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54. A Newly Identified Susceptibility Locus near FOXP1 Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus.

Author

Dai, James Y., de Dieu Tapsoba, Jean, Buas, Matthew F., Onstad, Lynn E., Levine, David M., Risch, Harvey A., Wong-Ho Chow, Bernstein, Leslie, Weimin Ye, Lagergren, Jesper, Bird, Nigel C., Corley, Douglas A., Shaheen, Nicholas J., Wu, Anna H., Reid, Brian J., Hardie, Laura J., Whiteman, David C., and Vaughan, Thomas L.

Abstract

Background: Important risk factors for esophageal adenocarcinoma and its precursor, Barrett's esophagus, include gastroesophageal reflux disease, obesity, and cigarette smoking. Recently, genome-wide association studies have identified seven germline single-nucleotide polymorphisms (SNP) that are associated with risk of Barrett's esophagus and esophageal adenocarcinoma. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear. Methods: We analyzed exposure and genotype data from the BEACON Consortium discovery phase GWAS, which included 1,516 esophageal adenocarcinoma case patients, 2,416 Barrett's esophagus case patients, and 2,187 control participants. We examined the seven newly identified susceptibility SNPs for interactions with body mass index, smoking status, and report of weekly heartburn or reflux. Logistic regression models were used to estimate ORs for these risk factors stratified by SNP genotype, separately for Barrett's esophagus and esophageal adenocarcinoma. Results: The odds ratio for Barrett's esophagus associated with at least weekly heartburn or reflux varied significantly with the presence of at least one minor allele of rs2687201 (nominal P = 0.0005, FDR = 0.042). ORs (95% CIs) for weekly heartburn or reflux among participants with 0, 1, or 2 minor alleles of rs2687201 were 6.17 (4.91-7.56), 3.56 (2.85-4.44), and 3.97 (2.47-6.37), respectively. No statistically significant interactions were observed for smoking status and body mass index. Conclusion: Reflux symptoms are more strongly associated with Barrett's esophagus risk among persons homozygous for the major allele of rs2687201, which lies approximately 75 kb downstream of the transcription factor gene FOXP1. Impact: The novel gene-exposure interaction discovered in this study provides new insights into the etiology of esophageal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Published
2015
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56. Early increases in plasminogen activator activity following partial hepatectomy in humans

Author

Mangnall, David, Smith, Kirsty, Bird, Nigel C, and Majeed, Ali W

Subjects
Research
Abstract

BACKGROUND: Increases in urokinase-like plasminogen activator (uPA) activity are reported to be amongst the earliest events occurring in remnant liver following partial hepatectomy in rats, and have been proposed as a key component of the regenerative response. Remodelling of the extracellular matrix, conversion of single chain hepatocyte growth factor to the active two-chain form and a possible activation of a mitogenic signalling pathway have all been ascribed to the increased uPA activity. The present study aimed to determine whether similar early increases in uPA activity could be detected in the remnant liver following resection of metastatic tumours in surgical patients. RESULTS: Eighteen patients undergoing partial hepatectomy for the removal of hepatic metastases secondary to primary colonic tumours were studied. Increased plasminogen activator activity was found in the final liver samples for the group of patients in whom the resection size was at least 50%. For smaller resections, the increased activity was not observed. The increased activity did not correlate with the age of the patient or with the time between the start of resection and the end of the operation. There was, however, a negative correlation between plasminogen activator activity and the time for which blood supply to the liver was clamped. CONCLUSIONS: Our findings are in accordance with those from experimental animal models and show, for the first time, that rapid increases in plasminogen activator activity can occur following similarly large liver resection in humans. Thus, increases in plasminogen activator activity are an early event in the remnant liver following major liver resection in man. Our observations provide support for the contention that increases in plasminogen activators play a key role in the initiation of hepatic regeneration in man.

Published
2004

59. Pleiotropic Analysis of Cancer Risk Loci on Esophageal Adenocarcinoma Risk.

Author

Eunjung Lee, Stram, Daniel O., Ek, Weronica E., Onstad, Lynn E., MacGregor, Stuart, Gharahkhani, Puya, Weimin Ye, Lagergren, Jesper, Shaheen, Nicholas J., Murray, Liam J., Hardie, Laura J., Gammon, Marilie D., Wong-Ho Chow, Risch, Harvey A., Corley, Douglas A., Levine, David M., Whiteman, David C., Bernstein, Leslie, Bird, Nigel C., and Vaughan, Thomas L.

