9 research outputs found
Molecular alterations in key-regulator genes among patients with T4 breast carcinoma
Background: Prognostic factors in patients who are diagnosed with T4 breast carcinomas are widely awaited. We
here evaluated the clinical role of some molecular alterations involved in tumorigenesis in a well-characterized
cohort of T4 breast cancer patients with a long follow-up period.
Methods: A consecutive series of 53 patients with T4 breast carcinoma was enrolled between 1992 and 2001 in
Sardinia, and observed up for a median of 125 months. Archival paraffin-embedded tissue sections were used for
immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses, in order to assess alterations in expression levels of survivin, p53, and pERK1-2 proteins as well as in amplification of CyclinD1 and h-prune genes.
The Kaplan-Meier and Cox regression methods were used for survival assessment and statistical analysis.
Results: Overall, patients carrying increased expression of pERK1-2 (p = 0.027) and survivin (p = 0.008) proteins as
well as amplification of h-prune gene (p = 0.045) presented a statistically-significant poorer overall survival in comparison with cases found negative for such alterations. After multivariate analysis, the pathological response to primary chemotherapy and the survivin overexpression in primary carcinoma represented the main parameters with a role as independent prognostic factors in our series.
Conclusions: Although retrospective, our study identified some molecular parameters with a significant impact on prediction of the response to therapy or prognosis among T4 breast cancer patients. Further large prospective studies are needed in order to validate the use of such markers for the management of these patients
Activating PIK3CA mutations coexist with BRAF or NRAS mutations in a limited fraction of melanomas
Background: Activated PI3K-AKT pathway may contribute to decrease sensitivity to inhibitors of key pathogenetic effectors (mutated BRAF, active NRAS or MEK) in melanoma. Functional alterations are deeply involved in PI3K-AKT activation, with a minimal role reported for mutations in PIK3CA, the catalytic subunit of the PI3K gene. We here assessed the prevalence of the coexistence of BRAF/NRAS and PIK3CA mutations in a series of melanoma samples. Methods: A total of 245 tumor specimens (212 primary melanomas and 33 melanoma cell lines) was screened for mutations in BRAF, NRAS, and PIK3CA genes by automated direct sequencing. Results: Overall, 110 (44.9%) samples carried mutations in BRAF, 26 (10.6%) in NRAS, and 24 (9.8%) in PIK3CA. All identified PIK3CA mutations have been reported to induce PI3K activation; those detected in cultured melanomas were investigated for their interference with the antiproliferative activity of the BRAF-mutant inhibitor vemurafenib. A reduced suppression in cell growth was observed in treated cells carrying both BRAF and PIK3CA mutations as compared with those presenting a mutated BRAF only. Among the analysed melanomas, 12/245 (4.9%) samples presented the coexistence of PIK3CA and BRAF/NRAS mutations. Conclusions: Our study further suggests that PIK3CA mutations account for a small fraction of PI3K pathway activation and have a limited impact in interfering with the BRAF/NRAS-driven growth in melanoma
Les livres nouveaux : Ouvrages signalés - Analyses
Abstract
Background: Alterations in key-regulator genes of disease pathogenesis (BRAF, cKIT, CyclinD1) have been evaluated
in patients with multiple primary melanoma (MPM).
Methods: One hundred twelve MPM patients (96 cases with two primary melanomas, 15 with three, and 1 with
four) were included into the study. Paired synchronous/asynchronous MPM tissues (N = 229) were analyzed for BRAF
mutations and cKIT/CyclynD1 gene amplifications.
Results: BRAF mutations were identified in 109/229 (48%) primary melanomas, whereas cKIT and CyclinD1
amplifications were observed in 10/216 (5%) and 29/214 (14%) tumor tissues, respectively. While frequency rates of
BRAF mutations were quite identical across the different MPM lesions, a significant increase of cKIT (p < 0.001) and
CyclinD1 (p = 0.002) amplification rates was observed between first and subsequent primary melanomas. Among
the 107 patients with paired melanoma samples, 53 (49.5%) presented consistent alteration patterns between first
and subsequent primary tumors. About one third (40/122; 32.8%) of subsequent melanomas presented a discrepant
pattern of BRAF mutations as compared to incident primary tumors.
Conclusions: The low consistency in somatic mutation patterns among MPM lesions from same patients provides
further evidence that melanomagenesis is heterogeneous and different cell types may be involved. This may have
implications in clinical practice due to the difficulties in molecularly classifying patients with discrepant primary
melanomas