مجال
التميز
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تميز دراسي وبحثي
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البحوث المنشورة
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البحث (1):
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عنوان البحث:
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A key genomic subtype associated
with lymphovascular invasion in invasive breast cancer
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تاريخ النشر:
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22/05/2019
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موجز عن البحث:
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Background Lymphovascular
invasion (LVI) is associated with the development of metastasis in invasive
breast cancer (BC). However, the complex molecular mechanisms of LVI, which
overlap with other oncogenic pathways, remain unclear. This study, using
available large transcriptomic datasets, aims to identify genes associated
with LVI in early-stage BC patients.
MethodsGene
expression data from the Molecular Taxonomy of Breast Cancer International
Consortium (METABRIC) cohort (n = 1565) was used as a discovery
dataset, and The Cancer Genome Atlas (TCGA; n = 854) cohort was
used as a validation dataset. Key genes were identified on the basis of
differential mRNA expression with respect to LVI status as characterised by
histological review. The relationships among LVI-associated genomic subtype,
clinicopathological features and patient outcomes were explored.
Results A
99-gene set was identified that demonstrated significantly different
expression between LVI-positive and LVI-negative cases. Clustering analysis
with this gene set further divided cases into two molecular subtypes
(subtypes 1 and 2), which were significantly associated with
pathology-determined LVI status in both cohorts. The 10-year overall survival
of subtype 2 was significantly worse than that of subtype 1.
Conclusion This
study demonstrates that LVI in BC is associated with a specific
transcriptomic profile with potential prognostic value.
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البحث (2):
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عنوان البحث:
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Utility of ankyrin
3 as a prognostic marker in androgen-receptor-positive breast cancer
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تاريخ النشر:
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02/04/2019
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موجز عن البحث:
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Purpose
Androgen receptor (AR) and AR signaling
pathways are thought to play a role in breast cancer (BC) and are potentially
related to treatment responses and outcomes. Ankyrin 3 (ANK3) is associated
with AR stability in cancer cells. In the present study, we investigated the
clinicopathological utility of ANK3 expression with emphasis on AR and its
associated signalling pathway at transcriptomic and proteomic phases.
Patients
and methods
The Molecular Taxonomy of Breast Cancer
International Consortium (METABRIC) cohort (n = 1980) and The Cancer Genome
Atlas (TCGA) dataset (n = 1039) were used to assess the expression and
significance of ANK3 mRNA and other AR signalling pathway-associated
gene signature. Using immunohistochemistry, ANK3 protein expression was
evaluated in large (n = 982) cohort of early-stage BC with long-term
follow-up and compared with clinicopathological characteristics and its
prognostic value in the whole cohort and the subgroups stratified by AR
protein expression.
Results
An AR-related gene signature was developed,
comprising 20 genes, which included ANK3. This AR-related gene signature
was significantly associated with AR mRNA expression, oestrogen
receptor, human epidermal growth factor receptor 2 (HER2) status and the
patients’ outcomes. In tumours with high AR protein expression (n = 614),
high ANK3 protein expression was significantly associated with progesterone
receptor positivity and it was independently associated with the good
outcomes (p = 0.025).
Conclusions
This study indicates that ANK3 is related
to AR signalling pathway and is associated with BC prognosis.
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البحث (3):
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عنوان البحث:
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Saccharomyces
cerevisiae-like 1 (SEC14L1) is a prognostic factor in breast cancer
associated with lymphovascular invasion
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تاريخ النشر:
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28/06/2018
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موجز عن البحث:
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Lymphovascular invasion is strongly related
to breast cancer metastasis. However, the underlying mechanisms of
lymphovascular invasion and its driver molecules in breast cancer remain to
be defined. In this study, we explore differential expression of genes in
large molecularly characterized and clinically annotated datasets of invasive
breast cancer patients (n = 8056) coupled with histological review and strict
definition for lymphovascular invasion status. The METABRIC series was used
to identify genes associated with lymphovascular invasion, as defined using
hematoxylin and eosin staining supplemented by immunohistochemistry, at the
genomic/transcriptomic levels. Saccharomyces cerevisiae-like 1 (SEC14L1) was
identified as one of the most significant genes associated with
lymphovascular invasion. The prognostic significance of SEC14L1 gene copy
number and mRNA expression was further investigated in the METABRIC series
and externally validated using the Breast Cancer Gene-Expression Miner v4.0.
Protein expression of SEC14L1 was also assessed using immunohistochemistry in
series of early stage breast cancer using tissue microarrays. SEC14L1 gene
copy number gain was significantly associated with high histological grade
and poor outcome. SEC14L1 mRNA expression showed positive association with
higher grade, lymph node metastasis, and poor outcome. SEC14L1 protein
overexpression was significantly associated with lymphovascular invasion
(p < 0.0001), higher grade (p = 0.011), HER2 positivity (p = 0.036), and
shorter survival (p = 0.00075). Our findings specify SEC14L1 as an
independent prognostic factor in breast cancer. Its association, at both
transcriptome and protein expression levels, with lymphovascular invasion and
outcome could imply an important role in tumor progression. A further
mechanistic insight into its molecular roles including potential therapeutic
utility is warranted.
