Surgery (Scholarly Articles)

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A mixed-methods study of the causes and impact of poor teamwork between junior doctors and nurses
(Oxford University Press (OUP), 2016-07-02) O'Connor, Paul; O'Dea, Angela; Lydon, Sinéad; Offiah, Gozie; Scott, Jennifer; Flannery, Antoinette; Lang, Bronagh; Hoban, Anthony; Armstrong, Catherine; Byrne, Dara; Health Services Executive; National Doctors Training and Planning
Objectives This study aimed to collect and analyse examples of poor teamwork between junior doctors and nurses; identify the teamwork failures contributing to poor team function; and ascertain if particular teamwork failures are associated with higher levels of risk to patients. Design Critical Incident Technique interviews were carried out with junior doctors and nurses. Setting Two teaching hospitals in the Republic of Ireland. Participants Junior doctors (n = 28) and nurses (n = 8) provided descriptions of scenarios of poor teamwork. The interviews were coded against a theoretical framework of healthcare team function by three psychologists and were also rated for risk to patients by four doctors and three nurses. Results A total of 33 of the scenarios met the inclusion criteria for analysis. A total of 63.6% (21/33) of the scenarios were attributed to ‘poor quality of collaboration’, 42.4% (14/33) to ‘poor leadership’ and 48.5% (16/33) to a ‘lack of coordination’. A total of 16 scenarios were classified as high risk and 17 scenarios were classified as medium risk. Significantly more of the high-risk scenarios were associated with a ‘lack of a shared mental model’ (62.5%, 10/16) and ‘poor communication’ (50.0%, 8/16) than the medium-risk scenarios (17.6%, 3/17 and 11.8%, 2/17, respectively). Conclusion Poor teamwork between junior doctors and nurses is common and places patients at considerable risk. Addressing this problem requires a well-designed complex intervention to develop the team skills of doctors and nurses and foster a clinical environment in which teamwork is supported.
Impact of mesenchymal stem cell secreted PAI-1 on colon cancer cell migration and proliferation
(Elsevier, 2013-05-16) Hogan, Niamh M.; Joyce, Myles R.; Murphy, J. Mary; Barry, Frank P.; O’Brien, Timothy; Kerin, Michael J.; Dwyer, Róisín M.
Mesenchymal Stem Cells are known to engraft and integrate into the architecture of colorectal tumours, with little known regarding their fate following engraftment. This study aimed to investigate mediators of Mesenchymal Stem Cells (MSC) and colon cancer cell (CCC) interactions. Mesenchymal stem cells and colon cancer cells (HT29 and HCT-116) were cultured individually or in co-culture on 3-dimensional scaffolds. Conditioned media containing all secreted factors was harvested at Day 1, 3 and 7. Chemokine secretion and expression were analysed by Chemi-Array, ELISA (Macrophage Migration Inhibitory Factor (MIF), Plasminogen Activator Inhibitor Type 1 (PAI-1)) and RQ-PCR. Colon cancer cell migration and proliferation in response to recombinant PAI-1, MSCs and MSCs + antibody to PAI-1was analysed using Transwell inserts and an MTS proliferation assay respectively. Chemi-Array revealed secretion of a wide range of factors by each cell population, including PAI-1and MIF. ELISA analysis revealed Mesenchymal Stem Cells to secrete the highest levels of PAI-1 (MSC mean 10.6 ng/mL, CCC mean 1.01 ng/mL), while colon cancer cells were the principal source of MIF. MSC-secreted PAI-1 stimulated significant migration of both CCC lines, with an antibody to the chemokine shown to block this effect (67-88% blocking,). A cell-line dependant effect on CCC proliferation was shown for Mesenchymal Stem Cell-secreted PAI-1 with HCT-116 cells showing decreased proliferation at all concentrations, and HT29 cells showing increased proliferation in the presence of higher PAI-1 levels. This is the first study to identify PAI-1 as an important mediator of Mesenchymal Stem Cell/colon cancer cell interactions and highlights the significant functional impact of Mesenchymal Stem Cell-secreted PAI-1 on colon cancer cells.
Mesenchymal stem cells in the colorectal tumor microenvironment: Recent progress and implications
(Wiley, 2012-01-30) Hogan, Niamh M.; Dwyer, Róisín M.; Joyce, Myles R.; Kerin, Michael J.
