29 research outputs found
A Malignant Gastrointestinal Stromal Tumor of the Gallbladder Immunoreactive for PDGFRA and Negative for CD 117 Antigen (c-KIT)
Gastrointestinal stromal tumors (GISTs) compose the largest category of well-recognized nonepithelial neoplasms of the gastrointestinal tract (GI). GISTs of the gallbladder are extremely rare tumors. Only four malignant, two benign and one GIST-like tumor of the gall bladder have ever been described. The four malignant GISTs were all positive for CD 117 antigen (c-kit). We present for the first time a malignant gastrointestinal stromal tumor of the gallbladder, immunoreactive for platelet-derived growth factor receptor alpha (PDGFRA) and negative for CD 117 antigen (c-KIT)
ERK/pERK expression and B-raf mutations in colon adenocarcinomas: correlation with clinicopathological characteristics
Clinical significance of AGE-RAGE axis in colorectal cancer: associations with glyoxalase-I, adiponectin receptor expression and prognosis
P53 immunoexpression as a prognostic marker for human astrocytomas:a meta-analysis and review of the literature
Resistance to Fas-Mediated Apoptosis Does Not Correlate to Structural Alterations or Expression Changes of the Death Receptor in Papillary Thyroid Carcinomas
An update on molecular alterations in melanocytic tumors with emphasis on Spitzoid lesions
Significant progress in the molecular pathology of melanocytic tumors
have revealed that benign neoplasms, so-called nevi, are initiated by
gain-of-function mutations in one of several primary oncogenes, such as
BRAF in acquired melanocytic nevi, NRAS in congenital nevi or GNAQ/GNA11
in blue nevi, with consequent MAPK and PI3K/AKT/mTOR activation.
Secondary genetic alterations overcome tumor suppressive mechanisms and
allow the progression to intermediate lesions characterized by TERT-p
mutation or to invasive melanomas displaying disruption of tumor
suppressor genes. Currently, melanoma is molecularly regarded as four
different diseases, namely BRAF, NRAS, NF1 and the “triple wild
type” subtypes, which are associated with particular
clinicopathological features. Melanocytic Spitzoid lesions include
benign Spitz nevus, atypical Spitz tumor (AST) and Spitzoid melanoma.
This is a challenging diagnostic group, particularly with regard to the
distinction between AST and Spitzoid melanoma on clinical and
histological grounds. Molecular analysis has identified the presence of
HRAS mutation, BAP1 loss (often accompanying by BRAF mutations) or
several kinase fusions in distinct categories of Spitz tumors. These
aberrations account for the rapid growth characteristic of Spitz nevi.
Subsequent growth is halted by various tumor suppressive mechanisms
abrogation of which allow the development of AST, now better classified
as low-grade melanocytic tumor. Although at present ancillary genetic
techniques have not been very helpful in the prediction of biological
behavior of AST, they have defined distinct tumor subsets differing with
regard to biology and histology. Finally, we discuss how novel molecular
markers may assist the differential diagnosis of melanoma, particularly
from malignant peripheral nerve sheath tumor (MPNST). It is anticipated
that the significant progress in the field of molecular pathology
regarding the various types of melanocytic tumors, will eventually
contribute to a more accurate histologic categorization, prediction of
biologic behavior and personalized treatment
mRNA coexpression patterns of Wnt pathway components and their clinicopathological associations in breast and colorectal cancer
Aberrant Wnt signaling is implicated in carcinogenesis triggering
efforts for the development of new therapeutic agents, many of which
have entered clinical trials. We extend our previous analysis of WNT3,
FZD7, LEFI expression levels in breast and colorectal cancer including
WNT2, FZD4 and beta-catenin expression, in an effort to delineate their
relative expression levels along with concurrent expression patterns and
possible prognostic value. We analyzed 82 breast and 102 colorectal
carcinomas for relative mRNA expression levels of the investigated genes
by RT-PCR relative quantification with the Delta Delta Ct method.
Statistical analysis was performed in order to determine associations of
relative mRNA expression and linear correlations. beta-catenin
expression was determined by immunochemistry. Regarding breast
carcinomas, decreased relative mRNA expression levels of WNT2, FZD4 were
found frequently and WNT2 expression was correlated with ER/ PR status
(p = 0.045/p = 0.028), whereas beta-catenin with grade (p = 0.026). In
colorectal carcinomas, increased relative mRNA expression levels of WNT2
and FZD4 were found in 59% and 32% of cases respectively, whereas
beta-catenin showed decreased mRNA expression levels in 57% of cases
and a correlation with pN-category (p = 0.037). Linear correlations were
observed between WNT2/FZD4 (R=0.542, p < 0.001), WNT2/beta-catenin
(R=0.254, p = 0.010), FZD4/beta-catenin (R=0.406, p < 0.001) expression
and a correlation between mRNA expression and membranous/cytoplasmic
beta-catenin emerged (p = 0.039/0.046). Our results suggest a possible
clinical significance for Wnt pathway gene expression levels in both
tumour types. The concurrent expression of the investigated genes as
well as the different expression profiles, underlines the complexity of
this pathway and the necessity of patient selection in order to maximize
the efficacy of drugs targeting Wnt pathway
Comprehensive Molecular Analysis of NSCLC; Clinicopathological Associations
Background
Selection of NSCLC patients for targeted therapy is currently based upon
the presence of sensitizing mutations in EGFR and EML4/ALK
translocations. The heterogeneity of molecular alterations in lung
cancer has led to the ongoing discovery of potential biomarkers and
targets in order to improve survival.
