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1.
J Pathol Inform ; 15: 100369, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38638195

ABSTRACT

The most widely accepted and used type of digital pathology (DP) is whole-slide imaging (WSI). The USFDA granted two WSI system approvals for primary diagnosis, the first in 2017. In Latin America, DP has the potential to reshape healthcare by enhancing diagnostic capabilities through artificial intelligence (AI) and standardizing pathology reports. Yet, we must tackle regulatory hurdles, training, resource availability, and unique challenges to the region. Collectively addressing these hurdles can enable the region to harness DP's advantages-enhancing disease diagnosis, medical research, and healthcare accessibility for its population. Americas Health Foundation assembled a panel of Latin American pathologists who are experts in DP to assess the hurdles to implementing it into pathologists' workflows in the region and provide recommendations for overcoming them. Some key steps recommended include creating a Latin American Society of Digital Pathology to provide continuing education, developing AI models trained on the Latin American population, establishing national regulatory frameworks for protecting the data, and standardizing formats for DP images to ensure that pathologists can collaborate and validate specimens across the various DP platforms.

2.
Cancers (Basel) ; 16(3)2024 Feb 05.
Article in English | MEDLINE | ID: mdl-38339430

ABSTRACT

Gastric cancer (GC) remains a formidable global health challenge, ranking among the top-five causes of cancer-related deaths worldwide. The majority of patients face advanced stages at diagnosis, with a mere 6% five-year survival rate. First-line treatment for metastatic GC typically involves a fluoropyrimidine and platinum agent combination; yet, predictive molecular markers have proven elusive. This review navigates the evolving landscape of GC biomarkers, with a specific focus on Claudin 18.2 (CLDN18.2) as an emerging and promising target. Recent phase III trials have unveiled the efficacy of Zolbetuximab, a CLDN18.2-targeting antibody, in combination with oxaliplatin-based chemotherapy for CLDN18.2-positive metastatic GC. As this novel therapeutic avenue unfolds, understanding the nuanced decision making regarding the selection of anti-CLDN18.2 therapies over other targeted agents in metastatic GC becomes crucial. This manuscript reviews the evolving role of CLDN18.2 as a biomarker in GC and explores the current status of CLDN18.2-targeting agents in clinical development. The aim is to provide concise insights into the potential of CLDN18.2 as a therapeutic target and guide future clinical decisions in the management of metastatic GC.

3.
Case Rep Oncol ; 16(1): 504-510, 2023.
Article in English | MEDLINE | ID: mdl-37469678

ABSTRACT

MUTYH-associated polyposis syndrome is an uncommon, autosomal recessive colorectal polyposis syndrome caused by biallelic inactivation of MUTYH. Most patients present with multiple colorectal polyps. However, other primary tumor sites have been described as less frequent. In this report, we describe the case of a young patient with a germline biallelic pathogenic MUTYH mutation with three different primary tumors. We focused on a metastatic gastric adenocarcinoma that presented with complete bowel obstruction secondary to extensive peritoneal carcinomatosis and achieved complete response upon treatment with immunotherapy. The patient's tumor presented with a high tumor mutational burden and a 100% combined positive score, which certainly contributed to the complete response to immunotherapy. To date, no studies have described the association of MUTYH-related tumors with high PD-L1 expression, but we hypothesized that it may be linked to the increased antigenicity of these cancers.