Abstract

Background: Several cancer-associated loci identified from genome-wide association studies (GWAS) have been associated with risks of multiple cancer sites, suggesting pleiotropic effects. We investigated whether GWAS-identified risk variants for other common cancers are associated with risk of esophageal adenocarcinoma (EA) or its precursor, Barrett's esophagus. Methods: We examined the associations between risks of EA and Barrett's esophagus and 387 SNPs that have been associated with risks of other cancers, by using genotype imputation data on 2,163 control participants and 3,885 (1,501 EA and 2,384 Barrett's esophagus) case patients from the Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study, and investigated effect modification by smoking history, body mass index (BMI), and reflux/heartburn. Results: After correcting for multiple testing, none of the tested 387 SNPs were statistically significantly associated with risk of EA or Barrett's esophagus. No evidence of effect modification by smoking, BMI, or reflux/heartburn was observed. Conclusions: Genetic risk variants for common cancers identified from GWAS appear not to be associated with risks of EA or Barrett's esophagus. Impact: To our knowledge, this is the first investigation of pleiotropic genetic associations with risks ofEAand Barrett's esophagus. [ABSTRACT FROM AUTHOR]

Published
2015
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60. MiRNA-Related SNPs and Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus: Post Genome-Wide Association Analysis in the BEACON Consortium

Author

Reid, Brian J., Onstad, Lynn, Peters, Ulrike, Bird, Nigel C., Risch, Harvey A., Liu, Geoffrey, Romero, Yvonne, Ye, Weimin, Hardie, Laura J., Bernstein, Leslie, Levine, David M., Chow, Wong-Ho, Vaughan, Thomas L., Gammon, Marilie D., Wu, Anna H., Casson, Alan G., Whiteman, David C., Fitzgerald, Rebecca C., Buas, Matthew F., Shaheen, Nicholas J., and Corley, Douglas A.

Subjects
3. Good health
Abstract

Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post-transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk.

61. Polymorphisms near TBX5 and GDF7 are associated with increased risk for Barrett's esophagus

Author

Palles, Claire, Chegwidden, Laura, Li, Xinzhong, Findlay, John M, Farnham, Garry, Castro Giner, Francesc, Peppelenbosch, Maikel P, Kovac, Michal, Adams, Claire L, Prenen, Hans, Briggs, Sarah, Harrison, Rebecca, Sanders, Scott, MacDonald, David, Haigh, Chris, Tucker, Art, Love, Sharon, Nanji, Manoj, DeCaestecker, John, Ferry, David, Rathbone, Barrie, Hapeshi, Julie, Barr, Hugh, Moayyedi, Paul, Watson, Peter, Zietek, Barbara, Maroo, Neera, Gay, Laura, Underwood, Tim, Boulter, Lisa, McMurtry, Hugh, Monk, David, Patel, Praful, Ragunath, Krish, Al Dulaimi, David, Murray, Iain, Koss, Konrad, Veitch, Andrew, Trudgill, Nigel, Nwokolo, Chuka, Rembacken, Bjorn, Atherfold, Paul, Green, Elaine, Ang, Yeng, Kuipers, Ernst J, Chow, Wu, Paterson, Stuart, Kadri, Sudarshan, Beales, Ian, Grimley, Charles, Mullins, Paul, Beckett, Conrad, Farrant, Mark, Dixon, Andrew, Kelly, Sean, Johnson, Matthew, Wajed, Shahjehan, Dhar, Anjan, Sawyer, Elinor, Roylance, Rebecca, Onstad, Lynn, Gammon, Marilie D, Corley, Douglas A, Shaheen, Nicholas J, Bird, Nigel C, Hardie, Laura J, Reid, Brian J, Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H, Casson, Alan G, Fitzgerald, Rebecca, Whiteman, David C, Risch, Harvey A, Levine, David M, Vaughan, Tom L, Verhaar, Auke P, Van Den Brande, Jan, Toxopeus, Eelke L, Spaander, Manon C, Wijnhoven, Bas PL, Van Der Laan, Luc JW, Krishnadath, Kausilia, Wijmenga, Cisca, Trynka, Gosia, McManus, Ross, Reynolds, John V, O'Sullivan, Jacintha, MacMathuna, Padraic, McGarrigle, Sarah A, Kelleher, Dermot, Vermeire, Severine, Cleynen, Isabelle, Bisschops, Raf, Tomlinson, Ian, and Jankowski, Janusz

