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4. Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes

Author

McAllan, L., primary, Baranasic, D., additional, Villicaña, S., additional, Zhang, W., additional, Lehne, B., additional, Adamo, M., additional, Jenkinson, A., additional, Elkalaawy, M., additional, Mohammadi, B., additional, Hashemi, M., additional, Yang, Y., additional, Zudina, L., additional, Lagou, V., additional, Tan, S., additional, Castillo-Fernandez, J., additional, Soong, R., additional, Elliott, P., additional, Scott, J., additional, Loh, M., additional, Prokopenko, I., additional, Lenhard, B., additional, Batterham, R. L., additional, Bell, J., additional, Chambers, J., additional, Kooner, J., additional, and Scott, W., additional

Published
2021
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5. Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies

Author

Wong, A. L., Soo, R. A., Tan, D. S., Lee, S. C., Lim, J. S., Marban, P. C., Kong, L. R., Lee, Y. J., Wang, L. Z., Thuya, W. L., Soong, R., Yee, M. Q., Chin, T. M., Cordero, M. T., Asuncion, B. R., Pang, B., Pervaiz, S., Hirpara, J. L., Sinha, A., Xu, W. W., Yuasa, M., Tsunoda, T., Motoyama, M., Yamauchi, T., and Goh, B. C.

Published
2015
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7. Production of methane and gaseous compounds by surface microbial activity in a small pockmark field, Dunmanus Bay, Ireland

Author

O'Reilly, S.S., primary, Jordan, S.F., additional, Monteys, X., additional, Simpson, A.J., additional, Allen, C.C.R., additional, Szpak, M.T., additional, Murphy, B.T., additional, McCarron, S.G., additional, Soong, R., additional, Wu, B., additional, Jenne, A., additional, Grey, A., additional, and Kelleher, B.P., additional

Published
2021
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8. Production of methane and gaseous compounds by surface microbial activity in a small pockmark field, Dunmanus Bay, Ireland

Author

O’Reilly, S.S., Jordan, S.F., Monteys, X., Simpson, A.J., Allen, C.C.R., Szpak, M., Murphy, B.T., McCarron, Stephen, Soong, R., Wu, B., Jenne, A., Grey, A., Kellegher, B.P., O’Reilly, S.S., Jordan, S.F., Monteys, X., Simpson, A.J., Allen, C.C.R., Szpak, M., Murphy, B.T., McCarron, Stephen, Soong, R., Wu, B., Jenne, A., Grey, A., and Kellegher, B.P.

Abstract

Marine pockmarks are globally widespread seabed depressions, conventionally thought to be formed by the accumulation and expulsion of microbial and thermogenic gas. However, other putative fluids and processes have been implicated in pockmark formation and gas escape to the atmosphere may be underestimated. Given the complex spectrum of aquatic settings, morphologies and sizes, there may also exist a spectrum of physical, chemical and biological processes that form pockmarks. Pockmarks in shallow coastal waters are now understood to be widespread, but the influence of physical dynamics (e.g. tides, storms, etc.), terrestrial processes and anthropogenic activities add considerable spatiotemporal complexity and uncertainty to our understanding of these features. Here, we revisit a field of small (ca. 2 m diameter), shallow (

Published
2021

15. Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study

Author

Iacopetta, B., Russo, A., Bazan, V., Dardanoni, G., Gebbia, N., Soussi, T., Kerr, D., Elsaleh, H., Soong, R., Kandioler, D., Janschek, E., Kappel, S., Lung, M., Leung, C.-S.S., Ko, J.M., Yuen, S., Ho, J., Leung, S.Y., Crapez, E., Duffour, J., Ychou, M., Leahy, D.T., O'Donoghue, D.P., Agnese, V., Cascio, S., Di Fede, G., Chieco-Bianchi, L., Bertorelle, R., Belluco, C., Giaretti, W., Castagnola, P., Ricevuto, E., Ficorella, C., Bosari, S., Arizzi, C.D., Miyaki, M., Onda, M., Kampman, E., Diergaarde, B., Royds, J., Lothe, R.A., Diep, C.B., Meling, G.I., Ostrowski, J., Trzeciak, L., Guzińska-Ustymowicz, K., Zalewski, B., Capellá, G.M., Moreno, V., Peinado, M.A., Lönnroth, C., Lundholm, K., Sun, X.F., Jansson, A., Bouzourene, H., Hsieh, L.-L., Tang, R., Smith, D.R., Allen-Mersh, T.G., Khan, Z.A.J., Shorthouse, A.J., Silverman, M.L., Kato, S., and Ishioka, C.

