27 research outputs found
K-ras, p53 mutations, and microsatellite instability (MSI) in gallbladder cancer
Despite the considerable progress in understanding the molecular
pathology of carcinogenesis, the genetic mechanisms underlying the
development and progression of gallbladder cancer (GC) are poorly
understood. The survival of GC patients is generally poor. Therefore, it
is very useful to define valuable prognostic factors. The most
extensively studied oncogenes in gallbladder carcinogenesis are ras,
commonly mutated in neoplasms of the gastrointestinal tract. K-ras
oncogene is altered in a subset of gallbladder patients and mainly in
those having anomalous junction of the pancreaticobiliary tract. Most of
the studies of genetic abnormalities in GC have focused on p53 gene. p53
mutation/overexpression and/or LOH is present in more than 50% of
gallbladder carcinomas, suggesting an important role in their
pathogenesis. However, these results have not any predictive value yet.
Moreover, the involvement of an alternative molecular pathway, that of
microsatellite instability (MSI), is found in a limited group of GC
patients. Additional research is necessary to establish its possible
relation to defects of the mismatch repair (MMR) system and its proposed
prognostic significance. Further elucidation of the molecular events
specific to GC will help to identify novel molecular targets for the
diagnosis and clinical management of the patients
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