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البحث (4):
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عنوان البحث:
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Clinicopathological
and prognostic significance of Ras association and pleckstrin homology
domains 1 (RAPH1) in breast cancer
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رابط إلى البحث:
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تاريخ النشر:
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28/07/2018
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موجز عن البحث:
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Background
Ras association and pleckstrin homology
domains 1 (RAPH1) is involved in cytoskeleton regulation and
re-epithelialisation in invasive carcinoma and, therefore, may play a key
role in carcinogenesis and metastasis. We, herein, investigated the
biological and clinical significance of RAPH1 in breast cancer using large
annotated cohorts.
Methods
The clinicopathological and prognostic
significance of RAPH1 was assessed at the genomic and
transcriptomic levels using The Cancer Genome Atlas (TCGA) dataset (n = 1039)
and the results were validated using the Molecular taxonomy of breast cancer
international consortium (METABRIC) cohort (n = 1980). RAPH1 protein
expression was evaluated by immunohistochemistry in a large,
well-characterised cohort of early-stage breast cancer (n = 1040).
Results
In both the TCGA and METABRIC
cohorts, RAPH1 mRNA expression and RAPH1 copy number
alteration were strongly correlated. RAPH1 mRNA overexpression was
significantly correlated with high expression of adhesion and EMT markers
including CDH1, TGFβ1 and CD44. RAPH1mRNA overexpression was a
significant predictor of a poor prognosis (Hazard ratio
3.88; p = 0.049). High RAPH1 protein expression was associated with
higher grade tumours with high proliferation index, triple negative phenotype
and high E-cadherin expression. High RAPH1 protein expression was an
independent predictor of shorter survival (Hazard ratio
4.37; p = 0.037).
Conclusions
High RAPH1 expression is correlated with
aggressive breast cancer phenotypes and provides independent prognostic value
in invasive breast cancer.
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البحث (5):
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عنوان البحث:
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Mediator complex (MED) 7: a biomarker
associated with good prognosis in invasive breast cancer, especially ER+
luminal subtypes
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رابط إلى البحث:
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تاريخ النشر:
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28/03/2018
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موجز عن البحث:
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Background
Mediator complex (MED) proteins have a key
role in transcriptional regulation, some interacting with the oestrogen
receptor (ER). Interrogation of the METABRIC cohort suggested that MED7 may
regulate lymphovascular invasion (LVI). Thus MED7 expression was assessed in
large breast cancer (BC) cohorts to determine clinicopathological
significance.
Methods
MED7 gene expression was investigated in
the METABRIC cohort (n = 1980) and externally validated using bc-GenExMiner
v4.0. Immunohistochemical expression was assessed in the Nottingham primary
BC series (n = 1280). Associations with clinicopathological variables and
patient outcome were evaluated.
Results
High MED7 mRNA and protein expression was
associated with good prognostic factors: low grade, smaller tumour size, good
NPI, positive hormone receptor status (p < 0.001), and negative LVI
(p = 0.04) status. Higher MED7 protein expression was associated with
improved BC-specific survival within the whole cohort and ER+/luminal
subgroup. Pooled MED7 gene expression data in the external validation cohort
confirmed association with better survival, corroborating with the protein
expression. On multivariate analysis, MED7 protein was independently
predictive of longer BC-specific survival in the whole cohort and Luminal A
subtype (p < 0.001).
Conclusions
MED7 is an important prognostic marker in
BC, particularly in ER+luminal subtypes, associated with improved survival
and warrants future functional analysis.
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البحث (6):
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عنوان البحث:
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Clinical and
biological roles of Kelch-like family member 7 in breast cancer: a marker of
poor prognosis
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رابط إلى البحث:
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تاريخ النشر:
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09/04/2018
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موجز عن البحث:
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Background
The functions of many proteins are tightly
regulated with a complex array of cellular functions including
ubiquitination. In cancer cells, aberrant ubiquitination may promote the
activity of oncogenic pathways with subsequent tumour progression. Kelch-like
family member 7 (KLHL7) is involved in the regulation of ubiquitination and
may play a role in breast cancer (BC). Present study aims to evaluate the
biological and clinical usefulness of KLHL7 in BC utilising large
well-characterised cohorts with long-term follow-up.
Methods
The relationships
between KLHL7 gene copy number alteration (CNA) and mRNA expression
and clinicopathological variables and clinical outcomes were evaluated in
1980 patients from the METABRIC BC cohort. Prognostic significance of KLHL7
mRNA was validated using the Breast Cancer Gene-Expression Miner v4.0
datasets (n = 5206). KLHL7 protein expression was assessed using
immunohistochemistry in a large annotated series of early-stage BC (n = 917)
with long-term follow-up.
Results
KLHL7 CNA was significantly correlated
with its mRNA expression. KLHL7 mRNA expression was higher in
luminal B and basal-like molecular subtypes and in higher grade tumours.
Increased KLHL7 protein expression was significantly correlated with features
of aggressive phenotype including lymphovascular invasion, high histological
grade, hormonal receptor negativity, high PIK3CA and p53 expression. Outcome
analysis showed that high KLHL7 expression is an independent predictor of
shorter survival (p = 0.0011).
Conclusions
KLHL7 appears to play an important role in
BC progression. High KLHL7 protein expression identified a subgroup of BC
with aggressive behaviour and provided independent prognostic information.
