inherited germ-line mutations in "high-penetrance," "moderate-penetrance," and "low-penetrance" breast cancer susceptibility genes. The remaining 90% of breast cancers are due to acquired somatic genetic and epigenetic alterations. A heterogeneous set of somatic alterations, including mutations and gene amplification, are reported to be involved in the etiology of breast cancer. Promoter hypermethylation of genes involved in DNA repair and hormone-mediated cell signaling, as well as altered expression of micro RNAs predicted to regulate key breast cancer genes, play an equally important role as genetic factors in development of breast cancer. Elucidation of the inherited and acquired genetic and epigenetic alterations involved in breast cancer may not only clarify molecular pathways involved in the development and progression of breast cancer itself, but may also have an important clinical and therapeutic impact on improving the management of patients with the disease.
RESUMO
King Ferrante I of Aragon, leading figure of the Italian Renaissance, died in 1494. The autopsy of his mummy revealed a tumor infiltrating the small pelvis. We examined the histologic and molecular features of this ancient tumor to investigate its primary origin. Hematoxylin-eosin, Van Gieson, and Alcian Blue staining showed neoplastic cells infiltrating muscular fibers and forming pseudo-glandular lumina disseminated in fibrous stroma with scarce mucus. A strong immunoreactivity of the neoplastic cells was shown for pancytokeratins and proliferating cell nuclear antigen. Molecular fingerprints were investigated by examining K-ras, BRAF, and microsatellite instability in ancient tumor DNA. Sequencing analysis showed G-to-A transition in codon 12 of K-ras. BRAF mutations and microsatellite instability were not observed. Because the presence of K-ras codon 12 mutation could be associated with exposure to chemical carcinogens, possibly present in some food items, paleodietary reconstruction of the King Ferrante I was carried out by carbon (δ(13)C ) and nitrogen (δ(15)N) stable isotopes analysis. δ(13)C and δ(15)N values found in bone collagen of the King were consistent with a massive intake of animal proteins. Overall, our data show that the tumor of Ferrante I was a mucinous adenocarcinoma with molecular fingerprints characteristic of colorectal carcinogenesis linked to K-ras pathway. Paleodietary reconstruction and historical chronicles indicate a strong consumption of meat by the King. The possible abundance of dietary carcinogens, related to meat consumption, could explain the K-ras mutation causing the colorectal tumor that killed Ferrante I more than 5 centuries ago.
Assuntos
Adenocarcinoma/história , Neoplasias Colorretais/história , Exposição Ambiental/história , Pessoas Famosas , Mutação , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Biomarcadores Tumorais/metabolismo , Carcinógenos/história , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Análise Mutacional de DNA , Dieta , Predisposição Genética para Doença , História do Século XV , Humanos , Itália , Masculino , Múmias/patologia , Paleopatologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genética , Proteínas ras/metabolismoRESUMO
BACKGROUND: The plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathogenesis of cancer. The 4G/5G promoter polymorphism of PAI-1 is potentially involved in regulating gene transcription. AIMS: To explore the role of the PAI-1 4G/5G repeat as target of microsatellite instability (MSI), 50 gastric carcinomas (GCs), characterized for MSI, were screened. METHODS: PAI-1 4G/5G was analysed by direct sequencing. RESULTS: Allelic imbalance was observed in 5 of the 50 (10%) GCs. Specifically, 2 cases (40%) harboured a G deletion and 3 (60%) a G insertion in tumour compared to normal DNA. These five cases were included in the subgroup of 20 GCs (25%) with high level of MSI (MSI-H). A statistically significant association emerged between PAI-1 mutations and MSI-H status (p=0.0073). The frequency of PAI-1 mutations was also evaluated, together with other known target genes, by analysing MSI-H GCs for mutations at selected coding repeats within genes controlling cell growth, apoptosis and DNA repair. Overall, mutation frequency ranged from 56.3% to 5.3%. CONCLUSION: The frequency of PAI-1 mutations here reported in MSI-H GCs is, accordingly, comparable with values obtained for real targets. The relatively high incidence of PAI-1 mutations is suggestive of a positive pressure towards selection in MSI-H GCs.
Assuntos
Instabilidade de Microssatélites , Mutação , Inibidor 1 de Ativador de Plasminogênio/genética , Neoplasias Gástricas/genética , Análise Mutacional de DNA , DNA de Neoplasias , Genótipo , Humanos , Mutação INDEL , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Tuberculosis represents one of the humankind's most socially devastating diseases. Despite a long history of medical research and the development of effective therapies, this disease remains a global health danger even in the 21st century. Tuberculosis may cause death but infected people with effective immunity may remain healthy for years, suggesting long-term host-pathogen co-existence. Because of its antiquity, a supposed association with human settlements and the tendency to leave typical lesions on skeletal and mummified remains, tuberculosis has been the object of intensive multidisciplinary studies, including paleo-pathological research. During the past 10 years molecular paleo-pathology developed as a new scientific discipline allowing the study of ancient pathogens by direct detection of their DNA. In this work, we reviewed evidences for tuberculosis in ancient human remains, current methods for identifying ancient mycobacterial DNA and explored current theories of Mycobacterium tuberculosis evolution and their implications in the global development of tuberculosis looking into the past and present at the same time.