Mesenchymal stem cells (MSCs) are nonhematopoietic multipotent adult stem cells. They have been shown to have a natural tropism for many tumors types, including colorectal, and are capable of escaping host immune surveillance. MSCs are known to engraft at tumors and integrate into their architecture, potentially as carcinoma-associated fibroblasts. In contrast with other malignancies, our understanding of the interactions between colorectal cancer cells and MSCs remains limited. Considering the established importance of inflammation in the colorectal cancer primary tumor microenvironment and the role of stromal cells in this process, there is a potential wealth of information to be gleaned from further investigation of interactions between these cell populations. Epithelialmesenchymal transition is central to colorectal cancer progression and MSCs have also been implicated in this process. This review explores the current knowledge (both in vitro and in vivo) of interactions between colorectal cancer cells and MSCs. It highlights potential effects of cell source, number and ratio on outcome of in vivo studies and explores strategies to more accurately explore their role in the primary tumor microenvironment. As our understanding of the underlying molecular processes in colorectal cancer develops, elucidation of these interactions will be central to development of novel therapeutic strategies for this prevalent disease.
Adenovirus-mediated and targeted expression of the sodium-iodide symporter permits in vivo radioiodide imaging and therapy of pancreatic tumors
(Mary Ann Liebert, 2006-06-15) Dwyer, Róisín M.; Bergert, Elizabeth R.; O'Connor, Michael K.; Gendler, Sandra J.; Morris, John C.
Pancreatic cancer is the fourth leading cause of cancer death in the United States. It is highly aggressive with no uniformly effective chemotherapy available for metastatic disease. The sodium–iodide symporter (NIS) is a transmembrane protein responsible for uptake of iodide into cells. The presence of NIS in thyroid cells permits diagnostic imaging and therapy of thyroid tumors, using radioiodide. Previous studies from this laboratory reported mucin-1 (MUC1)-driven expression of NIS in cancer cells. MUC1 overexpression has also been reported in 90% of pancreatic tumors. In this study Ad5/MUC1/NIS was used to infect pancreatic cancer cells both in vitro and in vivo, to investigate the potential for radioiodide imaging and ablation of this disease. In vitro studies revealed a 43-fold increase in iodide uptake in NIS-transduced cells compared with controls. In vivo imaging revealed effective iodide uptake and retention at the site of NIS-transduced tumors, with optimal uptake (13% of injected dose) observed 5 hr after iodide administration. Intravenous delivery was performed to investigate potential hepatotoxicity of the construct in the event of virus leakage. Intravenous injection of Ad5/CMV/NIS resulted in robust iodide uptake throughout mouse liver, whereas no uptake was detected in the liver of animals given Ad5/MUC1/NIS intravenously. Administration of therapeutic doses of 131I resulted in significant regression of NIS-transduced tumors, with a mean 50% reduction in volume within 10 weeks of therapy (p < 0.0001). The ability to target NIS expression to pancreatic cancer, which has such limited treatment options, may be highly beneficial and warrants further investigation.
Systemic chemokine levels in breast cancer patients and their relationship with circulating menstrual hormones
(Springer, 2008-06-04) Potter, Shirley M.; Dwyer, Róisín M.; Curran, Catherine E.; Hennessy, Emer; Harrington, Kate A.; Griffin, Damian G.; Kerin, Michael J.; National Breast Cancer Research Institute; Health Research Board
Introduction The chemokines Stromal Cell-Derived Factor-1 alpha (SDF-1 alpha/CXCL12) and Monocyte Chemotactic Protein-1 (MCP-1/CCL2) have been implicated in breast cancer progression. We recently reported elevated systemic MCP-1 in breast cancer patients. This study investigated circulating levels of SDF-1 alpha in breast cancer patients, and addressed potential hormonal regulation of these two potent chemokines. Methods SDF-1 alpha levels were determined by ELISA in 114 breast cancer patients and 85 controls, and correlated with clinical data. Blood samples were collected from 36 healthy premenopausal volunteers weekly for four weeks to measure Luteinising Hormone (LH), Follicular Stimulating Hormone (FSH), Oestradiol and Progesterone using a Bayer ADVIA(A (R)) Centaur Immunoassay system, in parallel with SDF-1 alpha and MCP-1. CXCL12 expression was determined using RQ-PCR in primary tumour stromal cells (n = 16) harvested at surgery. Results Plasma SDF-1 alpha was significantly higher in breast cancer patients than age-matched controls and had a significant correlation with tumour grade and epithelial subtype. Investigation of menstrual variations of these chemokines revealed lower SDF-1 alpha levels in the mid-luteal phase of the menstrual cycle and a significant positive correlation with circulating Oestradiol. MCP-1 levels showed no correlation with menstrual hormones. There was a trend towards increased CXCL12 expression in tumour compared to normal stromal cells. Conclusions The elevated level of SDF-1 alpha detected in breast cancer patients, and it's correlation with prognostic indicators, highlights the importance of this chemokine in disease progression. Elucidation of factors influencing chemokine secretion supports clarification of their role in tumourigenesis.
Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT)
(Springer, 2010-01-20) Martin, F. T.; Dwyer, Róisín M.; Kelly, J.; Khan, S.; Murphy, J. M.; Curran, C.; Miller, N.; Hennessy, E.; Dockery, P.; Barry, F. P.; O'Brien, T.; Kerin, Michael J.; National Breast Cancer Research Institute; Health Research Board; Royal College of Surgeons in Ireland
Bone marrow-derived mesenchymal stem cells (MSCs) are known to specifically migrate to and engraft at tumour sites. Understanding interactions between cancer cells and MSCs has become fundamental to determining whether MSC-tumour interactions should be harnessed for delivery of therapeutic agents or considered a target for intervention. Breast Cancer Cell lines (MDA-MB-231, T47D & SK-Br3) were cultured alone or on a monolayer of MSCs, and retrieved using epithelial specific magnetic beads. Alterations in expression of 90 genes associated with breast tumourigenicity were analysed using low-density array. Expression of markers of epithelial-mesenchymal transition (EMT) and array results were validated using RQ-PCR. Co-cultured cells were analysed for changes in protein expression, growth pattern and morphology. Gene expression and proliferation assays were also performed on indirect co-cultures. Following direct co-culture with MSCs, breast cancer cells expressed elevated levels of oncogenes (NCOA4, FOS), proto-oncogenes (FYN, JUN), genes associated with invasion (MMP11), angiogenesis (VEGF) and anti-apoptosis (IGF1R, BCL2). However, universal downregulation of genes associated with proliferation was observed (Ki67, MYBL2), and reflected in reduced ATP production in response to MSC-secreted factors. Significant upregulation of EMT specific markers (N-cadherin, Vimentin, Twist and Snail) was also observed following co-culture with MSCs, with a reciprocal downregulation in E-cadherin protein expression. These changes were predominantly cell contact mediated and appeared to be MSC specific. Breast cancer cell morphology and growth pattern also altered in response to MSCs. MSCs may promote breast cancer metastasis through facilitation of EMT.
Mesenchymal Stem Cells (MSCs) and cancer: tumour specific delivery vehicles or therapeutic targets?
(Mary Ann Liebert, 2010-09-30) Dwyer, Róisín M.; Kerin, Michael J.; Health Research Board; National Breast Cancer Research Institute
Mesenchymal stem cells (MSCs) are a subset of nonhematopoietic multipotent cells found primarily within the bone marrow stroma. The ability of MSCs to specifically home to sites of tumors and their metastases, while escaping host immune surveillance, holds tremendous promise for tumor-targeted delivery of therapeutic agents. Concerns that MSCs may have an inherent capacity for transformation have led to a number of studies investigating their stability in vitro, as significant ex vivo expansion will be necessary to yield the number of cells required for therapeutic applications. MSCs have also been seen to influence the morphology and proliferation of cells within their vicinity through a combination of cell-to-cell interactions and the secretion of chemoattractant cytokines. Understanding interactions between MSCs and tumor cells is required to support realization of their clinical potential. This review discusses MSCs and cancer in terms of (1) potential for transformation and de novo tumor formation, (2) interactions with epithelial cancer cells in tumor establishment, and (3) potential role after engraftment at the site of an established tumor. Elucidation of any potential negative effect of MSCs in the tumor setting will support development of protocols to minimize these effects while taking full advantage of the remarkable tumor-homing capacity of these cells. This review by Drs. Dwyer and Kerin discusses mesenchymal stem cells and cancer in terms of (1) potential for transformation and de novo tumor formation, (2) interactions with epithelial cancer cells in tumor establishment, and (3) potential role after engraftment at the site of an established tumor.
