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Lara Felicioni

Publications and source records attributed to Lara Felicioni.

8 recordsLinked to original sources
PubMed2006

Mutational analysis of the HER2 gene in lung tumors from Caucasian patients: mutations are mainly present in adenocarcinomas with bronchioloalveolar features.

Activating mutations in the tyrosine kinase domain of the HER2 gene have recently been reported in lung adenocarcinomas, mainly in East Asian patients. Our study was devised to evaluate the prevalence and nature of HER2 mutations in lung adenocarcinomas from Caucasian patients. The mutational status of the HER2 gene was evaluated in 403 lung adenocarcinomas by PCR-single strand conformation polymorphism analysis and direct sequencing of Exons 19 and 20. We found HER2 mutations in 9 (2.2%) cases. Seven (78%) of the mutations were in frame duplications/insertions at codons 776-779 (YVMA), the other 2 were base substitutions resulting in aminoacid changes. The hotspot mutation at bases 776-779 was previously found to be the most frequent HER2 mutation in Asiatic patients. The distribution of mutations was significantly different between conventional lung adenocarcinomas (CLAs) and lung adenocarcinomas with bronchioloalveolar features (ABAFs). Seven (6.2%) of 113 ABAFs and 2 (0.7%) of 290 CLA were mutated (p = 0.0025). In addition, the frequency of HER2 mutations was slightly higher in females (4.1%) than in males (1.8%) and in never smokers (3.1%) than in smokers (1.9%), but differences were not statistically significant. This series of tumors was also investigated for EGFR and K-ras mutations. EGFR mutations were observed in 43 (10.7%) cases, and K-ras mutations in 110 (27.3%) cases. EGFR, HER2 and K-ras mutations were found to be mutually exclusive events. The presence of HER2 mutations in a subset of patients with lung adenocarcinoma raise hope to treat these patients with HER2 specific kinase inhibitors.

Adenocarcinoma↗
PubMed2006

PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma.

Mutations in the PIK3CA gene have recently been reported in different human neoplasms, including breast cancer. This paper reports the results of a systematic analysis of PIK3CA mutations in different histological types of breast carcinoma. One hundred and eighty invasive breast carcinomas, comprising 74 ductal, 56 lobular, 22 mucinous, 20 medullary, and eight papillary, were selected on the basis of their histological type in a consecutive series of 780 breast cancers. Exons 1-20 of the PIK3CA gene were subjected to SSCP analysis followed by direct sequencing. PIK3CA mutations were observed in 46 (26%) of the 180 tumours examined: 23 (50%) mutations were located in exon 9, and 23 (50%) in exon 20. Mutations were frequent in lobular (46%), less frequent in ductal (22%), and uncommon in medullary (10%), mucinous (5%), and papillary tumours (12%) (p = 0.0002). Mutations in exon 9 were more frequent in lobular carcinomas (30% of cases) than in the other histological types (less than 5% of cases) (p = 0.00014). No significant differences were observed in the distribution of mutations in exon 20. There was no significant correlation between PIK3CA mutations and other clinicopathological and biological variables, including age, tumour size, lymph node metastases, oestrogen receptor (ER) status, progesterone receptor (PgR) status, p53 gene mutations, and p53 protein expression. The findings indicate that in invasive breast carcinomas, PIK3CA alterations are mainly present in lobular and ductal tumours, whereas the other histological types, known to be associated with a favourable prognosis, show a very low incidence of PIK3CA mutations.

Aged↗
PubMed2005

Identification of an aberrantly spliced form of HDMX in human tumors: a new mechanism for HDM2 stabilization.