4.
J Pathol ; 254(2): 147-158, 2021 06.
Article in English | MEDLINE | ID: mdl-33904171

ABSTRACT

Artificial intelligence (AI)-based systems applied to histopathology whole-slide images have the potential to improve patient care through mitigation of challenges posed by diagnostic variability, histopathology caseload, and shortage of pathologists. We sought to define the performance of an AI-based automated prostate cancer detection system, Paige Prostate, when applied to independent real-world data. The algorithm was employed to classify slides into two categories: benign (no further review needed) or suspicious (additional histologic and/or immunohistochemical analysis required). We assessed the sensitivity, specificity, positive predictive values (PPVs), and negative predictive values (NPVs) of a local pathologist, two central pathologists, and Paige Prostate in the diagnosis of 600 transrectal ultrasound-guided prostate needle core biopsy regions ('part-specimens') from 100 consecutive patients, and to ascertain the impact of Paige Prostate on diagnostic accuracy and efficiency. Paige Prostate displayed high sensitivity (0.99; CI 0.96-1.0), NPV (1.0; CI 0.98-1.0), and specificity (0.93; CI 0.90-0.96) at the part-specimen level. At the patient level, Paige Prostate displayed optimal sensitivity (1.0; CI 0.93-1.0) and NPV (1.0; CI 0.91-1.0) at a specificity of 0.78 (CI 0.64-0.89). The 27 part-specimens considered by Paige Prostate as suspicious, whose final diagnosis was benign, were found to comprise atrophy (n = 14), atrophy and apical prostate tissue (n = 1), apical/benign prostate tissue (n = 9), adenosis (n = 2), and post-atrophic hyperplasia (n = 1). Paige Prostate resulted in the identification of four additional patients whose diagnoses were upgraded from benign/suspicious to malignant. Additionally, this AI-based test provided an estimated 65.5% reduction of the diagnostic time for the material analyzed. Given its optimal sensitivity and NPV, Paige Prostate has the potential to be employed for the automated identification of patients whose histologic slides could forgo full histopathologic review. In addition to providing incremental improvements in diagnostic accuracy and efficiency, this AI-based system identified patients whose prostate cancers were not initially diagnosed by three experienced histopathologists. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Subject(s)
Artificial Intelligence , Prostatic Neoplasms/diagnosis , Aged , Aged, 80 and over , Biopsy , Biopsy, Large-Core Needle , Humans , Machine Learning , Male , Middle Aged , Pathologists , Prostate/pathology , Prostatic Neoplasms/pathology
5.
Clin Case Rep ; 8(12): 2725-2731, 2020 Dec.
Article in English | MEDLINE | ID: mdl-33363813

ABSTRACT

Breast cancer metastasis to the stomach is rare; invasive lobular carcinoma has a predilection to spread to the gastrointestinal system and is morphologically similar to primary diffuse gastric carcinoma. This case highlights heterogeneous metastatic progression and that documentation of heterogeneity is important for informing future treatment strategies and prognostication.

6.
J Pathol ; 244(4): 460-468, 2018 04.
Article in English | MEDLINE | ID: mdl-29344954

ABSTRACT

Mixed ductal-lobular carcinomas (MDLs) show both ductal and lobular morphology, and constitute an archetypal example of intratumoural morphological heterogeneity. The mechanisms underlying the coexistence of these different morphological entities are poorly understood, although theories include that these components either represent 'collision' of independent tumours or evolve from a common ancestor. We performed comprehensive clinicopathological analysis of a cohort of 82 MDLs, and found that: (1) MDLs more frequently coexist with ductal carcinoma in situ (DCIS) than with lobular carcinoma in situ (LCIS); (2) the E-cadherin-catenin complex was normal in the ductal component in 77.6% of tumours; and (3) in the lobular component, E-cadherin was almost always aberrantly located in the cytoplasm, in contrast to invasive lobular carcinoma (ILC), where E-cadherin is typically absent. Comparative genomic hybridization and multiregion whole exome sequencing of four representative cases revealed that all morphologically distinct components within an individual case were clonally related. The mutations identified varied between cases; those associated with a common clonal ancestry included BRCA2, TBX3, and TP53, whereas those associated with clonal divergence included CDH1 and ESR1. Together, these data support a model in which separate morphological components of MDLs arise from a common ancestor, and lobular morphology can arise via a ductal pathway of tumour progression. In MDLs that present with LCIS and DCIS, the clonal divergence probably occurs early, and is frequently associated with complete loss of E-cadherin expression, as in ILC, whereas, in the majority of MDLs, which present with DCIS but not LCIS, direct clonal divergence from the ductal to the lobular phenotype occurs late in tumour evolution, and is associated with aberrant expression of E-cadherin. The mechanisms driving the phenotypic change may involve E-cadherin-catenin complex deregulation, but are yet to be fully elucidated, as there is significant intertumoural heterogeneity, and each case may have a unique molecular mechanism. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Subject(s)
Breast Carcinoma In Situ/pathology , Breast Neoplasms/pathology , Carcinoma, Intraductal, Noninfiltrating/pathology , Neoplasms, Complex and Mixed/pathology , Adult , Aged , Aged, 80 and over , Antigens, CD/analysis , Antigens, CD/genetics , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Breast Carcinoma In Situ/chemistry , Breast Carcinoma In Situ/genetics , Breast Neoplasms/chemistry , Breast Neoplasms/genetics , Cadherins/analysis , Cadherins/genetics , Carcinoma, Intraductal, Noninfiltrating/chemistry , Carcinoma, Intraductal, Noninfiltrating/genetics , Comparative Genomic Hybridization , DNA Mutational Analysis , Disease Progression , Female , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Middle Aged , Mutation , Neoplasms, Complex and Mixed/chemistry , Neoplasms, Complex and Mixed/genetics , Phenotype , Exome Sequencing
7.
Sci Rep ; 6: 25505, 2016 05 05.
Article in English | MEDLINE | ID: mdl-27148852