Mesenchymal stem cell-mediated delivery of the sodium iodide symporter supports radionuclide imaging and treatment of breast cancer
(AlphaMed Press, 2011-05-23) Dwyer, Róisín M.; Ryan, James; Havelin, Ronan J.; Morris, John C.; Miller, Brian W.; Liu, Zhonglin; Flavin, Richard; O'Flatharta, Cathal; Foley, Mark J.; Barrett, Harrison H; Murphy, J. Mary; Barry, Frank P; O'Brien, Timothy; Kerin, Michael J.
Mesenchymal Stem Cells (MSCs) migrate specifically to tumors in vivo, and coupled with their capacity to bypass immune surveillance, are attractive vehicles for tumor-targeted delivery of therapeutic agents. This study aimed to introduce MSC-mediated expression of the sodium iodide symporter (NIS) for imaging and therapy of breast cancer. Tumor bearing animals received an intravenous or intratumoral injection of NIS expressing MSCs (MSC-NIS), followed by (99m) Technetium pertechnetate imaging 3-14 days later using a BazookaSPECT ¿-camera. Tissue was harvested for analysis of human NIS (hNIS) expression by relative quantitative-polymerase chain reaction. Therapy animals received an i.p. injection of (131) I or saline 14 days after injection of MSC-NIS, and tumor volume was monitored for 8 weeks. After injection of MSC-NIS, BazookaSPECT imaging revealed an image of animal intestines and chest area at day 3, along with a visible weak tumor image. By day 14, the tumor was visible with a significant reduction in radionuclide accumulation in nontarget tissue observed. hNIS gene expression was detected in the intestines, heart, lungs, and tumors at early time points but later depleted in nontarget tissues and persisted at the tumor site. Based on imaging/biodistribution data, animals received a therapeutic dose of (131) I 14 days after MSC-NIS injection. This resulted in a significant reduction in tumor growth (mean ± SEM, 236 ± 62 mm(3) vs. 665 ± 204 mm(3) in controls). The ability to track MSC migration and transgene expression noninvasively in real time before therapy is a major advantage to this strategy. This promising data supports the feasibility of this approach as a novel therapy for breast cancer.
Relationship between CCL5 and transforming growth factor-β1 (TGFβ1) in breast cancer
(Elsevier, 2011-06-12) Hartmann, Marion C.; Dwyer, Róisín M.; Costello, M.; Potter, Shirley M.; Curran, Catherine E.; Hennessy, Emer; Newell, John; Griffin, Damian G.; Kerin, Michael J.; National Breast Cancer Research Institute
Purpose Investigate circulating CCL5 in breast cancer patients and healthy controls, along with gene expression levels in corresponding tumour tissue and isolated primary stromal cells. Hormonal control of CCL5, and a potential relationship with TGFβ1, was also investigated. Methods Circulating levels of CCL5 and TGFβ1 were measured in 102 breast cancer patients and 66 controls using ELISA. Gene expression levels (CCL5, CCR5, TGFβ1, TGFβRII) were quantified in corresponding tumour tissue (n = 43), normal tissue (n = 16), and isolated tumour (n = 22) and normal (n = 3) stromal cells using RQ-PCR. CCL5 and circulating menstrual hormones (LH, FSH, Oestradiol, Progesterone) were analysed in serum samples from healthy, premenopausal volunteers (n = 60). Results TGFβ1 was significantly higher in breast cancer patients (Mean(SEM) 27.4(0.9) ng/ml) compared to controls (14.9(0.9) ng/ml). CCL5 levels decreased in the transition from node negative (59.6(3.7) ng/ml) to node positive disease (40.5(6.3) ng/ml) and increased again as the number of positive lymph nodes increased (⩾3 positive 50.95(9.8) ng/ml). A significant positive correlation between circulating CCL5 and TGFβ1 (r = 0.423, p < 0.0001) was observed, and mirrored at the gene expression level in tumour tissue from the same patients (r = 0.44, p < 0.001). CCL5, CCR5 and TGFβ1 expression was significantly higher in tumour compared to normal breast tissue (p < 0.001). A significant negative correlation was observed between circulating CCL5, Oestradiol and Progesterone (r = −0.50, r = −0.39, respectively, p < 0.05). Conclusion CCL5 expression is elevated in the tumour microenvironment. The data support a role for hormonal control of circulating CCL5 and also highlight a potentially important relationship between CCL5 and TGFβ1 in breast cancer.