The HDMX protein is closely related to HDM2 with which it shares different structural domains, particularly the p53 binding domain and the ring finger domain, where the two HDM proteins interact. Several oncogenic forms derived from splicing of HDM2 have been described in cancer. This work aimed at investigating whether analogous forms of HDMX exist in human tumors. Here, we report the characterization of an aberrantly spliced form of HDMX, HDMX211, isolated from the thyroid tumor cell line, ARO. HDMX211 binds and stabilizes the HDM2 protein. Although it lacks the p53 binding domain, HDMX211 also stabilizes p53 by counteracting its degradation by HDM2. However, the resulting p53 is transcriptionally inactive and increasingly associated to its inhibitor HDM2. Expression of HDMX211 strongly enhances the colony-forming ability of human cells in the presence or absence of wild-type p53. Conversely, depletion of HDMX211 by small interfering RNA significantly reduces the growth of ARO cells and increases their sensitivity to chemotherapy. Screening of lung cancer biopsies shows the presence of HDMX211 in samples that overexpress HDM2 protein, supporting a pathologic role for this new protein. This is the first evidence of a variant form of HDMX that has oncogenic potential independently of p53. HDMX211 reveals a new mechanism for overexpression of the oncoprotein HDM2. Most interestingly, it outlines a possible molecular explanation for a yet unclarified tumor phenotype, characterized by simultaneous overexpression of HDM2 and wild-type p53.

Alternative Splicing↗
PubMed2005

Int6 expression can predict survival in early-stage non-small cell lung cancer patients.

PURPOSE: The Int6 gene was originally identified as a common insertion site for the mouse mammary tumor virus in virally induced mouse mammary tumors. Recent studies indicate that Int6 is a multifaceted protein involved in the regulation of protein translation and degradation through binding with three complexes: the eukaryotic translation initiation factor 3, the proteasome regulatory lid, and the constitutive photomorphogenesis 9 signalosome. This study aimed to investigate the prognostic role of Int6 in a large series of stage I non-small cell lung cancers (NSCLC) patients with long-term follow-up. EXPERIMENTAL DESIGN: We determined the methylation status of Int6 DNA by methylation-specific PCR and the steady-state levels of Int6 RNA by quantitative real-time reverse transcription-PCR in 101 NSCLCs and matched normal lung tissues. RESULTS: In 27% of the tumors, Int6 RNA levels were reduced relative to normal tissue. In 85% of the tumors with reduced Int6 expression, the transcription promoter and first exon were hypermethylated, whereas only 4% of the tumors with elevated Int6 RNA levels were hypermethylated (P <0.000001). Low levels of Int6 RNA were found a significant predictor of overall and disease-free survival (P=0.0004 and P=0.0020, respectively). A multivariate analysis confirmed that low Int6 expression was the only independent factor to predict poor prognosis, for both overall (P=0.0006) and disease-free (P=0.024) survival. CONCLUSIONS: Our results suggest that Int6 expression, evaluated by quantitative real-time PCR, may represent a new prognostic factor in patients with stage I NSCLC.

Adult↗
PubMed2005

EGFR mutations in non-small-cell lung cancer: analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment.

PURPOSE: It has been reported that EGFR mutations in lung carcinomas make the disease more responsive to treatment with tyrosine kinase inhibitors. We decided to evaluate the prevalence of EGFR mutations in a large series of non-small-cell lung carcinomas (NSCLCs) and to develop a rapid and sensitive screening method. PATIENTS AND METHODS We examined 860 consecutive NSCLC patients for EGFR mutations in exons 18, 19, and 21 using a dual technical approach--direct sequencing of polymerase chain reaction (PCR) products and PCR single-strand conformation polymorphism (SSCP) analysis. Moreover, all lung adenocarcinomas were analyzed for K-ras mutations at codon 12 by allele-specific oligoprobe hybriditations. RESULTS: There were no EGFR mutations in 454 squamous carcinomas and 31 large cell carcinomas investigated. Thirty-nine mutations were found in the series of 375 adenocarcinomas (10%). Mutations were present in 26% of 86 bronchioloalveolar carcinomas (BACs) and in 6% of 289 conventional lung adenocarcinomas; P = .000002. EGFR mutations and K-ras mutations were mutually exclusive. A multivariable analysis revealed that BAC histotype, being a never smoker, and female sex were independently associated with EGFR mutations (odds ratios: 4.542, 3.632, and 2.895, respectively). The SSCP analysis was accurate and sensitive, allowing identification of mutations that were undetectable (21% of cases) by direct sequencing. CONCLUSION: Mutations in the EGFR tyrosine kinase domain define a new molecular type of lung carcinoma, more frequent in particular subsets of patients. The SSCP assay is a rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer.