ABSTRACT

Regulation of Ca(2+) transport is vital in physiological processes, including lactation, proliferation and apoptosis. The plasmalemmal Ca(2+) pump isoform 2 (PMCA2) a calcium ion efflux pump, was the first protein identified to be crucial in the transport of Ca(2+) ions into milk during lactation in mice. In these studies we show that PMCA2 is also expressed in human epithelia undergoing lactational remodeling and also report strong PMCA2 staining on apical membranes of luminal epithelia in approximately 9% of human breast cancers we assessed. Membrane protein expression was not significantly associated with grade or hormone receptor status. However, PMCA2 mRNA levels were enriched in Basal breast cancers where it was positively correlated with survival. Silencing of PMCA2 reduced MDA-MB-231 breast cancer cell proliferation, whereas silencing of the related isoforms PMCA1 and PMCA4 had no effect. PMCA2 silencing also sensitized MDA-MB-231 cells to the cytotoxic agent doxorubicin. Targeting PMCA2 alone or in combination with cytotoxic therapy may be worthy of investigation as a therapeutic strategy in breast cancer. PMCA2 mRNA levels are also a potential tool in identifying poor responders to therapy in women with Basal breast cancer.


Subject(s)
Breast Neoplasms/genetics , Calcium/metabolism , Carcinoma, Basal Cell/genetics , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic , Plasma Membrane Calcium-Transporting ATPases/genetics , Antibiotics, Antineoplastic/pharmacology , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Calcium Signaling , Carcinoma, Basal Cell/drug therapy , Carcinoma, Basal Cell/mortality , Carcinoma, Basal Cell/pathology , Cell Line, Tumor , Cell Membrane/drug effects , Cell Membrane/enzymology , Cell Membrane/pathology , Cell Proliferation , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Doxorubicin/pharmacology , Epithelial Cells/enzymology , Epithelial Cells/pathology , Female , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Isoenzymes/metabolism , Lactation/physiology , Mammary Glands, Human/enzymology , Mammary Glands, Human/pathology , Plasma Membrane Calcium-Transporting ATPases/antagonists & inhibitors , Plasma Membrane Calcium-Transporting ATPases/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Survival Analysis
8.
Am J Hum Genet ; 98(5): 830-842, 2016 05 05.
Article in English | MEDLINE | ID: mdl-27087319

ABSTRACT

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.


Subject(s)
Adenocarcinoma/genetics , Adenomatous Polyposis Coli Protein/genetics , Adenomatous Polyposis Coli/genetics , Adenomatous Polyps/genetics , Exons/genetics , Point Mutation/genetics , Stomach Neoplasms/genetics , Allelic Imbalance/genetics , DNA Copy Number Variations/genetics , Exome/genetics , Female , Gastric Mucosa/metabolism , Genetic Linkage/genetics , High-Throughput Nucleotide Sequencing/methods , Humans , Loss of Heterozygosity , Male , Pedigree , Promoter Regions, Genetic/genetics
9.
J Pathol ; 238(4): 489-94, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26510554