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البحث (7):
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عنوان البحث:
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Chemokine (C‐C motif)
receptor 7 (CCR7) associates with the tumour immune microenvironment but not
progression in invasive breast carcinoma
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تاريخ النشر:
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28/01/2017
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موجز عن البحث:
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Some previous studies have reported that
the chemokine (C‐C motif) receptor 7 (CCR7) plays a role in
breast cancer, is associated with lymph node metastasis and drives the site
of distant metastasis. However, the impact of its expression on patient
outcome and its association with tumour infiltrating inflammatory cells
remain to be validated. We evaluated CCR7 protein expression by
immunohistochemistry in a large well characterized cohort (n = 866) of
early invasive primary breast cancers. CCR7 was expressed in the cytoplasm
and membrane of tumour cells. We observed a weak positive association of high
CCR7 expression when in either cellular component, but not both together,
with axillary lymph node stage 3 tumours (p = 0.043). Logistic regression
analysis of lymph node stage revealed no independent predictive value for
CCR7 expression. CCR7 expression was higher in HER2 positive tumours (p = 0.03)
and associated with positive CD68+ FOXP3+ tumour infiltrating cells. CCR7
staining was negatively associated with CD3+ cells. There was no significant
association of CCR7 expression with breast cancer recurrence or survival. We
conclude that while CCR7 is not a useful biomarker for predicting lymph node
metastasis, it may reflect altered intra‐ and inter‐cellular
signalling related to the immune microenvironment. The subcellular
localization of CCR7 appears to affect the nature of these interactions.
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البحث (8):
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عنوان البحث:
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Rho-GTPase activating-protein
18: a biomarker associated with good prognosis in invasive breast cancer
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رابط إلى البحث:
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تاريخ النشر:
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22 /08/2017
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موجز عن البحث:
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Background:
The prognostic value of lymphovascular
invasion (LVI) in breast cancer (BC) has been demonstrated in several
independent studies. However, identification of driver molecules for LVI
remains a challenging task. Large-scale transcriptomic profiling of histologically
validated LVI can potentially identify genes that regulate LVI.
Methods:
Integrative bio-informatics analyses of the
METABRIC study were performed utilising a subset of strictly defined LVI
using histological and immunohistochemical (IHC) criteria. ARHGAP18 was
among the top differentially expressed genes between LVI+ and LVI− BC with a
1.8-fold change. The prognostic impact of ARHGAP18 gene expression
was assessed in the METABRIC data set (n=1980) and externally validated using
the online BC gene expression data sets utilising bc-GenExMiner v4.0
(n=2016). Subsequently, ARHGAP18 protein expression was assessed on a large
cohort of invasive BC (n=959) with long-term follow-up using IHC.
Results:
Pooled analysis of ARHGAP18 mRNA
expression showed that overexpression was associated with better outcome
(P<0.001, hazard ratio (HR)=0.82, 95% CI 0.75–0.90). ARHGAP18 protein was
expressed in the cytoplasm and nuclei of the tumour cells and its expression
was positively associated with good prognostic variables. Lack of cytoplasmic
expression showed associations with LVI (P=0.006), epithelial-mesenchymal
transition and the HER+ subtype (P=0.01). Loss of nuclear expression was
associated with higher grade, HER2+ and high Ki67LI (P=0.001). Cytoplasmic
and nuclear expression showed a positive association with improved survival
independent of other variables (P=0.01, HR=0.74, 95% CI 0.60–87).
Conclusions:
ARHGAP18 expression at transcriptomic and
protein levels is associated with improved patients’ outcomes whose deregulation
may play a role in tumour progression and the development of LVI in BC.
Further assessment of its potential therapeutic value in BC is warranted.
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البحث (9):
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عنوان البحث:
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Further evidence to support
bimodality of oestrogen receptor expression in breast cancer
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رابط إلى البحث:
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تاريخ النشر:
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20/09/2016
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موجز عن البحث:
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Aims
Although oestrogen receptor (ER)‐negative
breast cancers (BCs) do not respond to hormone therapy, the response of ER‐positive
BCs is reported to be variable, which may suggest a dose‐dependent
effect. The aim of this study was to assess the pattern of ER expression in
BCs at the protein (immunohistochemistry) and transcriptome (microarray‐based
gene expression) levels.
Methods
and results
ER immunohistochemical (IHC) expression was
assessed in a large series of BCs, including 3649 core biopsies and 1892
cases prepared as tissue microarrays (TMAs) stained with specific
antibodies. ESR1 mRNA expression was assessed in the METABRIC study
(1980 cases), by the use of the Linear Models for Microarray Data (limma)
software, and the results were compared with protein levels. IHC data
confirmed the bimodality of ER expression, with 92.2% and 89.2% of the cases
showing completely negative (<1%) or highly positive (≥70%) expression on
the cores and TMAs, respectively. Weakly positive cases (1–10%) and
intermediately positive (11–69%) cases were infrequent (2.7% and 5.1%, and
1.6% and 9.2%, in cores and TMAs, respectively), and did not show survival
difference from ER‐negative tumours. When full‐face
sections of the corresponding excision specimens were immunostained, 47% of
the ER‐low/intermediate
group were deemed to be ER‐negative. Transcriptomic data
not only showed a significant correlation between ESR1 mRNA and protein expression levels, but
also confirmed the bimodality of ER expression at the mRNA level.