Subjects
Risk, Esophageal Neoplasms, Polymorphism, Single Nucleotide, 3. Good health, Growth Differentiation Factors, Intestinal Metaplasia, Barrett Esophagus, Susceptibility, Bone Morphogenetic Proteins, Humans, Genetic Predisposition to Disease, EAC, T-Box Domain Proteins, Cancer, Genome-Wide Association Study
Abstract

BACKGROUND & AIMS: Barrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations. METHODS: We performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. RESULTS: We identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR] = 1.14; 95% CI: 1.09-1.18; P = 1.8 × 10(-11)) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; P = 7.5 × 10(-9)). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNP associated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR = 0.90; 95% CI: 0.87-0.93; P = 3.72 × 10(-9)). CONCLUSIONS: We identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

62. Risk of Esophageal Adenocarcinoma Decreases With Height, Based on Consortium Analysis and Confirmed by Mendelian Randomization

Author

Casson, Alan G., Whiteman, David C., Thrift, Aaron P., Bird, Nigel C., Romero, Yvonne, Onstad, Lynn, Risch, Harvey A., Liu, Geoffrey, Gammon, Marilie D., Vaughan, Thomas L., Hardie, Laura J., Levine, David M., Chow, Wong Ho, Corley, Douglas A., Shaheen, Nicholas J., Ye, Weimin, Wu, Anna H., Bernstein, Leslie, and Reid, Brian J.

Subjects
2. Zero hunger, surgical procedures, operative, digestive system, digestive system diseases, 3. Good health
Abstract

Risks for some cancers increase with height. We investigated the relationship between height and risk of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE).

63. Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett's Esophagus

Author

Dong, Jing, Levine, David M, Buas, Matthew F, Zhang, Rui, Onstad, Lynn, Fitzgerald, Rebecca C, Stomach And Oesophageal Cancer Study (SOCS) Consortium, Corley, Douglas A, Shaheen, Nicholas J, Lagergren, Jesper, Hardie, Laura J, Reid, Brian J, Iyer, Prasad G, Risch, Harvey A, Caldas, Carlos, Caldas, Isabel, Pharoah, Paul D, Liu, Geoffrey, Gammon, Marilie D, Chow, Wong-Ho, Bernstein, Leslie, Bird, Nigel C, Ye, Weimin, Wu, Anna H, Anderson, Lesley A, MacGregor, Stuart, Whiteman, David C, Vaughan, Thomas L, and Thrift, Aaron P

Subjects
2. Zero hunger, Male, Esophageal Neoplasms, Genetic Variants, Environmental Exposure, Adenocarcinoma, Middle Aged, Polymorphism, Single Nucleotide, Risk Assessment, United Kingdom, 3. Good health, Barrett Esophagus, Esophagus, Risk Factors, Humans, Female, Genetic Predisposition to Disease, Esophageal Neoplasm, Aged, Genome-Wide Association Study
Abstract

BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett's esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE. METHODS: We collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett's and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett's Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case-control logistic regression to test for gene-environment interactions. RESULTS: For EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03-34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10-7, P = 1.83×10-7, and P = 3.58×10-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10-7) and pack-years of smoking history (P = 2.82×10-7), respectively. CONCLUSION: The associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.

64. Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Author

Al Dulaimi, David, Johnson, Matthew, Trynka, Gosia, Prenen, Hans, Atherfold, Paul, Li, Xinzhong, Vaughan, Tom L., Ye, Weimin, Love, Sharon, Van Der Laan, Luc J.W., Boulter, Lisa, Rathbone, Barrie, Shaheen, Nicholas J., Underwood, Tim, Decaestecker, John, Roylance, Rebecca, Chow, Wu, Reid, Brian J., Van Den Brande, Jan, Watson, Peter, Ang, Yeng, Monk, David, Bisschops, Raf, Farrant, Mark, Farnham, Garry, O'Sullivan, Jacintha, Dhar, Anjan, Bernstein, Leslie, Beales, Ian, Toxopeus, Eelke L., Wijmenga, Cisca, Hapeshi, Julie, Tucker, Art, Sanders, Scott, Nwokolo, Chuka, Moayyedi, Paul, Kadri, Sudarshan, Vermeire, Severine, Bird, Nigel C., Barr, Hugh, Ragunath, Krish, Gammon, Marilie D., Liu, Geoffrey, Briggs, Sarah, Castro Giner, Francesc, Harrison, Rebecca, Romero, Yvonne, Patel, Praful, Kelly, Sean, Krishnadath, Kausilia, Casson, Alan G., Cleynen, Isabelle, Macdonald, David, Beckett, Conrad, McGarrigle, Sarah A., Adams, Claire L., Fitzgerald, Rebecca, Reynolds, John V., Dixon, Andrew, Whiteman, David C., Kuipers, Ernst J., McManus, Ross, Wu, Anna H., Tomlinson, Ian, Wijnhoven, Bas P.L., Zietek, Barbara, Risch, Harvey A., Chegwidden, Laura, Rembacken, Bjorn, Mullins, Paul, Haigh, Chris, Corley, Douglas A., Verhaar, Auke P., Trudgill, Nigel, Ferry, David, Palles, Claire, Murray, Iain, Green, Elaine, Nanji, Manoj, Levine, David M., Maroo, Neera, Spaander, Manon C., Wajed, Shahjehan, Kovac, Michal, Sawyer, Elinor, McMurtry, Hugh, Hardie, Laura J., Gay, Laura, Findlay, John M., Paterson, Stuart, Peppelenbosch, Maikel P., Veitch, Andrew, Grimley, Charles, Macmathuna, Padraic, Onstad, Lynn, Koss, Konrad, Kelleher, Dermot, and Jankowski, Janusz

Subjects
3. Good health
Abstract

Background & AimsBarrett's esophagus (BE) increases the risk of esophageal adenocarcinoma (EAC). We found the risk to be BE has been associated with single nucleotide polymorphisms (SNPs) on chromosome 6p21 (within the HLA region) and on 16q23, where the closest protein-coding gene is FOXF1. Subsequently, the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) identified risk loci for BE and esophageal adenocarcinoma near CRTC1 and BARX1, and within 100 kb of FOXP1. We aimed to identify further SNPs that increased BE risk and to validate previously reported associations.MethodsWe performed a genome-wide association study (GWAS) to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls.ResultsWe identified 2 SNPs not previously associated with BE: rs3072 (2p24.1; odds ratio [OR]= 1.14; 95% CI: 1.09–1.18; P= 1.8× 10−11) and rs2701108 (12q24.21; OR= 0.90; 95% CI: 0.86–0.93; P= 7.5× 10−9). The closest protein-coding genes were respectively GDF7 (rs3072), which encodes a ligand in the bone morphogenetic protein pathway, and TBX5 (rs2701108), which encodes a transcription factor that regulates esophageal and cardiac development. Our data also supported in BE cases 3 risk SNPs identified by BEACON (rs2687201, rs11789015, and rs10423674). Meta-analysis of all data identified another SNPassociated with BE and esophageal adenocarcinoma: rs3784262, within ALDH1A2 (OR= 0.90; 95% CI: 0.87–0.93; P=3.72× 10−9).ConclusionsWe identified 2 loci associated with risk of BE and provided data to support a further locus. The genes we found to be associated with risk for BE encode transcription factors involved in thoracic, diaphragmatic, and esophageal development or proteins involved in the inflammatory response.

65. A Newly Identified Susceptibility Locus near FOXP1 Modifies the Association of Gastroesophageal Reflux with Barrett's Esophagus

Author

Bernstein, Leslie, Onstad, Lynn E., De Dieu Tapsoba, Jean, Reid, Brian J., Wu, Anna H., Levine, David M., Bird, Nigel C., Lagergren, Jesper, Vaughan, Thomas L., Buas, Matthew F., Dai, James Y., Corley, Douglas A., Risch, Harvey A., Hardie, Laura J., Shaheen, Nicholas J., Ye, Weimin, Whiteman, David C., and Chow, Wong Ho

Subjects
2. Zero hunger, digestive system diseases, 3. Good health
Abstract

Important risk factors for esophageal adenocarcinoma (EA) and its precursor, Barrett’s esophagus (BE) include gastroesophageal reflux disease, obesity, and cigarette-smoking. Recently, genome-wide association studies have identified seven germline single nucleotide polymorphisms (SNPs) that are associated with risk of BE and EA. Whether these genetic susceptibility loci modify previously identified exposure-disease associations is unclear.

66. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus

Author

Levine, David M, Ek, Weronica E, Zhang, Rui, Liu, Xinxue, Onstad, Lynn, Sather, Cassandra, Lao-Sirieix, Pierre, Gammon, Marilie D, Corley, Douglas A, Shaheen, Nicholas J, Bird, Nigel C, Hardie, Laura J, Murray, Liam J, Reid, Brian J, Chow, Wong-Ho, Risch, Harvey A, Nyrén, Olof, Ye, Weimin, Liu, Geoffrey, Romero, Yvonne, Bernstein, Leslie, Wu, Anna H, Casson, Alan G, Chanock, Stephen J, Harrington, Patricia, Caldas, Isabel, Debiram-Beecham, Irene, Caldas, Carlos, Hayward, Nicholas K, Pharoah, Paul D, Fitzgerald, Rebecca C, Macgregor, Stuart, Whiteman, David C, and Vaughan, Thomas L

Subjects
Male, Esophageal Neoplasms, Genotype, Adenocarcinoma, Polymorphism, Single Nucleotide, digestive system diseases, 3. Good health, Barrett Esophagus, Genetic Loci, Case-Control Studies, Humans, Female, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Esophageal adenocarcinoma is a cancer with rising incidence and poor survival. Most such cancers arise in a specialized intestinal metaplastic epithelium, which is diagnostic of Barrett's esophagus. In a genome-wide association study, we compared esophageal adenocarcinoma cases (n = 2,390) and individuals with precancerous Barrett's esophagus (n = 3,175) with 10,120 controls in 2 phases. For the combined case group, we identified three new associations. The first is at 19p13 (rs10419226: P = 3.6 × 10(-10)) in CRTC1 (encoding CREB-regulated transcription coactivator), whose aberrant activation has been associated with oncogenic activity. A second is at 9q22 (rs11789015: P = 1.0 × 10(-9)) in BARX1, which encodes a transcription factor important in esophageal specification. A third is at 3p14 (rs2687201: P = 5.5 × 10(-9)) near the transcription factor FOXP1, which regulates esophageal development. We also refine a previously reported association with Barrett's esophagus near the putative tumor suppressor gene FOXF1 at 16q24 and extend our findings to now include esophageal adenocarcinoma.

68. Effects of Pro-Inflammatory Cytokines on the Production of Soluble Fractalkine and ADAM17 by HepG2 Cells.

Author

Turner, Sharon L., Mangnall, David, Bird, Nigel C., Blair-Zajdel, Maria E., and Bunning, Rowena A. D.

Subjects
*LIVER cancer patients, *CYTOKINES, *ENZYME-linked immunosorbent assay, *LIVER cells, *FLOW cytometry, *TUMOR necrosis factors, *REVERSE transcriptase polymerase chain reaction, *GENE transfection
Abstract

Background & Aims: Soluble fractalkine is increased in the liver during times of injury; however the effect of pro-inflammatory cytokines in this process is currently unknown. The aim of this study was to determine whether pro-inflammatory cytokines elevated in patients with hepatocellular carcinoma influence fractalkine shedding from HepG2 cells and whether ADAM17 was involved in this process. Methods: In vitro experiments were performed in the human hepatocellular carcinoma cell line HepG2. Soluble fractalkine was detected using an ELISA. ADAM17 expression was investigated using quantitative real time (reverse transcription)-polymerase chain reaction and flow cytometry. Short interfering RNA transfection was used to down-regulate ADAM17 expression. Results: Soluble fractalkine was present in supernatants of HepG2 cells, and was significantly increased by interleukin-1β (p⩽0.005) and tumour necrosis factor-α (p⩽0.043), but not by interleukin- 6 (p⩾0.316). This corresponded to minor increases in ADAM17 protein, but not ADAM17 mRNA, following the same treatments. However, the down-regulation of ADAM17 protein did not affect fractalkine shedding. Conclusions: This study showed that soluble fractalkine is up-regulated under inflammatory conditions associated with hepatocellular carcinoma development, but ADAM17 does not appear to be responsible for regulating this process. [ABSTRACT FROM AUTHOR]