ABSTRACT

Epithelial to mesenchymal transition (EMT) is a cellular phenotype switching phenomenon which occurs during normal development and is proposed to promote tumour cell invasive capabilities during tumour progression. Invasive lobular carcinoma (ILC) is a histological special type of breast cancer with a peculiar aetiology - the tumour cells display an invasive growth pattern, with detached, single cells or single files of cells, and a canonical feature is the loss of E-cadherin expression. These characteristics are indicative of an EMT or at the very least that they represent some plasticity between phenotypes. While some gene expression profiling data support this view, the tumour cells remain epithelial and limited immunohistochemistry data suggest that EMT markers may not feature prominently in ILC. We assessed the expression of a panel of EMT markers (fibronectin, vimentin, N-cadherin, smooth muscle actin, osteonectin, Snail, Twist) in 148 ILCs and performed a meta-analysis of publically available molecular data from 154 ILCs. Three out of 148 (2%) ILCs demonstrated an early and coordinated alteration of multiple EMT markers (down-regulation of E-cadherin, nuclear TWIST, and up-regulation of vimentin, osteonectin, and smooth muscle actin). However, the data overall do not support a role for EMT in defining the phenotypic peculiarities of the majority of ILCs. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Subject(s)
Breast Neoplasms/pathology , Carcinoma, Lobular , Epithelial Cells/pathology , Epithelial-Mesenchymal Transition/physiology , Biomarkers, Tumor/metabolism , Breast Neoplasms/metabolism , Cadherins/metabolism , Carcinoma, Lobular/genetics , Carcinoma, Lobular/metabolism , Cell Line, Tumor , Epithelial Cells/metabolism , Female , Humans , Immunohistochemistry/methods , Neoplasm Invasiveness , Phenotype , Transcription Factors/metabolism
10.
J Pathol ; 237(3): 363-78, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26172396

ABSTRACT

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.


Subject(s)
Biomarkers, Tumor/genetics , Brain Neoplasms/genetics , Brain Neoplasms/secondary , Gene Expression Profiling/methods , Genomics/methods , Biomarkers, Tumor/metabolism , Brain Neoplasms/drug therapy , Brain Neoplasms/enzymology , DNA Mutational Analysis , Enzyme Activation , Gene Amplification , Gene Dosage , Gene Expression Regulation, Neoplastic , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Immunohistochemistry , Ligands , Molecular Targeted Therapy , Mutation , Phenotype , Phosphorylation , Precision Medicine , Predictive Value of Tests , Protein Kinase Inhibitors/therapeutic use , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/genetics , Receptor, ErbB-3/metabolism , Receptor, ErbB-4/genetics , Receptor, ErbB-4/metabolism , Tumor Microenvironment
11.
Oncotarget ; 6(6): 3932-46, 2015 Feb 28.
Article in English | MEDLINE | ID: mdl-25668816

ABSTRACT

HER2-positive breast tumors are associated with a high risk of brain relapse. HER3 is thought to be an indispensible signaling substrate for HER2 (encoded by ERBB2) and is induced in breast cancer-brain metastases, though the molecular mechanisms by which this oncogenic dimer promotes the development of brain metastases are still elusive. We studied the effects of the HER3-HER2 ligand, heregulin (neuregulin-1, broadly expressed in the brain), on luminal breast cancer cell lines in vitro. Treatment of SKBr3 (ERBB2-amplified), MDA-MB-361 (ERBB2-amplified, metastatic brain tumor-derived) and MCF7 (HER2-positive, not ERBB2-amplified) cells with exogenous heregulin increased proliferation and adhesive potential, concomitant with induction of cyclin D1 and ICAM-1, and suppression of p27. All three cell lines invaded through matrigel toward a heregulin chemotactic signal in transwell experiments, associated with activation of extracellular cathepsin B and matrix metalloproteinase-9 (MMP-9). Moreover, heregulin induced breast cancer cell transmigration across a tight barrier of primary human brain microvascular endothelia. This was dependent on the activity of HER2, HER3 and MMPs, and was completely abrogated by combination HER2-HER3 blockade using Herceptin® and the humanized HER3 monoclonal antibody, EV20. Collectively these data suggest mechanisms by which the HER3-HER2 dimer promotes development of metastatic tumors in the heregulin-rich brain microenvironment.