Published
2006
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20. Comprehensive biomarker analyses identifies HER2, EGFR, MET RNA expression and thymidylate synthase 5'UTR SNP as predictors of benefit from S-1 adjuvant chemotherapy in Japanese patients with stage II/III gastric cancer

Author

Yoshikawa, T, Aoyama, T, Sakamaki, K, Oshima, T, Lin, J, Zhang, S, Sapari, NS, Soong, R, Tan, I, Chan, XB, Bottomley, D, Hewitt, LC, Arai, T, Teh, BT, Epstein, D, Ogata, T, Kameda, Y, Miyagi, Y, Tsuburaya, A, Morita, S, Grabsch, HI, and Tan, P

Abstract

Purpose: A comprehensive molecular analysis was conducted to identify prognostic and predictive markers for adjuvant S-1 chemotherapy in stage II/III Japanese gastric cancer (GC) patients and to evaluate their potential suitability for alternative cytotoxic or targeted drugs. Experimental Design: We investigated genetic polymorphisms of enzymes potentially involved in 5-fluoruracil (5-FU) metabolism as well as platinum resistance, previously identified genomic subtypes potentially predicting 5-FU benefit, and mRNA expression levels of receptor tyrosine kinases and KRAS as potential treatment targets in a single institution cohort of 252 stage II/III GC patients treated with or without S-1 after D2 gastrectomy. Results: 88% and 62% GC had a potentially 5-FU sensitive phenotype by SNP analyses of TS 3'UTR, and TS 5'UTR, respectively. 24%, 46%, 40%, 5%, and 44% GC had a potentially platinum sensitive phenotype by SNP analyses of GSTP1, ERCC1 rs11615, ERCC1 rs3212986, ERCC2, and XRCC1, respectively. High HER2, EGFR, FGFR2, or MET mRNA expression was observed in 49%, 66%, 72%, and 54% GC, respectively. High HER2 expression was the only significant prognosticator (HR=3.912, 95%CI: 1.706-8.973, p=0.0005). High HER2 (p=0.031), low EGFR (p=0.124), high MET (p=0.165) RNA expression, and TS 5'UTR subtype 2R/2R, 2R/3C, or 3C (p=0.058) were significant independent predictors for S-1 resistance. Conclusions: The present study suggests that platinum-based or RTK targeted agents could be alternative treatment options for a substantial subgroup of Japanese GC patients currently treated with S-1. HER2, EGFR, MET, and TS 5'UTR SNP appear to be promising predictive markers for S-1 resistance warranting validation in an independent GC series.

Published
2019

22. Determinants of variability of five programmed death ligand-1 immunohistochemistry assays in non-small cell lung cancer samples.

Author

Soo, RA, Yun Lim, JS, Asuncion, BR, Fazreen, Z, Herrera, MC, Mohd Omar, MF, Diem Phuong, NH, Seet, JE, Amanuel, B, Iacopetta, B, Byrne, D, Hendry, S, Fox, S, Soong, R, Soo, RA, Yun Lim, JS, Asuncion, BR, Fazreen, Z, Herrera, MC, Mohd Omar, MF, Diem Phuong, NH, Seet, JE, Amanuel, B, Iacopetta, B, Byrne, D, Hendry, S, Fox, S, and Soong, R