Influence of stromal–epithelial interactions on breast cancer in vitro and in vivo
(Springer, 2011-02-23) Potter, Shirley M.; Dwyer, Róisín M.; Hartmann, Marion C.; Khan, Sonja; Boyle, Marie P.; Curran, Catherine E.; Kerin, Michael J.; Health Research Board; Breast Cancer Ireland; National Breast Cancer Research Institute
Stromal cell-secreted chemokines including CCL2 have been implicated in the primary tumor microenvironment, as mediators of tumor cell migration, proliferation, and angiogenesis. Expression of CCL2 and its principal receptor CCR2 was analyzed by RQ-PCR in primary tumor cells and breast cancer cell lines. Breast cancer cell lines (MDA-MB-231, T47D) were co-cultured directly on a monolayer of primary breast tumor and normal stromal cells, retrieved using EpCAM+ magnetic beads, and changes in expression of CCL2, CCR2, MMP11, ELK1, VIL2, and Ki67 detected by RQ-PCR. Epithelial cell migration and proliferation in response to stromal cell-secreted factors was also analyzed. In vivo, tumor xenografts were formed by co-injecting T47D cells with primary tumor stromal cells. Following establishment, tumors were harvested and digested, epithelial cells retrieved and analyzed by RQ-PCR. Whole tumor tissue was also analyzed by immunohistochemistry for CD31 and the VIL2 encoded protein Ezrin. Tumor stromal cells expressed significantly higher levels of CCL2 than normal cells, with no CCR2 expression detected. Primary epithelial cells and breast cancer cell lines expressed elevated CCL2, with relative expression of CCR2 found to be higher than the ligand. Interaction of breast cancer epithelial cells with primary tumor, but not normal stromal cells, stimulated increased expression of CCL2 (8-fold), ELK1 (6-fold), VIL2 (6-fold), and MMP11 (17-fold). Factors secreted by stromal cells, including CCL2, stimulated a significant increase in epithelial cell migration, with no effect on cell proliferation in vitro observed. In vivo, the presence of stromal cells resulted in tumors of increased volume, mediated at least in part through neoangiogenesis demonstrated by immunohistochemistry (CD31). Admixed tumor xenografts exhibited increased expression of Ki67, MMP11, VIL2, and ELK1. Elevated Ezrin protein was also detected, with increased cytoplasmic localization. The results presented highlight mechanisms through which breast cancer epithelial cells can harness stromal cell biology to support tumor progression.
Screening of exosomal microRNAs from colorectal cancer cells
(IOS Press, 2017-01-03) Clancy, Cillian; Khan, Sonja; Glynn, Claire L.; Holian, Emma; Dockery, Peter; Lalor, Pierce; Brown, James A.L.; Joyce, Myles R.; Kerin, Michael J.; Dwyer, Róisín M.; Breast Cancer Research; Irish Cancer Society
BACKGROUND: Cells release extracellular membrane vesicles including microvesicles known as exosomes. Exosomes contain microRNAs (miRNAs) however the full range within colorectal cancer cell secreted exosomes is unknown.OBJECTIVE: To identify the full range of exosome encapsulated miRNAs secreted from 2 colorectal cancer cell lines and to investigate engineering of exosomes over-expressing miRNAs.METHODS: Exosomes were isolated from HCT-116 and HT-29 cell lines. RNA was extracted from exosomes and microRNA array performed. Cells were engineered to express miR-379 (HCT-116-379) or a non-targeting control (HCT-116-NTC) and functional effects were determined. Exosomes secreted by engineered cells were transferred to recipient cells and the impact examined.RESULTS: Microvesicles 40-100 nm in size secreted by cell lines were visualised and confirmed to express exosomal protein CD63. HT-29 exosomes contained 409 miRNAs, HCT-116 exosomes contained 393, and 338 were common to exosomes from both cell lines. Selected targets were validated. HCT-116-379 cells showed decreased proliferation (12-15% decrease, p
Employing mesenchymal stem cells to support tumor-targeted delivery of extracellular vesicle (EV)-encapsulated microRNA-379
(Springer Nature, 2018-01-25) O’Brien, K. P.; Khan, S.; Gilligan, K. E.; Zafar, H.; Lalor, P.; Glynn, C.; O’Flatharta, C.; Ingoldsby, H.; Dockery, P.; De Bhulbh, A.; Schweber, J. R.; St John, K.; Leahy, M.; Murphy, J. M.; Gallagher, W. M.; O’Brien, T.; Kerin, Michael J.; Dwyer, Róisín M.