Aim
This study aimed to detect alterations in EGFR, KRAS, BRAF, PIK3CA,
MET-gene copy number and ALK rearrangements in a large cohort of 956
NSCLC patients of Hellenic origin using highly sensitive techniques and
correlations with clinicopathological characteristics.
Results
Mutations were detected in EGFR 10.6%(101 out of 956 samples), KRAS
26.5% (191 out of 720 samples), BRAF 2.5% (12 out of 471 samples),
PIK3CA 3.8% (7 out of 184 samples), MET gene amplification was detected
in 18% (31 out of 170) and ALK rearrangements in 3.7% (4 out of 107
samples). EGFR mutations were detected in exon 19 (61.4% of mutant
cases), exon 21 p.Leu858Arg (19.8%), exon 20 (15.8%), exon 18 (2.9%)
and were correlated with gender histology, smoking status and TTF1
staining. p.Thr790Met mutant cases (3.9%) displayed concurrent
mutations in exons 19 or 21. Negative TTF-1 staining showed strong
negative predictive value for the presence of EGFR mutations. KRAS
mutations were associated with histology, the most common mutation being
p.Gly12Cys (38%).
Discussion
In conclusion, only 89 patients were eligible for EGFR-TKIs and ALK
inhibitors therapy, whereas 257 patients showed other alterations,
highlighting the necessity for a detailed molecular profiling
potentially leading to more efficient individualized therapies for NSCLC
patients
Comprehensive Molecular Analysis of NSCLC; Clinicopathological Associations.
Selection of NSCLC patients for targeted therapy is currently based upon the presence of sensitizing mutations in EGFR and EML4/ALK translocations. The heterogeneity of molecular alterations in lung cancer has led to the ongoing discovery of potential biomarkers and targets in order to improve survival.This study aimed to detect alterations in EGFR, KRAS, BRAF, PIK3CA, MET-gene copy number and ALK rearrangements in a large cohort of 956 NSCLC patients of Hellenic origin using highly sensitive techniques and correlations with clinicopathological characteristics.Mutations were detected in EGFR 10.6% (101 out of 956 samples), KRAS 26.5% (191 out of 720 samples), BRAF 2.5% (12 out of 471 samples), PIK3CA 3.8% (7 out of 184 samples), MET gene amplification was detected in 18% (31 out of 170) and ALK rearrangements in 3.7% (4 out of 107 samples). EGFR mutations were detected in exon 19 (61.4% of mutant cases), exon 21 p.Leu858Arg (19.8%), exon 20 (15.8%), exon 18 (2.9%) and were correlated with gender histology, smoking status and TTF1 staining. p.Thr790Met mutant cases (3.9%) displayed concurrent mutations in exons 19 or 21. Negative TTF-1 staining showed strong negative predictive value for the presence of EGFR mutations. KRAS mutations were associated with histology, the most common mutation being p.Gly12Cys (38%).In conclusion, only 89 patients were eligible for EGFR -TKIs and ALK inhibitors therapy, whereas 257 patients showed other alterations, highlighting the necessity for a detailed molecular profiling potentially leading to more efficient individualized therapies for NSCLC patients
A detailed immunohistochemical analysis of the PI3K/AKT/mTOR pathway in lung cancer: Correlation with PIK3CA, AKT1, K-RAS or PTEN mutational status and clinicopathological features
The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene
homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is
upregulated in a number of human cancers, including non-small cell lung
cancer (NSCLC). Its potential role in NSCLC progression provides an
attractive target for anticancer therapy. The expression of
phosphorylated mTOR (p-mTOR), phosphorylated AKT (p-AKT), p85 alpha and
p110 gamma subunits of PI3K, phosphorylated p70S6K (p-p70S6K),
phosphatase and tensin homolog (PTEN) and phosphorylated 4E-BP1
(p-4E-BP1) was examined by immunohistochemistry in 102 NSCLC specimens.
The results were correlated with clinicopathological features. We also
examined 61 of our cases for the presence of PIK3CA, AKT1, PTEN and
K-RAS mutations. A common PIK3CA mutation was detected at exon 9 in 2
samples (p.E545K), whereas another sample displayed a rare mutation
(p.D1018N). Furthermore, 10 out of 54 cases (18.5%) had a K-RAS
mutation at codon 12, 5 had a PTEN mutation (exons 7 and 8) and 1 case
had an AKT1 mutation (p.E17K). PTEN mutations were associated with nodal
metastases. The expression of p-mTOR positively correlated with that of
p-AKT and p-p70S6K and was higher in adenocarcinomas along with nuclear
p110 gamma PI3K expression, whereas p-4E-BP1 expression was higher in
squamous cell carcinomas. We also established a positive association
between p85 alpha PI3K or p110 gamma PI3K and cytoplasmic p-AKT and its
downstream effectors. An inverse correlation was noted between p-4E-BP1
immunoexpression and tumour status and nuclear p-AKT expression as
regards tumour stage. Univariate survival analysis demonstrated that
p-4E-BP1 expression, either alone or in combination with cytoplasmic
p-AKT expression had an adverse prognostic significance in
adenocarcinomas. The combination of p-4E-BP1 and cytoplasmic p-AKT
expression remained significant in the multivariate analysis as a
function of their interaction with histological type. Our data
demonstrate the significance of p-4E-BP1 immunoexpression as a molecular
marker of prognostic value in adenocarcinomas, particularly when
combined with p-AKT