Adenocarcinoma↗
PubMed2003

Human telomerase reverse transcriptase mRNA expression assessed by real-time reverse transcription polymerase chain reaction predicts chemosensitivity in patients with ovarian carcinoma.

PURPOSE: To evaluate in vivo whether the expression of the human telomerase reverse transcriptase (hTERT) gene, the catalytic subunit of the telomerase complex, is predictive of response to chemotherapy in ovarian cancer patients. PATIENTS AND METHODS: Fifty-nine advanced-stage ovarian cancer patients who were treated with platinum-based chemotherapy were studied. hTERT levels were evaluated by real-time reverse transcriptase polymerase chain reaction (RT-PCR) on tumor specimens obtained before the treatment. Variables were analyzed by the chi(2) and Fisher's exact tests. Logistic regression analysis was also performed to account for the effects of all the covariates investigated (residual disease, stage, histotype, and grade). RESULTS: Twenty-eight (47%) of the 59 tumors showed low hTERT levels, whereas 31 (53%) tumors displayed high hTERT levels. Seventy-five percent of complete responders showed high levels of hTERT expression, whereas 66% of partial responders or nonresponders exhibited low hTERT levels (P =.002). Only residual disease and hTERT expression were independent predictors of response (odds ratios, 13.455 and 7.586, respectively). The combination of these two parameters provides powerful predictive information: 18 of the 20 patients with residual disease more than 2 cm and low hTERT levels were partial responders or nonresponders, whereas 11 of the 12 patients with residual disease less than 2 cm and high hTERT levels showed a complete response (chi(2) = 21,416; P <.00001). CONCLUSION: Our data indicate that hTERT expression, measured by real-time RT-PCR, is a possible independent marker of response to platinum-based therapy in advanced stage ovarian cancer patients. Prospective validation of this marker will be required to further define its predictive value.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Prediction of survival in stage I lung carcinoma patients by telomerase function evaluation.

Telomerase activity and telomerase reverse transcriptase (hTERT) expression are elevated in human malignancies. We have investigated telomerase activity measured by the telomeric repeat amplification protocol (TRAP) assay and hTERT levels by real-time RT-PCR in stage I non-small-cell lung carcinomas. The purposes of our study included the comparison of these two techniques in the assessment of telomerase function and the evaluation of their prognostic significance. Telomerase activity and hTERT levels were determined in 90 stage I non-small-cell lung carcinoma patients, using TRAP assay and real-time RT-PCR, respectively. Variables were analyzed by the chi(2) and Fisher exact tests. Survival was analyzed by the Kaplan-Meier method. Multivariate analysis was performed with the Cox's proportional hazards model. Telomerase activity was elevated in 60 (67%) carcinomas. hTERT was elevated in 43 (48%) carcinomas. Only 21 (23%) tumors had low telomerase function by both TRAP and hTERT expression levels. Telomerase activity and hTERT were significantly correlated (p = 0.017), although 35 cases displayed discordant results. Both telomerase activity and hTERT levels were significantly associated with poor patient overall and disease-free survival (p = 0.019 and p = 0.018 for TRAP, and p = 0.011 and p = 0.012 for hTERT, respectively). Among the 21 patients with tumors displaying low telomerase function, defined by both TRAP and hTERT expression levels, only one succumbed to the disease (p = 0.0053). Our results suggest that the two techniques used in this study evaluate separate aspects of telomerase function and their combination provides powerful prognostic information in lung cancer patients.

Adult↗