Subject(s)
Blood-Brain Barrier/metabolism , Breast Neoplasms/pathology , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Neuregulin-1/metabolism , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/metabolism , Blood-Brain Barrier/enzymology , Blood-Brain Barrier/pathology , Brain/blood supply , Breast Neoplasms/enzymology , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Cell Line, Tumor , Cell Movement/physiology , Endothelial Cells/metabolism , Female , Humans , MCF-7 Cells , Signal Transduction
12.
Oncotarget ; 5(10): 3261-72, 2014 May 30.
Article in English | MEDLINE | ID: mdl-24811120

ABSTRACT

In contrast to extensive studies on familial breast cancer, it is currently unclear whether defects in DNA double strand break (DSB) repair genes play a role in sporadic breast cancer development and progression. We performed analysis of immunohistochemistry in an independent cohort of 235 were sporadic breast tumours. This analysis suggested that RAD51 expression is increased during breast cancer progression and metastasis and an oncogenic role for RAD51 when deregulated. Subsequent knockdown of RAD51 repressed cancer cell migration in vitro and reduced primary tumor growth in a syngeneic mouse model in vivo. Loss of RAD51 also inhibited associated metastasis not only in syngeneic mice but human xenografts and changed the metastatic gene expression profile of cancer cells, consistent with inhibition of distant metastasis. This demonstrates for the first time a new function of RAD51 that may underlie the proclivity of patients with RAD51 overexpression to develop distant metastasis. RAD51 is a potential biomarker and attractive drug target for metastatic triple negative breast cancer, with the capability to extend the survival of patients, which is less than 6 months.


Subject(s)
Rad51 Recombinase/genetics , Triple Negative Breast Neoplasms/genetics , Animals , Cell Line, Tumor , Female , Heterografts , Humans , Immunoblotting , Immunohistochemistry , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness/genetics , Neoplasm Metastasis , Oligonucleotide Array Sequence Analysis , Rad51 Recombinase/metabolism , Tissue Array Analysis , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology
13.
PLoS One ; 7(7): e40742, 2012.
Article in English | MEDLINE | ID: mdl-22815804

ABSTRACT

The protein tyrosine phosphatase receptor J, PTPRJ, is a tumor suppressor gene that has been implicated in a range of cancers, including breast cancer, yet little is known about its role in normal breast physiology or in mammary gland tumorigenesis. In this paper we show that PTPRJ mRNA is expressed in normal breast tissue and reduced in corresponding tumors. Meta-analysis revealed that the gene encoding PTPRJ is frequently lost in breast tumors and that low expression of the transcript associated with poorer overall survival at 20 years. Immunohistochemistry of PTPRJ protein in normal human breast tissue revealed a distinctive apical localisation in the luminal cells of alveoli and ducts. Qualitative analysis of a cohort of invasive ductal carcinomas revealed retention of normal apical PTPRJ localization where tubule formation was maintained but that tumors mostly exhibited diffuse cytoplasmic staining, indicating that dysregulation of localisation associated with loss of tissue architecture in tumorigenesis. The murine ortholog, Ptprj, exhibited a similar localisation in normal mammary gland, and was differentially regulated throughout lactational development, and in an in vitro model of mammary epithelial differentiation. Furthermore, ectopic expression of human PTPRJ in HC11 murine mammary epithelial cells inhibited dome formation. These data indicate that PTPRJ may regulate differentiation of normal mammary epithelia and that dysregulation of protein localisation may be associated with tumorigenesis.


Subject(s)
Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Epithelial Cells/enzymology , Mammary Glands, Animal/enzymology , Mammary Glands, Human/enzymology , Animals , Breast Neoplasms/genetics , Cell Differentiation/genetics , Cell Line, Tumor , Down-Regulation/genetics , Epithelial Cells/pathology , Epithelium/enzymology , Epithelium/pathology , Female , Gene Dosage/genetics , Gene Expression Regulation, Neoplastic , Genetic Loci/genetics , Humans , Introns/genetics , Mammary Glands, Animal/growth & development , Mammary Glands, Animal/pathology , Mammary Glands, Human/pathology , Mammary Neoplasms, Animal/enzymology , Mammary Neoplasms, Animal/genetics , Mammary Neoplasms, Animal/pathology , Meta-Analysis as Topic , Mice , Mice, Inbred C57BL , Pregnancy , RNA, Antisense/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor-Like Protein Tyrosine Phosphatases, Class 3/genetics , Receptor-Like Protein Tyrosine Phosphatases, Class 3/metabolism
14.
Mol Cancer Ther ; 11(10): 2158-68, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22807578