Abstract

Programmed death ligand-1 (PD-L1) expression as determined by immunohistochemistry (IHC) is potentially predictive of clinical outcome. The aim of this study was to assess the concordance of reported PD-L1 IHC assays and investigate factors influencing variability. Consecutive sections from 20 non-small cell lung cancers (NSCLCs) comprising resection, core biopsy, cytology and pleural fluid samples underwent IHC with 5 different antibody/autostainer combinations: 22C3/Link48, 28-8/BOND-MAX, E1L3N/BOND-MAX, SP142/BenchMark and SP263/BenchMark. PD-L1 RNA levels were assessed using RNAscope. The frequency of positive cases using scoring thresholds from clinical trials was 72%, 33%, 61%, 56%, and 33% for the 5 IHC protocols respectively, and 33% for RNAscope. Pairwise agreement on the classification of cases as positive or negative for PD-L1 expression ranged from 61%-94%. On a continuous scale, the lowest correlation was between 28-8/BOND-MAX and SP142/BenchMark (R2=0.25) and highest was between 22C3/Link48 and E1L3N/BOND-MAX (R2=0.71). When cases were ordered according to tumor cell (TC)%, a similar ranking of cases across IHC protocols could be observed, albeit with different quanta and limits of detection. Single-slide OPAL 7-color fluorescence IHC analysis revealed a high degree of co-localization of staining from the 5 PD-L1 antibodies. Using SP142 antibody in a BOND-MAX protocol led to increased TC% quanta, while retaining a similar ranking of samples according to TC%. The results of this study highlight tumor PD-L1 status can vary significantly according to IHC protocol. Protocol-dependent staining intensities and nominated thresholds for positivity contribute to this variability, while the antibody used appears to be less of a factor.

Published
2018

23. An evaluation of the challenges to developing tumor BRCA1 and BRCA2 testing methodologies for clinical practice

Author

Ellison, G, Ahdesmaki, M, Luke, S, Waring, PM, Wallace, A, Wright, R, Rothlisberger, B, Ludin, K, Merkelbach-Bruse, S, Heydt, C, Ligtenberg, MJL, Mensenkamp, AR, de Castro, DG, Jones, T, Vivancos, A, Kondrashova, O, Pauwels, P, Weyn, C, Hahnen, E, Hauke, J, Soong, R, Lai, Z, Dougherty, B, Carr, TH, Johnson, J, Mills, J, Barrett, JC, Ellison, G, Ahdesmaki, M, Luke, S, Waring, PM, Wallace, A, Wright, R, Rothlisberger, B, Ludin, K, Merkelbach-Bruse, S, Heydt, C, Ligtenberg, MJL, Mensenkamp, AR, de Castro, DG, Jones, T, Vivancos, A, Kondrashova, O, Pauwels, P, Weyn, C, Hahnen, E, Hauke, J, Soong, R, Lai, Z, Dougherty, B, Carr, TH, Johnson, J, Mills, J, and Barrett, JC

Abstract

Ovarian cancer patients with germline or somatic pathogenic variants benefit from treatment with poly ADP ribose polymerase (PARP) inhibitors. Tumor BRCA1/2 testing is more challenging than germline testing as the majority of samples are formalin-fixed paraffin embedded (FFPE), the tumor genome is complex, and the allelic fraction of somatic variants can be low. We collaborated with 10 laboratories testing BRCA1/2 in tumors to compare different approaches to identify clinically important variants within FFPE tumor DNA samples. This was not a proficiency study but an inter-laboratory comparison to identify common issues. Each laboratory received the same tumor DNA samples ranging in genotype, quantity, quality, and variant allele frequency (VAF). Each laboratory performed their preferred next-generation sequencing method to report on the variants. No false positive results were reported in this small study and the majority of methods detected the low VAF variants. A number of variants were not detected due to the bioinformatics analysis, variant classification, or insufficient DNA. The use of hybridization capture or short amplicon methods are recommended based on a bioinformatic assessment of the data. The study highlights the importance of establishing standards and standardization for tBRCA testing particularly when the test results dictate clinical decisions regarding life extending therapies.