Conclusions
Our study provides further evidence that ER
expression is bimodal, and that it is observed at both the mRNA and protein
levels. The reported poor survival of BC patients with low ER expression in
the early clinical trials may be related to the inclusion of ER‐negative
cases.
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البحث (10):
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عنوان البحث:
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Ki67 expression in
invasive breast cancer: the use of tissue microarrays compared with whole
tissue sections
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رابط إلى البحث:
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تاريخ النشر:
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06/05/2017
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موجز عن البحث:
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Background
Although the prognostic value of Ki67 in
breast cancer is well documented, using optimal cut-points for patient
stratification, reproducibility of the scoring and interpretation of the
results remains a matter of debate particularly when using tissue microarrays
(TMAs). This study aims to assess Ki67 expression assessed on TMAs and their
matched whole tissue sections (WTS). Moreover, whether the cut-off used for
WTS is reproducible on TMA in BC molecular classes and the association
between Ki67 expression cut-off, assessed on TMAs and WTS, and
clinicopathological parameters and patient outcome were tested.
Method
A large series (n = 707) of
primary invasive breast tumours were immunostained for Ki67 using both TMA
and WTS and assessed as percentage staining and correlated with each other,
clinicopathological parameters and patient outcome. In
addition, MKI67 mRNA expression was correlated with Ki67 protein
levels on WTS and TMAs in a subset of cases included in the METABRIC study.
Results
There was moderate concordance in Ki67
expression between WTS and TMA when analysed as a continuous variable
(Intraclass correlation coefficient = 0.61) and low concordance
when dichotomised (kappa value = 0.3). TMA showed low levels of
Ki67 with mean percentage of expression of 35 and 22% on WTS and TMA,
respectively. MKI67 mRNA expression was significantly correlated
with protein expression determined on WTS (Spearman
Correlation, r = 0.52) and to a lesser extent on TMA
(r = 0.34) (p < 0.001). Regarding prediction of
patient outcome, statistically significant differences were detected upon
stratification of patients with tumours expressing Ki67 at 10, 15, 20, 25 or
30% in TMA. Using TMA, ≥20% Ki67 provided the best prognostic cut-off
particularly in triple-negative and HER2-positive classes.
Conclusion
Ki67 expression in breast cancer can be
evaluated using TMA although different cut-points are required to emulate
results from WTS. A cut-off of ≥20% for Ki67 expression in BC provides
the best prognostic correlations when TMAs are used.
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البحث (11):
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عنوان البحث:
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Molecular Mechanisms Underlying
Lymphovascular Invasion in Invasive Breast Cancer
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تاريخ النشر:
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31/08/2015
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موجز عن البحث:
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Lymphovascular invasion (LVI), the presence
of malignant cells within lymphovascular channels, is a crucial step in the
invasion-metastasis cascade. LVI, when identified morphologically in the
peritumoural area, is regarded as an indicator of metastatic potential and is
strongly associated with a poor prognosis in many solid tumours, including
breast cancer (BC). Although molecular mechanisms associated with the
development of LVI have been extensively studied, details of driver genes,
and molecular pathways and mechanisms involved in its development in BC,
remain poorly defined. Although invasive BC cells have the ability to invade
surrounding stroma, only those that can interact with endothelial cells,
penetrate the vascular wall and withstand the intravascular stress will
develop LVI and complete metastatic dissemination. Identification of
additional molecular events associated with LVI in the primary tumour and
characterisation of the contribution of the tumour micro-environment to
modulating biological processes leading to LVI in BC remain a challenging
task. This stems not only from the complexity of the molecular alterations in
the primary tumour and the interactions with different components of its
micro-environment but also from the subjective nature of LVI assessment in
human BC. In this review, we discuss the clinicopathological features and the
current knowledge of the molecular mechanisms underlying LVI in BC.
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المؤتمرات العلمية:
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المؤتمر (1):
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عنوان المؤتمر:
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207th Scientific Meeting of the Pathological Society of Great
Britain & Ireland
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تاريخ الإنعقاد:
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19/01/2017
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مكان
الإنعقاد:
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London, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Lympho-Vascular Invasion (LVI)
Supervised Transcriptomic Study Disclosed Clusters of Genes with Significant
Prognostic Importance in Invasive Breast Carcinoma Poster
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ملخص المشاركة:
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Introduction:
Defining the particular molecular mechanism of LVI in BC is challenging. In
this study, we have inspected the transcriptomic data of differentially
expressed genes along with their corresponding gene copy number alterations
(CNA) in METABRIC breast cancer (BC) cohort.
Methods:
Precisely defined subcategories of BC cases with definite (LVI+/-) status
were derived from METABRIC BC cohort (n=1980) using morphological assessment
and Immunohistochemistry, (n=172). Profiles of mRNA expression and CNA for
each probe were generated by utilising Illumina Bead-Array microarray
technology. Statistical analysis of gene expression data was performed using
Linear Model for Microarray (LIMMA) software package, and SPSS for
descriptive and bivariate statistics. Optimisation of Immunohistochemistry
(IHC) protocol for selected targets is currently underway.