ABSTRACT

Calcium signaling is a critical regulator of cell proliferation. Elevated expression of calcium channels and pumps is a characteristic of some cancers, including breast cancer. We show that the plasma membrane calcium channel TRPV6, which is highly selective for Ca(2+), is overexpressed in some breast cancer cell lines. Silencing of TRPV6 expression in a breast cancer cell line with increased endogenous TRPV6 expression leads to a reduction in basal calcium influx and cellular proliferation associated with a reduction in DNA synthesis. TRPV6 gene amplification was identified as one mechanism of TRPV6 overexpression in a subset of breast cancer cell lines and breast tumor samples. Analysis of two independent microarray expression datasets from breast tumor samples showed that increased TRPV6 expression is a feature of estrogen receptor (ER)-negative breast tumors encompassing the basal-like molecular subtype, as well as HER2-positive tumors. Breast cancer patients with high TRPV6 levels had decreased survival compared with patients with low or intermediate TRPV6 expression. Our findings suggest that inhibitors of TRPV6 may offer a novel therapeutic strategy for the treatment of ER-negative breast cancers.


Subject(s)
Breast Neoplasms/metabolism , Calcium Channels/metabolism , Receptors, Estrogen/metabolism , TRPV Cation Channels/antagonists & inhibitors , TRPV Cation Channels/metabolism , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Calcium/metabolism , Calcium Channels/genetics , Cell Count , Cell Cycle , Cell Line, Tumor , Cell Movement , Cell Survival , Down-Regulation/genetics , Female , Gene Amplification/genetics , Gene Dosage/genetics , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Survival Analysis , TRPV Cation Channels/genetics
15.
Breast Cancer Res Treat ; 135(1): 153-65, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22718308

ABSTRACT

The progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) marks a critical step in the evolution of breast cancer. There is some evidence to suggest that dynamic interactions between the neoplastic cells and the tumour microenvironment play an important role. Using the whole-genome cDNA-mediated annealing, selection, extension and ligation assay (WG-DASL, Illumina), we performed gene expression profiling on 87 formalin-fixed paraffin-embedded (FFPE) samples from 17 patients consisting of matched IDC, DCIS and three types of stroma: IDC-S (<3 mm from IDC), DCIS-S (<3 mm from DCIS) and breast cancer associated-normal stroma (BC-NS; >10 mm from IDC or DCIS). Differential gene expression analysis was validated by quantitative real time-PCR, immunohistochemistry and immunofluorescence. The expression of several genes was down-regulated in stroma from cancer patients relative to normal stroma from reduction mammoplasties. In contrast, neoplastic epithelium underwent more gene expression changes during progression, including down regulation of SFRP1. In particular, we observed that molecules related to extracellular matrix (ECM) remodelling (e.g. COL11A1, COL5A2 and MMP13) were differentially expressed between DCIS and IDC. COL11A1 was overexpressed in IDC relative to DCIS and was expressed by both the epithelial and stromal compartments but was enriched in invading neoplastic epithelial cells. The contributions of both the epithelial and stromal compartments to the clinically important scenario of progression from DCIS to IDC. Gene expression profiles, we identified differential expression of genes related to ECM remodelling, and specifically the elevated expression of genes such as COL11A1, COL5A2 and MMP13 in epithelial cells of IDC. We propose that these expression changes could be involved in facilitating the transition from in situ disease to invasive cancer and may thus mark a critical point in disease development.


Subject(s)
Breast Neoplasms/genetics , Carcinoma, Ductal, Breast/genetics , Carcinoma, Intraductal, Noninfiltrating/genetics , Epithelial Cells/metabolism , Gene Expression Profiling , Stromal Cells/metabolism , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Carcinoma, Intraductal, Noninfiltrating/metabolism , Carcinoma, Intraductal, Noninfiltrating/pathology , Collagen Type V/biosynthesis , Collagen Type V/genetics , Collagen Type XI/biosynthesis , Collagen Type XI/genetics , Disease Progression , Extracellular Matrix/genetics , Female , Gene Expression Regulation, Neoplastic , Humans , Intercellular Signaling Peptides and Proteins/biosynthesis , Intercellular Signaling Peptides and Proteins/genetics , Matrix Metalloproteinase 13/biosynthesis , Matrix Metalloproteinase 13/genetics , Membrane Proteins/biosynthesis , Membrane Proteins/genetics , Tumor Microenvironment
16.
Breast Cancer Res ; 13(4): R73, 2011 Jul 25.
Article in English | MEDLINE | ID: mdl-21787400