Published
2010

69. The Multifaceted Role of the Microenvironment in Liver Metastasis: Biology and Clinical Implications.

Author

den Eynden, Gert G. Van, Majeed, Ali W., Illemann, Martin, Vermeulen, Peter B., Bird, Nigel C., Høyer-Hansen, Gunilla, Eefsen, Rikke Løvendahl, Reynolds, Andrew R., and Brodt, Pnina

Subjects
*METASTASIS, *COLON cancer, *RECTAL cancer, *LIVER cancer, *CHEMOKINES
Abstract

The liver is host to many metastatic cancers, particularly colorectal cancer, for which the last 2 decades have seen major advances in diagnosis and treatment. The liver is a vital organ, and the extent of its involvement with metastatic disease is a major determinant of survival. Metastatic cells arriving in the liver via the bloodstream encounter the microenvironment of the hepatic sinusoid. The interactions of the tumor cells with hepatic sinusoidal and extrasinusoidal cells (endothelial, Kupffer, stellate, and inflammatory cells) determine their fate. The sinusoidal cells can have a dual role, sometimes fatal to the tumor cells but also facilitatory to their survival and growth. Adhesion molecules participate in these interactions and may affect their outcome. Bone marrow-- derived cells and chemokines also play a part in the early battle for survival of the metastases. Once the tumor cells have arrested and survived the initial onslaught, tumors can grow within the liver in 3 distinct patterns, reflecting differing host responses, mechanisms of vascularization, and proteolytic activity. This review aims to present current knowledge of the interactions between the host liver cells and the invading metastases that has implications for the clinical course of the disease and the response to treatment. [ABSTRACT FROM AUTHOR]

Published
2013
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70. Tumor stromal phenotypes define VEGF sensitivity--letter.

Author

Van den Eynden GG, Bird NC, Dirix LY, Eefsen RL, Gao ZH, Høyer-Hansen G, Illemann M, Majeed AW, Metrakos P, Reynolds AR, Vainer B, van Dam PJ, Van Laere SJ, Vermeulen PB, Vidal-Vanaclocha F, and Brodt P

Subjects
Humans, Antibodies, Monoclonal, Humanized administration & dosage, Neoplasms genetics, Stromal Cells metabolism, Vascular Endothelial Growth Factor A genetics
Published
2014
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71. Natural history of hepatic metastases from colorectal cancer--pathobiological pathways with clinical significance.

Author

Paschos KA, Majeed AW, and Bird NC

Subjects
Apoptosis, Cadherins metabolism, Cell Adhesion Molecules metabolism, Hepatic Stellate Cells cytology, Humans, Kupffer Cells pathology, Liver pathology, Matrix Metalloproteinases metabolism, Mutation, Neoplasm Invasiveness, Neoplasm Metastasis, Neovascularization, Pathologic, Treatment Outcome, Colorectal Neoplasms pathology, Liver Neoplasms secondary
Abstract

Colorectal cancer hepatic metastases represent the final stage of a multi-step biological process. This process starts with a series of mutations in colonic epithelial cells, continues with their detachment from the large intestine, dissemination through the blood and/or lymphatic circulation, attachment to the hepatic sinusoids and interactions with the sinusoidal cells, such as sinusoidal endothelial cells, Kupffer cells, stellate cells and pit cells. The metastatic sequence terminates with colorectal cancer cell invasion, adaptation and colonisation of the hepatic parenchyma. All these events, termed the colorectal cancer invasion-metastasis cascade, include multiple molecular pathways, intercellular interactions and expression of a plethora of chemokines and growth factors, and adhesion molecules, such as the selectins, the integrins or the cadherins, as well as enzymes including matrix metalloproteinases. This review aims to present recent advances that provide insights into these cell-biological events and emphasizes those that may be amenable to therapeutic targeting.

Published
2014
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72. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus.