Results: The
total valid probes with mRNA and CNA data was (n= 24,368). Probes with
perfect matching sequence to reverse strand, statistically significant with
LVI+/-, positive Log-Fc and average expression values were exclusively
selected, (n=273). Then, the probes were divided into two lists according to
LVI status (upregulated when LVI+, n= 20) and (upregulated when LVI-, n= 22).
Promising results were initiated by the upregulated SEC14L1, which
demonstrates positive association with LVI+ (p-value < 0.004), CN gains
(p-value < 0.000), lymph node stage (p-value < 0.000), tumour size
(p-value < 0.002), tumour grade (p-value < 0.000), and BC-specific
survival (p-value < 0.000).
Conclusions: The
results obtained from this study encourage the concept of LVI is driven by
several genes and redundant pathways. Further integrated functional studies
are essential to decipher the molecular mechanisms of LVI.
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المؤتمر (2):
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عنوان المؤتمر:
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9th Joint Meeting of the British Division of the International
Academy of Pathology and the Pathological Society of Great Britain &
Ireland
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تاريخ الإنعقاد:
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28/06/2016
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مكان
الإنعقاد:
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Nottingham, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Clinicopathological Impact of
C-C Chemokine Receptor Type 7 (CCR7) Protein Expression in Triple Negative
Breast Carcinoma (TNBC)
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ملخص المشاركة:
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Purpose of the Study:
Chemoattractants are potent regulatory mediators in numerous malignancies,
including invasive breast cancer (BC). C-C chemokine receptor type 7 (CCR7)
is a transmembrane protein normally expressed in lymphoid tissues regulating
the targeted migration of lymphocytes to the lymph nodes. However, its
aberrant expression in BC may promote the site-specific metastasis. This
study investigated the clinicopathological interactions of CCR7 protein
expression in tripe-negative breast carcinoma (TNBC).
Methods:
Immunohistochemistry for CCR7 protein expression was conducted on tissue
microarray (TMA) sections of a well-characterised series of TNBC (n=139).
Statistical analysis was performed engaging robust archival
clinicopathological data.
Summary of Results: CCR7
protein expression in TNBC was positively identified in cytoplasm (50.4%) and
cell membrane (51.8%). High CCR7 expression was associated with a younger age
at diagnosis (61.4%; p=0.009), premenopausal status (59.5%; p=0.022), and
negative nodal status (59.8%; p=0.004). Lung distant metastasis was also
correlated significantly with the cytoplasmic positive expression of CCR7
(76.9%; p=0.047). On the other hand, positive membranous expression of CCR7
was associated with higher occurrence of liver distant metastasis (75.0%;
p=0.045).
Conclusions: CCR7
protein expression in TNBC may be associated with visceral metastasis in
invasive BC. This preferential site-specific metastatic tropism in TNBC is
possibly attributed to the subcellular localisation of CCR7 expression.
Further molecular and functional studies are warranted to decipher the
biological roles of CCR7 in TNBC.
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الرابط:
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المؤتمر (3):
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عنوان المؤتمر:
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9th Joint Meeting of the British Division of the International
Academy of Pathology and the Pathological Society of Great Britain &
Ireland
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تاريخ الإنعقاد:
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28/06/2016
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مكان
الإنعقاد:
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Nottingham, UK
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طبيعة المشاركة:
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Oral presentation
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عنوان المشاركة:
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Multiple Coagulation Factor
Deficiency Protein-2 (MCFD2) as a Potential Prognostic Germ Cell Marker in
Invasive Breast Carcinoma: a Transcriptome-Driven Study
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ملخص المشاركة:
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Purpose of the Study:
Genes driving the development of lymphovascular invasion (LVI) in breast
cancer (BC) remain unknown. In this study we attempted to validate at the
protein level differentially expressed genes correlated with LVI in BC and
examined associations with clinicopathological and molecular features.
Methods: Subgroups
of positive and negative LVI status were identified in subsets of the
METABRIC BC cohort using morphology and immunohistochemistry (IHC D2-40). A
differential transcriptomic profile correlating with LVI status in both
subgroups was identified from microarray data analysis, (LVI+, n= 91) and
(LVI–, n= 83). The copy number aberration (CNA) gain ratio was calculated for
each transcript in both subgroups. IHC protocols were implemented in a large
series of invasive BCs (n= 1282). Clinicopathological and molecular
significance of MCFD2 expression was determined statistically.
Summary of Results:
Multiple coagulation factor deficiency-2 (MCFD2) ranked first in CNA gain
ratio, (score = 4.56). IHC demonstrated that MFCD2 is expressed in the
cytoplasm of invasive tumour cells. Low cytoplasmic expression of MFCD2 was
found to be significantly associated with increased risk of development of
regional recurrence, (p = 0.021). High cytoplasmic expression of MFCD2 showed
a significant positive correlation with the p53 coactivator TADA3 (p=0.039)
but negative association with the growth factor TFF1 (p=0.007). No
significant association between protein expression and LVI could be
identified in our cohort.