ABSTRACT

INTRODUCTION: The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a significant role in the activation of cellular responses to DNA double-strand breaks through subsequent phosphorylation of central players in the DNA damage-response pathway. Recent studies have confirmed that some specific variants in the ATM gene are associated with increased breast cancer (BC) risk. However, the magnitude of risk and the subset of variants that are pathogenic for breast cancer remain unresolved. METHODS: To investigate the role of ATM in BC susceptibility, we studied 76 rare sequence variants in the ATM gene in a case-control family study of 2,570 cases of breast cancer and 1,448 controls. The variants were grouped into three categories based on their likely pathogenicity, as determined by in silico analysis and analyzed by conditional logistic regression. Likely pathogenic sequence variants were genotyped in 129 family members of 27 carrier probands (15 of which carried c.7271T > G), and modified segregation analysis was used to estimate the BC penetrance associated with these rare ATM variants. RESULTS: In the case-control analysis, we observed an odds ratio of 2.55 and 95% confidence interval (CI, 0.54 to 12.0) for the most likely deleterious variants. In the family-based analyses, the maximum-likelihood estimate of the increased risk associated with these variants was hazard ratio (HR) = 6.88 (95% CI, 2.33 to 20.3; P = 0.00008), corresponding to a 60% cumulative risk of BC by age 80 years. Analysis of loss of heterozygosity (LOH) in 18 breast tumors from women carrying likely pathogenic rare sequence variants revealed no consistent pattern of loss of the ATM variant. CONCLUSIONS: The risk estimates from this study suggest that women carrying the pathogenic variant, ATM c.7271T > G, or truncating mutations demonstrate a significantly increased risk of breast cancer with a penetrance that appears similar to that conferred by germline mutations in BRCA2.


Subject(s)
Breast Neoplasms/genetics , Cell Cycle Proteins/genetics , DNA-Binding Proteins/genetics , Genetic Predisposition to Disease , Protein Serine-Threonine Kinases/genetics , Tumor Suppressor Proteins/genetics , Ataxia Telangiectasia Mutated Proteins , Case-Control Studies , Female , Genetic Variation , Humans , Logistic Models , Loss of Heterozygosity , Middle Aged , Mutation, Missense , White People/genetics
17.
Endocr Pathol ; 22(2): 103-7, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21499728

ABSTRACT

We report a follicular carcinoma of thyroid that showed a range of histologic appearances, with microfollicular, macrofollicular/pseudopapillary, oncocytic, and poorly differentiated areas. We used comparative genomic hybridization to detect the major DNA copy number changes in each component, in order to study the inter-relationships among them. All showed gains in 11q and 17q, suggesting that these were early events in the development of the tumor, and these were the only changes in the follicular component. The other components each showed additional gains and losses, some unique to one component. The oncocytic component showed most changes, including loss on 16q in the region of the E-cadherin gene. This was associated with reduced intensity of immunostaining for E-cadherin specifically in that component. No mutations in the E-cadherin gene were detected in this component. The demonstration that some DNA copy number changes are consistent across each component suggests that they are all clonally related. The additional chromosomal and immunohistochemical heterogeneity across the macrofollicular/pseudopapillary, oncocytic, and poorly differentiated components would be consistent with the emergence of subclones, possibly as part of tumor progression.


Subject(s)
Adenocarcinoma, Follicular/secondary , Comparative Genomic Hybridization/methods , DNA Copy Number Variations/genetics , Gene Dosage , Thyroid Neoplasms/pathology , Adenocarcinoma, Follicular/genetics , Adenocarcinoma, Follicular/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cadherins/metabolism , Chromosomes, Human, Pair 16 , Disease Progression , Gene Expression Profiling , Humans , Male , Middle Aged , Sequence Analysis, DNA , Thyroid Neoplasms/genetics , Thyroid Neoplasms/metabolism
18.
Hum Mutat ; 32(6): 678-87, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21394826

