Tumori eredo-familiari di mammella ed ovaio: analisi mutazionale dei geni BRCA1 e BRCA2

Sulla base delle informazioni ad oggi disponibili, si stima che circa il 5-10% dei carcinomi mammari ed ovarici insorga su base eredo-familiare. Nel corso degli anni ‘90, sono stati identificati due geni oncosoppressori che, se mutati, sono responsabili della comparsa sia di tumori mammari che ovarici. Questi geni sono stati chiamati BReast CAncer susceptibility gene 1 e 2 ovvero BRCA1 e BRCA2. Le mutazioni di questi geni si trasmettono con modalità di tipo autosomico dominante. Da un punto di vista clinico, l’importanza nel rilevare mutazioni in questi geni, risiede nel fatto che i soggetti, portatori di mutazioni predisponenti, hanno un elevato rischio di ammalarsi di tumore. Il nostro studio si è proposto di valutare l’incidenza delle mutazioni germinali di BRCA1 e BRCA2 sia nei pazienti con neoplasia della mammella e/o dell’ovaio sia nei parenti dei pazienti portatori. L’identificazione dei soggetti candidati allo studio, si è basata sulle caratteristiche dell’anamnesi familiare e sui risultati forniti da programmi informatici quali BRCAPRO e Manchester Scoring System. Lo studio della sequenza nucleotidica di tutti gli esoni dei geni BRCA1 e BRCA2 è stato effettuato tramite sequenziamento diretto; mentre lo studio di grandi riarrangiamenti genici è stato effettuato grazie alla tecnica MLPA (Multiplex Ligation Probe Amplification). Ad oggi, sono stati selezionati 741 pazienti, di cui 692 donne e 49 uomini, con un’età mediana d’insorgenza della malattia di 44 anni (range 16-84). L’analisi mutazionale di BRCA1 e BRCA2 è stata completata su 725 pazienti. In totale sono state identificate 191 mutazioni, di cui 52 in BRCA1: 4 - 19 frameshift, 17 missenso 3 nonsenso, 2 mutazioni nel sito di splicing, 7 varianti introniche e 4 riarrangiamenti genici; e 57 in BRCA2: - 21 frameshift, 4 nonsenso, 20 missenso, 5 silenti, 5 varianti introniche e 2 mutazioni nel sito di splicing. Lo studio è stato esteso poi a 256 soggetti sani, parenti dei pazienti analizzati, dei quali 188 donne e 68 uomini. L’analisi è stata completata su 181 soggetti. Sono state trovate, in totale 77 mutazioni, di cui 22 in BRCA1 e 17 in BRCA2. I dati raccolti finora confermano la possibilità di rilevare mutazioni predisponenti allo sviluppo di carcinomi mammari ed ovarici in soggetti ad alto rischio. I soggetti identificati potranno quindi sottoporsi a strategie preventive

Gastrointestinal neuroendocrine tumors: Searching the optimal treatment strategy-A literature review

Neuroendocrine tumors of the gastro-entero-pancreatic system (GEP-NETs) are a heterogeneous group of neoplasms, with different malignant potential and behavior. Many treatment options are available. Surgery should be considered for localized tumors and in some selected cases of metastatic disease. Somatostatin analogs, useful for symptoms control in functioning tumors, are also effective to inhibit tumor progression in specific settings. The multi-TKI sunitinib and of the mTOR-inhibitor everolimus are efficacy for metastatic pancreatic NET (P-NET) treatment. Chemotherapy is generally used in symptomatic and progressive NETs. Peptide receptor radionuclide therapy (PRRT) should be recommended after failure of medical therapy. For tumors confined to the liver ablative techniques should be considered. Nevertheless a shared therapeutic sequence for GEP-NET treatment still does not exist. In this review, we analyzed available data trying to identify the better treatment strategy and to suggest potential therapeutic algorithms distinguishing P-NETs from gastrointestinal NETs (GI-NETs)

Prognostic impact of mismatch repair genes germline defects in colorectal cancer patients: are all mutations equal?

Background: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, caused by germline mutations in MisMatch Repair (MMR) genes, particularly in MLH1, MSH2 and MSH6. Patients with LS seem to have a more favourable prognosis than those with sporadic CRC, although the prognostic impact of different mutation types is unknown. Aim of our study is to compare survival outcomes of different types of MMR mutations in patients with LS-related CRC. Methods: 302 CRC patients were prospectively selected on the basis of Amsterdam or Revised Bethesda criteria to undergo genetic testing: direct sequencing of DNA and MLPA were used to examine the entire MLH1, MSH2 and MSH6 coding sequence. Patients were classified as mutation-positive or negative according to the genetic testing result. Results: A deleterious MMR mutation was found in 38/302 patients. Median overall survival (OS) was significantly higher in mutation-positive vs mutation-negative patients (102.6 vs 77.7 months, HR:0.63, 95%CI:0.46-0.89, p = 0.0083). Different types of mutation were significantly related with OS: missense or splicing-site mutations were associated with better OS compared with rearrangement, frameshift or non-sense mutations (132.5 vs 82.5 months, HR:0.46, 95%CI:0.16-0.82, p = 0.0153). Conclusions: Our study confirms improved OS for LS-patients compared with mutation-negative CRC patients. In addition, not all mutations could be considered equal: the better prognosis in CRC patients with MMR pathogenic missense or splicing site mutation could be due to different functional activity of the encoded MMR protein. This matter should be investigated by use of functional assays in the future