Conclusions: The
results obtained endorse that the higher cytoplasmic expression levels of
MCFD2 is correlated with good prognosis and better outcomes in invasive BC
but does
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الرابط:
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المؤتمر (4):
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عنوان المؤتمر:
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9th Joint Meeting of the British Division of the International
Academy of Pathology and the Pathological Society of Great Britain &
Ireland
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تاريخ الإنعقاد:
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28/06/2016
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مكان
الإنعقاد:
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Nottingham, UK
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طبيعة المشاركة:
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Oral presentation
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عنوان المشاركة:
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Vesicular Transporter Proteins
in Invasive Breast Cancer: Clinicopathological Relevance of
Synaptosomal-Associated Protein-23 (SNAP23)
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ملخص المشاركة:
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Purpose of the Study:
Vesicular transportation and efficient focal exocytosis of proteins are
essential for progression and metastasis of invasive breast cancer (BC). In
our search for genes driving lymphovascular invasion (LVI) in BC utilising
the well-characterised METABRIC cohort, Synaptosomal-associated protein-23
(SNAP23), a member of the SNARE protein family, was revealed as an important
differentially expressed gene correlated with LVI status.
Methods: To
further validate the role of SNAP23 in BC, the cytoplasmic (CP) and
membranous (MB) expression levels of SNAP23 was assessed
immunohistochemically on a large annotated series of BC (n= 1240).
Summary of Results:
Protein expression of SNAP23 was observed in the membrane (57.3%) and
cytoplasm (33.7%) of invasive tumour cells. SNAP23-MB expression was
associated with site-specific distant metastasis, namely to the pleura
(75.9%;p < 0.041). Also, SNAP23-MB was positively correlated with the
BRCA1-associated RING domain protein BARD1 (58.8%;p < 0.027) while the
expression of SNAP23-CP was negatively associated with the
Metastasis-associated protein MTA1(62.5%;p < 0.022). No significant
association between SNAP23 and LVI was identified at the protein level.
Conclusions:
SNAP23 may mediate pathways of the invasion-metastasis cascade and could
potentially govern the tropism of metastatic BC cells to specific distal
organs. Though not directly correlated with LVI at the protein level in spite
of correlations at the transcriptome level, it may be an important passenger
in the complex molecular cascade controlling metastatic mechanisms
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الرابط:
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المؤتمر (5):
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عنوان المؤتمر:
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9th Joint Meeting of the British Division of the International
Academy of Pathology and the Pathological Society of Great Britain &
Ireland
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تاريخ الإنعقاد:
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28/06/2016
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مكان
الإنعقاد:
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Nottingham, UK
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طبيعة المشاركة:
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Oral presentation
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عنوان المشاركة:
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Ankyrin 3 Protein may Influence
DNA-Damage Response Pathways and the Immune Response in Invasive Breast
Carcinoma
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ملخص المشاركة:
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Purpose of the Study:
Ankyrin3 (ANK3), extensively studied in neuronal signalling, is a member of
the adapter protein family maintaining the plasma membrane scaffold in
epithelial cells through interactions with E-Cadherin. It has been implicated
in colorectal carcinogenesis [BMC Genomics. 2011 Oct 14; 12:505] and bladder
tumour recurrence [Oncotarget, 2016 Jan 19; 7(3): 2629]. However, its role in
breast cancer (BC) remains unknown. This study investigated the protein
expression of ANK3 in BC and correlations with clinicopathological variables.
Methods:
Immunohistochemistry procedure was applied on tissue microarray (TMA)
sections of well-characterised series of BC (n=1234). Statistical analysis
was performed for clinicopathological correlations and associations with
other biomarkers.
Summary of Results: The
expression of ANK3 protein was cytoplasmic; with the majority of cases
(67.6%) showing high expression levels. Significant positive associations
were identified with DNA-damage response markers including p53 (p=0.029),
CHK1 (p=0.01), PARP1 (p=0.001), BARD1 (p=0.001), Ku70/Ku80 (p= 0.034). In
terms of immune-related markers, high ANK3 expression was positively
associated with B lymphocyte marker, CD20 (p=0.036) and T lineage regulator
FOXP3 (p=0.005). No direct associations were observed between ANK3 and
clinico-pathological parameters. Conclusions: ANK3 protein in BC
interacts with DNA damage response pathways including p53 suggesting a role
for membrane scaffold proteins during DNA damage repair. The positive
association of CD20/FOXP3 and ANK3 expression potentially mirrors the complex
partnership on immune system regulation by novel signalling proteins like
ANK3. Further functional characterisation will unravel the pathobiology of
ANK3 in BC
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الرابط:
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المؤتمر (6):
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عنوان المؤتمر:
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9th Joint Meeting of the British Division of the International
Academy of Pathology and the Pathological Society of Great Britain &
Ireland
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تاريخ الإنعقاد:
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28/06/2016
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مكان
الإنعقاد:
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Nottingham, UK
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طبيعة المشاركة:
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Oral presentation
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عنوان المشاركة:
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Expression of CUL4A in invasive
Breast Cancer: a Biomarker of Good Prognosis Related to Tumour
Differentiation
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ملخص المشاركة:
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Purpose of the Study: The
contribution of cellular proteins that modulate biological processes leading
to disease progression remain as challenging task. Cullin-4a (CUL4A) is a
ligase playing a critical role in the ubiquitination pathway. The covalent
binding of ubiquitin to target proteins is a major post-translational process
that alters their functions and thus regulates a diverse array of cellular
processes including the degradation of DNA damage-response proteins,
chromatin regulation, and cell cycle regulation.