ABSTRACT

Clinical management of breast cancer families is complicated by identification of BRCA1 and BRCA2 sequence alterations of unknown significance. Molecular assays evaluating the effect of intronic variants on native splicing can help determine their clinical relevance. Twenty-six intronic BRCA1/2 variants ranging from the consensus dinucleotides in the splice acceptor or donor to 53 nucleotides into the intron were identified in multiple-case families. The effect of the variants on splicing was assessed using HSF matrices, MaxEntScan and NNsplice, followed by analysis of mRNA from lymphoblastoid cell lines. A total of 12 variants were associated with splicing aberrations predicted to result in production of truncated proteins, including a variant located 12 nucleotides into the intron. The posterior probability of pathogenicity was estimated using a multifactorial likelihood approach, and provided a pathogenic or likely pathogenic classification for seven of the 12 spliceogenic variants. The apparent disparity between experimental evidence and the multifactorial predictions is likely due to several factors, including a paucity of likelihood information and a nonspecific prior probability applied for intronic variants outside the consensus dinucleotides. Development of prior probabilities of pathogenicity incorporating bioinformatic prediction of splicing aberrations should improve identification of functionally relevant variants and enhance multifactorial likelihood analysis of intronic variants.


Subject(s)
Alternative Splicing , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , Introns/genetics , Breast Neoplasms/pathology , Cell Line, Tumor , Computational Biology , Exons/genetics , Female , Genetic Variation , Humans , Mutation , RNA, Messenger/genetics
19.
Knee Surg Sports Traumatol Arthrosc ; 19(5): 811-5, 2011 May.
Article in English | MEDLINE | ID: mdl-21290117

ABSTRACT

PURPOSE: To evaluate whether clinical factors enable prediction of the diameter of hamstring tendons harvested for anterior cruciate ligament (ACL) reconstruction. METHODS: Eighty patients were submitted for reconstruction of the ACL with hamstring tendons in a quadruple manner. During surgery the diameter of the graft was measured. The variables analyzed were: age, gender, weight, height, operated side, dominant side, leg length, thigh length, thigh diameter, body mass index (BMI), and sports activity. The data was collected pre-operatively and correlated with the diameter of the graft. RESULTS: The diameter of the graft was strongly related to gender, height, leg length, thigh length, weight, and thigh diameter. Women presented significantly smaller graft diameter than men; as well as weight, height, leg length, and thigh length. Men with height equal to or greater than 1.80 m showed average graft diameter greater than the total group, and greater percentage of 9 mm grafts. CONCLUSION: The diameter of the hamstring graft is significantly associated to weight, height, leg length, thigh length, thigh diameter, and gender. The variable that had most influence was height, followed by gender and leg length. The variables BMI, age, sports activity, and dominant side did not present correlation. Tendon diameter was larger in men than in women. Men with a height equal to or greater than 1.80 m had a higher prevalence of 9 mm grafts and had a larger average tendon diameter. LEVEL OF EVIDENCE: Prospective cross sectional collection of data, Level IV.


Subject(s)
Anterior Cruciate Ligament/surgery , Plastic Surgery Procedures/methods , Tendon Transfer/methods , Adolescent , Adult , Age Factors , Arthroscopy , Body Height , Body Mass Index , Body Weight , Chi-Square Distribution , Cross-Sectional Studies , Female , Humans , Intraoperative Period , Linear Models , Male , Middle Aged , Prospective Studies , Sex Factors , Thigh/anatomy & histology , Treatment Outcome
20.
Genet Res Int ; 2011: 219189, 2011.
Article in English | MEDLINE | ID: mdl-22567347

ABSTRACT

Our knowledge of the biology underlying the development of brain metastases (BM) from breast cancer has improved over the last decade due to large clinical epidemiological studies, animal models of metastasis, and the use of high-resolution gene expression profiling technologies. However, there are still major gaps in our understanding of the mechanisms utilized by breast cancer cells to colonize the brain microenvironment, thus our arsenal of therapies remains relatively nonspecific, and the prognosis for breast cancer patients with BM remains poor. Additional insights into these mechanisms are necessary to facilitate the development of new preventive and curative therapeutic regimens to block this fatal disease. This paper aims to provide a general overview for the readers of what has been achieved in this field of research and its translation into clinical practice to date and to highlight exciting new areas of research that promise to inform the development of new targeted therapies for BM.

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