Assuntos
Tuberculose/história , História do Século XV , História do Século XVI , História do Século XVII , História do Século XVIII , História do Século XIX , História Antiga , História Medieval , Humanos , Técnicas de Diagnóstico Molecular , Múmias , Mycobacterium/genéticaRESUMO
No study has evaluated the performance of BRCA1/2 mutations prediction models in male breast cancer (MBC) series. Although rare, MBC deserves attention because male and female breast cancers share many characteristics, including the involvement of genetic predisposition factors such as BRCA1/BRCA2 mutations. Indeed, the occurrence of MBC is a commonly used criterion to select families for BRCA mutation testing. We evaluated the performance and clinical effectiveness of four different predictive models in a population-based series of 102 Italian MBC patients characterized for BRCA1/2 mutations. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for each risk model at the 10% threshold. The area under the ROC (AUC) curves and its corresponding asymptotic 95% CIs were calculated as a measure of the accuracy. In our study, the BRCAPRO version 5.0 had the highest combination of sensitivity, specificity, NPV and PPV for the combined probability and for the discrimination of BRCA2 mutations. In individuals with negative breast-ovarian cancer family history, BRCAPRO 5.0 reached a high discriminatory capacity (AUC=0.92) in predicting BRCA2 mutations and showed values of sensitivity, specificity, NPV and PPV of 0.5, 0.98, 0.97 and 0.67, respectively, for the combined probability. BRCAPRO version 5.0 can be particularly useful in dealing with non-familial MBC, a circumstance that often represents a challenging situation in genetic counseling.
Assuntos
Neoplasias da Mama Masculina/genética , Neoplasias da Mama Masculina/terapia , Aconselhamento Genético/métodos , Modelos Genéticos , Área Sob a Curva , Feminino , Humanos , Masculino , Curva ROC , SoftwareRESUMO
Gastric cancers with mismatch repair (MMR) inactivation are characterised by microsatellite instability (MSI). In this study, the transcriptional profile of 38 gastric cancers with and without MSI was analysed. Unsupervised analysis showed that the immune and apoptotic gene networks efficiently discriminated these two cancer types. Hierarchical clustering analysis revealed numerous gene expression changes associated with the MSI phenotype. Amongst these, the p53-responsive genes maspin and 14-3-3 sigma were significantly more expressed in tumours with than without MSI. A tight immunosurveillance coupled with a functional p53 gene response is consistent with the better prognosis of MSI cancers. Frequent silencing of MLH1 and downregulation of MMR target genes, such as MRE11 and MBD4, characterised MSI tumours. The downregulation of SMUG1 was also a typical feature of these tumours. The DNA repair gene expression profile of gastric cancer with MSI is of relevance for therapy response.
Assuntos
Reparo de Erro de Pareamento de DNA/genética , Perfilação da Expressão Gênica , Genes p53/genética , Instabilidade de Microssatélites , Análise de Sequência com Séries de Oligonucleotídeos , Neoplasias Gástricas/genética , Idoso , Idoso de 80 Anos ou mais , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Regiões Promotoras Genéticas/genéticaRESUMO
PURPOSE: The epidermal growth factor receptor (EGFR) is overexpressed in several tumor types, and its expression is influenced by the length of a 5'-end microsatellite repeat (CA)n: the longer the repeat, the lower the expression. Dinucleotide repeats accumulate insertion/deletion types of mutations in tumors with microsatellite instability. We designed this study to estimate the occurrence of these mutations in EGFR(CA)n and their relevance in carcinogenesis of microsatellite instability-positive colon and gastric tumors. EXPERIMENTAL DESIGN: We analyzed the frequency of EGFR(CA)n mutations in vivo in 55 colorectal and 14 gastric microsatellite instability-positive cancers, and in vitro in single-cell clone cultures of microsatellite instability-positive colon tumor cell line LS174. Single-cell clone cultures with different repeat lengths were analyzed by fluorescent-activated cell sorter for EGFR cell-surface expression. A correlation analysis was done between EGFR(CA)n mutations and mutations in KRAS, BRAF, and p53. RESULTS: Unlike single-cell clone cultures, which exhibited higher rate of deletions compared with insertions, most of EGFR(CA)n mutations in colon and gastric tumors were insertions. Longer EGFR(CA)n correlated with lower EGFR cell-surface expression in single-cell clone cultures. In colon cancers, the elongation of the repeat was associated negatively with mutations in KRAS and BRAF, but not in p53. CONCLUSIONS: The EGFR(CA)n elongation observed in tumors cannot be explained by an intrinsic property of this repeat favoring insertions versus deletions. Instead, a selection for repeat elongation occurs in microsatellite instability-positive tumors, leading to EGFR down-regulation. These findings suggest that in microsatellite instability-positive tumors current therapies targeting EGFR overexpression may have either no effect or an opposite to the expected effect.