Methods:
CUL4A expression was assessed in a large clinically annotated cohort (n=988)
of invasive BC with long-term follow-up using IHC and TMA. The Cancer Genome
Atlas (TCGA) and bc-GenExMiner v3.2 were used for validation. Summary of
Results: CUL4A showed cytoplasmic and nuclear expression where
over-expression showed significant association with lower grade (p<0.001)
, less mitotic figures (p<0.001) more tubule formation (p<0.001),
histological types of excellent/good prognosis (p<0.001) good NPI
prognostic subgroup (p=0.01), negative LVI (p=0.023), ER+ (p<0.001), PR+
(p<0.001), HER2- (p=0.003) and luminal-A subtype (p<0.001), and DNA
damage response proteins [BRCA1/2, PARP-1, BARD1, Rad51, ATM, ART, and CHEK1.
High expression of CUL4A was significantly associated with an improved
survival (p<0.001) and time to distant metastasis (p=0.04), independent of
tumour size, stage and grade. CUL4A showed 3.41% CNA and/or mutations in the
TCGA dataset with non-significant impact of these derangements on outcome.
Although pooled CUL4A mRNA data (n=3925) showed non-significant association
with outcome, over-expression was significantly associated with better
outcome in 4 datasets, and with worse outcome in 3 datasets. Conclusions:
Our results identified the scaffold protein CUL4A as a biomarker of good
prognostic impact in BC. Its expression pattern alludes to a role in tumour
differentiation; findings worthy of further investigation.
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الرابط:
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المؤتمر (7):
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عنوان المؤتمر:
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9th Joint Meeting of the British Division of the International
Academy of Pathology and the Pathological Society of Great Britain &
Ireland
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تاريخ الإنعقاد:
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28/06/2016
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مكان
الإنعقاد:
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Nottingham, UK
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طبيعة المشاركة:
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Oral presentation
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عنوان المشاركة:
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Further Evidence to Support that
Oestrogen Receptor Expression in Breast Cancer is Bimodal
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ملخص المشاركة:
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Purpose of the Study:
Although oestrogen receptor (ER)-negative breast cancers (BC) do not respond
to hormone therapy, the response of ER-positive BC is reported to be variable
which may suggest a dose dependent effect. This study aimed to assess the
pattern of ER-expression at the protein (IHC) and transcriptome
(microarray-based gene expression) levels.
Methods: ER
IHC expression was assessed on a large series of BC including 3649 core
biopsies and 1887cases prepared as TMA stained using different but recent
more sensitive detection systems. ESR1 mRNA expression was assessed on the
METABRIC study (1980 cases). The gene expression data was analysed by Linear
Models for Microarray Data (LIMMA) and results were compared with protein
levels.
Results:
Bimodality of ER IHC expression was evident on our series with 92.2% and
89.2% of the cases showed completely negative (0%) or highly positive (≥70%)
expression on the cores and TMA respectively. While weak positive cases
(1-10%) and intermediate-expression (11%–69%) cases were infrequent (2.7%
& 5.1% and 1.6% & 9.2% respectively). Interestingly, re-staining
full-face sections of the low and intermediate groups revealed the large
majority often related to the negative or strongly positive classes. The
METABRIC data not only showed significant correlation between ESR1 mRNA and
protein expression but also confirmed the bimodality of ER at the mRNA
levels.
Conclusion: Our
study provides further evidence that ER expression is essentially bimodal and
that this bimodality is observed at both mRNA and protein levels. The
reported poor survival of BC patients with low ER-expression in the early
clinical trials may be related to the inclusion of ER-negative cases.
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الرابط:
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المؤتمر (8):
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عنوان المؤتمر:
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9th Joint Meeting of the British Division of the International
Academy of Pathology and the Pathological Society of Great Britain &
Ireland
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تاريخ الإنعقاد:
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28/06/2016
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مكان
الإنعقاد:
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Nottingham, UK
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طبيعة المشاركة:
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Poster presentation
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عنوان المشاركة:
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Rho-GTPase Activating-protein 18
(ARHGAP18): A Biomarker Associated with Lymphovascular Invasion in Invasive
Breast Cancer
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ملخص المشاركة:
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Purpose of the Study:
Although lymphovascular invasion (LVI) is recognised as a crucial early step
in metastatic cascade and breast cancer (BC) mortality, driver molecular
pathways and potential therapeutic targets associated with LVI remain
lacking. This stems from complexity of the process as well as limitations of
study designs and power. We hypothesised that large-scale genomic and
transcriptomic profiling of histologically validated LVI can potentially
identify LVI-driver genes.
Methods:
Integrative bio-informatics analysis of gene expression and copy number
aberration (CNA) data was applied to identify key LVI-associated genes in
strictly selected two subsets of the METABRIC study. LVI status of these
cases has been validated histologically and immunohistochemically. ARHGAP18
showed significant CNA fold change between LVI+ and LVI- cases. ARHGAP18 was
assessed in a large cohort of BC with long-term follow-up using IHC and TMA.
The prognostic impact of ARHGAP18 gene expression was externally validated
within the online BC gene expression datasets using bc-GenExMiner v3.0.