Author

Su Z, Gay LJ, Strange A, Palles C, Band G, Whiteman DC, Lescai F, Langford C, Nanji M, Edkins S, van der Winkel A, Levine D, Sasieni P, Bellenguez C, Howarth K, Freeman C, Trudgill N, Tucker AT, Pirinen M, Peppelenbosch MP, van der Laan LJ, Kuipers EJ, Drenth JP, Peters WH, Reynolds JV, Kelleher DP, McManus R, Grabsch H, Prenen H, Bisschops R, Krishnadath K, Siersema PD, van Baal JW, Middleton M, Petty R, Gillies R, Burch N, Bhandari P, Paterson S, Edwards C, Penman I, Vaidya K, Ang Y, Murray I, Patel P, Ye W, Mullins P, Wu AH, Bird NC, Dallal H, Shaheen NJ, Murray LJ, Koss K, Bernstein L, Romero Y, Hardie LJ, Zhang R, Winter H, Corley DA, Panter S, Risch HA, Reid BJ, Sargeant I, Gammon MD, Smart H, Dhar A, McMurtry H, Ali H, Liu G, Casson AG, Chow WH, Rutter M, Tawil A, Morris D, Nwokolo C, Isaacs P, Rodgers C, Ragunath K, MacDonald C, Haigh C, Monk D, Davies G, Wajed S, Johnston D, Gibbons M, Cullen S, Church N, Langley R, Griffin M, Alderson D, Deloukas P, Hunt SE, Gray E, Dronov S, Potter SC, Tashakkori-Ghanbaria A, Anderson M, Brooks C, Blackwell JM, Bramon E, Brown MA, Casas JP, Corvin A, Duncanson A, Markus HS, Mathew CG, Palmer CN, Plomin R, Rautanen A, Sawcer SJ, Trembath RC, Viswanathan AC, Wood N, Trynka G, Wijmenga C, Cazier JB, Atherfold P, Nicholson AM, Gellatly NL, Glancy D, Cooper SC, Cunningham D, Lind T, Hapeshi J, Ferry D, Rathbone B, Brown J, Love S, Attwood S, MacGregor S, Watson P, Sanders S, Ek W, Harrison RF, Moayyedi P, de Caestecker J, Barr H, Stupka E, Vaughan TL, Peltonen L, Spencer CC, Tomlinson I, Donnelly P, and Jankowski JA

Subjects
Adult, Aged, Case-Control Studies, Female, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Male, Middle Aged, Models, Genetic, Barrett Esophagus genetics, Chromosomes, Human, Pair 16, Genetic Predisposition to Disease, Major Histocompatibility Complex, Polymorphism, Single Nucleotide
Abstract

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined=4.09×10(-9); odds ratio (OR)=1.21, 95% confidence interval (CI)=1.13-1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined=2.74×10(-10); OR=1.14, 95% CI=1.10-1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

Published
2012
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73. Liver regeneration and its impact on post-hepatectomy metastatic tumour recurrence.

Author

Paschos KA and Bird NC

Subjects
Hepatocyte Growth Factor physiology, Humans, Neoplasm Recurrence, Local, Transforming Growth Factor beta1 physiology, Tumor Necrosis Factor-alpha physiology, Hepatectomy, Liver Neoplasms secondary, Liver Neoplasms surgery, Liver Regeneration
Abstract

Hepatic resection remains the primary potentially curative therapeutic modality for liver metastases. The regenerative process that occurs postoperatively is a complex phenomenon, orchestrated by molecular cascades involving growth factors, cytokines, proteolytic enzymes and other proteins. Unfortunately, some of these molecules, such as hepatocyte growth factor, tumour growth factor beta and matrix metalloproteinases also promote tumour growth and may contribute to the recurrence of liver metastasis. The reactivation of dormant micrometastases or the intrahepatic accumulation of circulating malignant cells has been suggested as the responsible mechanism, although not clearly understood. Current clinical and experimental research has developed inhibitors of several regenerative molecules, attempting to treat tumour reappearance within the liver. Despite the considerable progress of the last decade, multiple queries remain to be clarified concerning liver regeneration, as well as its impact on post-hepatectomy tumour recurrence. This review describes the responsible molecular pathways and the clinical importance of post-hepatectomy liver regeneration, and investigates how the regenerative process may promote metastatic tumour recurrence.

Published
2010

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