Expectations and psychological issues before genetic counseling: analysis of distress determinant factors

Hereditary non-polyposis colorectal cancer (HNPCC) and Hereditary Breast and Ovarian Cancer Syndrome (HBOC) are the most common hereditary cancer syndromes in which a genetic test is available. Potential risks associated with testing include psychological harm, emotional distress and insurance problems

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A germline missense mutation in exon 3 of the MSH2 gene in a Lynch syndrome family: correlation with phenotype and localization assay

Lynch syndrome is caused by germline mutations in any of the MisMatch Repair (MMR) genes. About 37% of MSH2 variants are missense variants causing single amino-acid substitutions. Whether missense variants affect the normal function of MMR proteins is crucial both to provide affected families a more accurate risk assessment and to offer predictive testing to family members. Here we report one family, fulfilling both Amsterdam I and II criteria and Bethesda guidelines, referred to our center for genetic counselling. The proband and some of her relatives have been investigated for microsatellite instability (MSI), immunohistochemical MMR protein staining, direct sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). Also Subcellular Localization Assay and Splice site predictions analyses were used. A germline missense variant of uncertain significance (exon 3, p.Val161Asp) was found in MSH2 gene in proband and in some relatives. The variant was associated with lack of expression of MSH2 protein (DMMR) and MSI-High status in tumour tissues. The localization assay of the MSH2 protein showed an abnormal subcellular localization pattern of the corresponding protein. Finally, splice-site prediction analysis ruled out a potential role of new splice sites as the cause behind the lack of expression of MSH2 protein and we suppose a potential correlation with other forms of post-transcriptional regulation (circular RNAs). The variant here reported shows a high correlation with phenotype and is located in an evolutionary conserved domain. The localization assay also suggest a potential pathogenic role, thus supporting further research on this matter

The role of angiogenetic single-nucleotide polymorphisms in thymic malignancies and thymic benign lesions

We previously showed that selected single-nucleotide-polymorphisms (SNPs) of genes involved in angiogenesis influence the aggressiveness of thymic epithelial tumors (TETs). This study analyzes their role in TETs and in thymic benign lesions, in order to investigate potential correlation with risk and outcome

Clinical impact of different exosomes' protein expression in pancreatic ductal carcinoma patients treated with standard first line palliative chemotherapy.

IntroductionPancreatic ductal adenocarcinoma is associated to dismal prognosis despite the use of palliative chemotherapy, partly due to the lack of knowledge of biological processes underlying disease progression. Exosomes have been identified as biomarkers sources in different cancer types. Aim of the study was to analyse the contents of circulating exosomes in patients with pancreatic cancer who received palliative chemotherapy.Patients and methodsPatients were submitted to blood sample collection before chemotherapy (T0) and after 3 months (T3). We quantified by an ELISA-based technique specific proteins of cancer-derived exosomes (CD44,CD44v6,EpCAM,CD9,CD81,Tspan8,Integrin α6,Integrin β4,CD24,CXCR4). We correlated the baseline levels of these factors and changes between T3 and T0 and survival outcomes. Survival analyses were performed by Kaplan-Meier method. Correlation was assessed by log-rank test and level of statistical significance was set at 0.05. Multivariate analysis was performed by logistic regression analysis.ResultsNineteen patients were enrolled. EpCAM T0 levels and increased EpCAM levels from T0 to T3 were those mostly associated with differences in survival. Patients having higher EpCAM had median progression free survival (PFS) of 3.18vs7.31 months (HR:2.82,95%CI:1.03-7.73,p = 0.01). Overall survival (OS) was shorter for patients having higher EpCAM (5.83vs16.45 months,HR:6.16,95%CI:1.93-19.58,p = 0.0001) and also response rates (RR) were worse (20%vs87%,p = 0.015). EpCAM increase during treatment was associated with better median PFS (2.88vs7.31 months,HR:0.24,95%CI:0.04-1.22,p = 0.003). OS was also better (8.75vs11.04 months, HR:0.77,95%CI:0.21-2.73,p = 0.66) and RR were 60%vs20% (p = 0.28). Among clinical factors that might determine changes on PFS and OS, only ECOG PS was associated to significantly worse PFS and OS (p = 0.0137andConclusionsPancreatic cancer patients exosomes express EpCAM, whose levels change during treatment. This represents a useful prognostic factor and also suggests that future treatment modalities who target EpCAM should be tested in pancreatic cancer patients selected by exosome EpCAM expression