Adult Mesenchymal Stem Cells (MSCs) have a well-established tumor-homing capacity, highlighting potential as tumor-targeted delivery vehicles. MSCs secrete extracellular vesicle (EV)-encapsulated microRNAs, which play a role in intercellular communication. The aim of this study was to characterize a potential tumor suppressor microRNA, miR-379, and engineer MSCs to secrete EVs enriched with miR-379 for in vivo therapy of breast cancer. miR-379 expression was significantly reduced in lymph node metastases compared to primary tumor tissue from the same patients. A significant reduction in the rate of tumor formation and growth in vivo was observed in T47D breast cancer cells stably expressing miR-379. In more aggressive HER2-amplified HCC-1954 cells, HCC-379 and HCC-NTC tumor growth rate in vivo was similar, but increased tumor necrosis was observed in HCC-379 tumors. In response to elevated miR-379, COX-2 mRNA and protein was also significantly reduced in vitro and in vivo. MSCs were successfully engineered to secrete EVs enriched with miR-379, with the majority found to be of the appropriate size and morphology of exosomal EVs. Administration of MSC-379 or MSC-NTC cells, or EVs derived from either cell population, resulted in no adverse effects in vivo. While MSC-379 cells did not impact tumor growth, systemic administration of cell-free EVs enriched with miR-379 was demonstrated to have a therapeutic effect. The data presented support miR-379 as a potent tumor suppressor in breast cancer, mediated in part through regulation of COX-2. Exploiting the tumor-homing capacity of MSCs while engineering the cells to secrete EVs enriched with miR-379 holds exciting potential as an innovative therapy for metastatic breast cancer.
Circulating MicroRNAs in cancer
(Humana Press, 2016-11-09) O’Brien, Killian P.; Ramphul, Eimear; Howard, Linda; Gallagher, William M.; Malone, Carmel; Kerin, Michael J.; Dwyer, Róisín M.; Irish Cancer Society
It is believed that microRNAs have potential as circulating biomarkers of disease, however successful clinical implementation remains a challenge. This chapter highlights broad variations in approaches to microRNA analysis where whole blood, serum and plasma have each been employed as viable sources. Further discrepancies in approaches are seen in endogenous controls and extraction methods utilised. This has resulted in contradictory publications, even when the same microRNA is targeted in the same disease setting. Analysis of blood samples highlighted the impact of both collection method and storage, on the microRNA profile. Analysis of a panel of microRNAs across whole blood, serum and plasma originating from the same individual emphasised the impact of starting material on microRNA profile. This is a highly topical field of research with immense potential for translation into the clinical setting. Standardisation of sample harvesting, processing and analysis will be key to this translation. Methods of sample harvesting, preservation and analysis are outlined, with important mitigating factors highlighted.
Clinical applications of gene expression in colorectal cancer.
(2013) Kerin, Michael J.; |~|
Despite developments in diagnosis and treatment, 20% of colorectal cancer (CRC) patients present with metastatic disease and 30% of cases recur after curative surgery. Furthermore, the molecular factors involved in prognosis and response to therapy in CRC is poorly understood. The aims of this study were to quantitatively examine the expression of target genes in colorectal cancer and to correlate their expression levels with clinico-pathological variables.
The KRAS-Variant Is Associated with Risk of Developing Double Primary Breast and Ovarian Cancer
(2012) Kerin, Michael J.; McVeigh, Terri; Dorairaj, Jemima J.; Heneghan, Helen M.; Miller, Nicola; |~|
Purpose: A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is associated with an increased risk of developing several cancers. Because this variant is most strongly associated with ovarian cancer risk in patients from hereditary breast and ovarian families (HBOC), and with the risk of premenopausal triple negative breast cancer, we evaluated the association of the KRAS-variant with women with personal histories of both breast and ovarian cancer, referred to as double primary patients.Experimental Design: Germline DNA from double primary patients was tested for the KRAS-variant (n = 232). Confirmation of pathologic diagnoses, age of diagnoses, interval between ovarian cancer diagnosis and sample collection, additional cancer diagnoses, and family history were obtained when available. All patients were tested for deleterious BRCA mutations.Results: The KRAS-variant was significantly enriched in uninformative (BRCA negative) double primary patients, being found in 39% of patients accrued within two years of their ovarian cancer diagnosis. Furthermore, the KRAS-variant was found in 35% of uninformative double primary patients diagnosed with ovarian cancer post-menopausally, and was significantly associated with uninformative double primary patients with a positive family history. The KRAS-variant was also significantly enriched in uninformative patients who developed more then two primary cancers, being found in 48% of women with two breast primaries plus ovarian cancer or with triple primary cancers.Conclusions: These findings further validate the importance of the KRAS-variant in breast and ovarian cancer risk, and support the association of this variant as a genetic marker for HBOC families previously considered uninformative.
Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer.
(Nature Publishing Group (Macmillan), 2013-04) Kerin, Michael J.; Miller, Nicola; |~|
TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOGs, we analyzed ~480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 × 10!-7), lower risks for estrogen receptor (ER)-negative (P = 1.0 × 10!-8) and BRCA1 mutation carrier (P = 1.1 × 10!-5) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 × 10!-14), higher risk of low-malignant-potential ovarian cancer (P = 1.3 × 10!-15) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 × 10!-12) and BRCA1 mutation carrier (P = 1.6 × 10!-14) breast and invasive ovarian (P = 1.3 × 10!-11) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.
Large-scale genotyping identifies 41 new loci associated with breast cancer risk.
(Nature Publishing Group (Macmillan), 2013-03-27) Kerin, Michael J.; Miller, Nicola; |~|
Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10!¿8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
MicroRNA expression in colorectal cancer.
(IOS Press, 2012-12-17) Hogan, Niamh M.; Joyce, Myles R.; |~|
Colorectal cancer is a common disease entity with a multi-factorial aetiology which remains poorly understood. It is estimated that in 2008, colorectal cancerwas responsible for 8% of all cancer deaths, making it the fourth most common cause of death from cancer [10]. Prognosis is heavily linked to stage at diagnosis. The major cause of death is development of metastasis in liver, abdominal lymph nodes,and lung, forwhich there is no cure [21]. According to the most recently defined American Joint Committee on Cancer (AJCC) system for colonic adenocarcinoma, 5-year stage-specific survivals were 93.2% for stage I disease compared with 8.1% for stage IV [34], highlighting a need for novel early detection strategies. Colorectal cancer, at least theoretically, is a disease entity which is amenable to early detection, since it exhibits a stepwise progression of carcinogenesis from benign polyps to adenocarcinoma, over a period of time. The majority of national screening programmes currently centre on the use of colonoscopy or faecal immunohistochemistry/occult blood testing. Colonoscopy is an expensive, invasive procedure which carries a significant risk of intestinal perforation (1:700). Faecal testing ismore cost effective and less invasive but sacrifices sensitivity and specificity. Carcinoembryonic antigen, the only blood test currently available, exhibits low sensitivity and specificity. Hence, there is greatneed for new biomarkers for early detection of CRC.
Enlarging neck masses in the elderly - Histological and surgical considerations.
(2013) O'Sullivan MD, McAnena KS, Egan C, Waters PS, McCann PJ, Kerin MJ; |~|
INTRODUCTION: Anaplastic carcinoma of the thyroid is a rare but aggressive malignancy which can present with a rapidly enlarging neck mass or compressive sequelae of cough, dyspnoea, dysphagia and hoarseness. Treatment of such tumours is commonly palliative however they occasionally represent surgical challenges due to their rapid growth, diagnostic difficulty and locoregional spread. PRESENTATION OF CASE: A 75 year-old retired veterinary surgeon was referred with a 2 month history of a painless, enlarging neck mass. The patient denied any secondary compressive symptoms or general symptoms of malignancy. On examination a large right-sided neck mass measuring 7cm - 5cm was appreciated which was fixed, hard and irregular with associated adenopathy. DISCUSSION: We discuss the diagnostic challenges posed by anaplastic carcinoma of the thyroid and the difficulties in selecting the appropriate intervention in this aggressive disease process. CONCLUSION: Anaplastic carcinoma of the thyroid is encountered infrequently in clinical practice and can generate diagnostic and therapeutic challenges.
11q13 is a susceptibility locus for hormone receptor positive breast cancer.
(Wiley, 2012-07) Kerin, Michael J.; Miller, Nicola; |~|
A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P â ¤ 3 Ã 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 Ã 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype.

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