Summary of Results:
Cytoplasmic expression of ARHGAP18 showed significant association with LVI,
the Nottingham Prognostic Index, and luminal subtype. Nuclear over-expression
was associated with lower grade, better NPI, histological types of
excellent/good prognosis, HER2-, low Ki67 and luminal subtype. Cytoplasmic
and nuclear expression showed significant association with longer BC survival
and distant-recurrence free survival; p<0.05), ), independent of other
factors. Using External validation cohorts (n=2,016), high ARHGAP18 mRNA
expression showed significant association with longer DMFS (p<0.001,
HR=0.82, 95% CI 0.75-0.90).
Conclusions:
ARHGAP18 is associated with improved outcome in BC at CNA, gene expression,
and protein levels. The association with LVI warrants further validation both
in functional and prospective studies to have clearer insight into its exact
roles in this complex process.
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الرابط:
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المؤتمر (9):
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عنوان المؤتمر:
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8th Joint
Meeting of the British Division of the International Academy of Pathology and
the Pathological Society of Great Britain & Ireland
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تاريخ الإنعقاد:
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23-25/06/2015
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مكان
الإنعقاد:
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Dublin, Republic of Ireland
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طبيعة المشاركة:
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Oral presentation
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عنوان المشاركة:
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Exploring Molecular Mechanisms
Underlying Lymphovascular Invasion in Breast Cancer
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ملخص المشاركة:
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Purpose of the study:
Lymphovascular Invasion (LVI) is a crucial step in the metastatic cascade in
breast cancer (BC) and is associated with poor prognosis. This study
investigated the molecular mechanisms associated with LVI interrogating
subsets of the METABRIC series.
Methods:
Histological/ immunohistochemistry (D2-40) supplemented LVI were determined
in subsets of the METABRIC BC cohort. Cases were stratified into LVI+ and
LVI- subgroups. Genes correlating with LVI status were identified in both
test (n=179) and validation (n=356) sets from expression profiles using
Linear Models for Microarray (LIMMA) data analyses. Biological functions of
differentially expressed genes and relevant pathways were explored on
multiple platforms.
Summary of results:
Initial analysis identified 34362 genes differentially expressed between LVI
subgroups. 915 (adjusted p<0.05) overlapping transcripts were identified
from test and validation sets, some of which have not been previously linked
with LVI. Examples of overlapping genes include APPL1, AQR, CD46, CUL4A,
MCFD2, PAPOLA, POT1, RANBP2, SNX4, SUMO1, TLK1, ZNF181/644, SNAP23 etc.
Biological function/pathway analysis reveals clusters regulating invasion,
transcription, immuneregulation, protein binding and catalytic functions. For
example, the proteolysis related SUMO pathway was enriched in both subsets.
Conclusions:
Global expression profiling combined with robust histopathological
characterisation provides a useful platform to decipher molecular pathways
relevant to LVI. Further identification of driver genes associated with LVI
is underway combining RNA expression with corresponding copy number
alterations, followed by functional analysis.
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الرابط:
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Click here
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المؤتمر (10):
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عنوان المؤتمر:
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Cancer and Stem Cells (CASC)
Divisional Meeting
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تاريخ الإنعقاد:
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02/05/2017
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مكان
الإنعقاد:
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Nottingham, UK
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طبيعة المشاركة:
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Oral &Poster presentation
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عنوان المشاركة:
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Loss of MCFD2 expression in
breast cancer is associated with lymphovascular invasion and poor outcome
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ملخص المشاركة:
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Introduction: The
mechanisms underlying lymphovascular invasion (LVI) in breast cancer (BC)
remains unclear. In this study, LVI-supervised approach was applied to
well-characterised series of BC to assess genes associated with LVI at the
global transcriptomic level. MCFD2 was identified among the LVI-related
differentially expressed genes. The clinicopathological and prognostic
significance of MCFD2 was investigated in a large series of BC using
Immunohistochemistry (IHC) on tissue microarrays (TMA).
Materials & Methods:
LVI status was strictly defined in a subset of the METABRIC cohort, (n=174),
using H&E stained and IHC (CD34 and D2-40) stained sections. Genes
differentially expressed with LVI was determined through analysing gene
expression in the test and validation sets. MCFD2 was further investigated in
two large cohorts of BC at the level of mRNA (n=1980), and protein expression
(n=1282). Associations with clinicopathological variables, a large panel of
related proteins and patient outcome were evaluated.
Results: Loss
of MCFD2 transcription was associated with LVI (p=0.003), and shorter
survival (OS) (p=0.029). At the protein level, loss of MCFD2 expression
was associated with LVI (p=0.001), higher tumour grade (p<5.73×10-13),
larger tumour size (p=0.021), and poor Nottingham Prognostic Index (NPI),
(p<5.65×10-7). It was also associated with loss of estrogen receptor (ER)
(p<4×10-6), triple-negative phenotype (p<6×10-6) and HER2 positivity
(p<0.021). Moreover, loss of MCFD2 was associated with epithelial mesenchymal
transition with reduced expression of E-cadherin, (p<1.60×10-7), and
overexpression of N-cadherin, (p<0.012). Patient with negative MCFD2
expression showed shorter BC specific survival (p<0.002) with frequent
recurrence (p<0.003) including distant metastasis
(p<0.023).
Conclusion: Our
study identifies MCFD2 as an important prognostic marker in BC associated
with LVI and outcome. Studying differentially expressed genes in strictly
defined subgroups is a promising approach to unravel the complexity of LVI
mechanisms in BC, and to identify potential therapeutic targets.
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