Published
2018

24. miREM: an expectation-maximization approach for prioritizing miRNAs associated with gene-set

Author

Hadi, LHA, Lin, QXX, Tri, TM, Loh, M, Ng, HK, Salim, A, Soong, R, Benoukraf, T, Hadi, LHA, Lin, QXX, Tri, TM, Loh, M, Ng, HK, Salim, A, Soong, R, and Benoukraf, T

Abstract

BACKGROUND: The knowledge of miRNAs regulating the expression of sets of mRNAs has led to novel insights into numerous and diverse cellular mechanisms. While a single miRNA may regulate many genes, one gene can be regulated by multiple miRNAs, presenting a complex relationship to model for accurate predictions. RESULTS: Here, we introduce miREM, a program that couples an expectation-maximization (EM) algorithm to the common approach of hypergeometric probability (HP), which improves the prediction and prioritization of miRNAs from gene-sets of interest. miREM has been made available through a web-server ( https://bioinfo-csi.nus.edu.sg/mirem2/ ) that can be accessed through an intuitive graphical user interface. The program incorporates a large compendium of human/mouse miRNA-target prediction databases to enhance prediction. Users may upload their genes of interest in various formats as an input and select whether to consider non-conserved miRNAs, amongst filtering options. Results are reported in a rich graphical interface that allows users to: (i) prioritize predicted miRNAs through a scatterplot of HP p-values and EM scores; (ii) visualize the predicted miRNAs and corresponding genes through a heatmap; and (iii) identify and filter homologous or duplicated predictions by clustering them according to their seed sequences. CONCLUSION: We tested miREM using RNAseq datasets from two single "spiked" knock-in miRNA experiments and two double knock-out miRNA experiments. miREM predicted these manipulated miRNAs as having high EM scores from the gene set signatures (i.e. top predictions for single knock-in and double knock-out miRNA experiments). Finally, we have demonstrated that miREM predictions are either similar or better than results provided by existing programs.

Published
2018

26. Guidance Statement On BRCA1/2 Tumor Testing in Ovarian Cancer Patients

Author

Capoluongo, E., Ellison, G., Lopez-Guerrero, J.A., Penault-Llorca, F., Ligtenberg, M.J.L., Banerjee, S., Singer, C., Friedman, E., Markiefka, B., Schirmacher, P., Buttner, R., Asperen, C.J. van, Ray-Coquard, I., Endris, V., Kamel-Reid, S., Percival, N., Bryce, J., Rothlisberger, B., Soong, R., Castro, D.G. de, Capoluongo, E., Ellison, G., Lopez-Guerrero, J.A., Penault-Llorca, F., Ligtenberg, M.J.L., Banerjee, S., Singer, C., Friedman, E., Markiefka, B., Schirmacher, P., Buttner, R., Asperen, C.J. van, Ray-Coquard, I., Endris, V., Kamel-Reid, S., Percival, N., Bryce, J., Rothlisberger, B., Soong, R., and Castro, D.G. de

Abstract

Item does not contain fulltext, The approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum-sensitive relapsed high-grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer. Furthermore, testing of tumor samples to identify the estimated 3%-9% of patients with somatic BRCA1/2 mutations who, in addition to germline carriers, could benefit from PARPi therapy is also now being considered. This new testing paradigm poses some challenges, in particular the technical and analytical difficulties of analyzing chemically challenged DNA derived from formalin-fixed, paraffin-embedded specimens. The current manuscript reviews some of these challenges and technical recommendations to consider when undertaking BRCA1/2 testing in tumor tissue samples to detect both germline and somatic BRCA1/2 mutations. Also provided are considerations for incorporating genetic analysis of ovarian tumor samples into the patient pathway and ethical requirements.

Published
2017

27. Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity

Author

Wahl, S. (Simone), Drong, A. (Alexander), Lehne, B. (Benjamin), Loh, M. (Marie), Scott, W.R. (William R.), Kunze, S. (Sonja), Tsai, P.-C. (Pei-Chien), Ried, J.S. (Janina S.), Zhang, W. (Weihua), Yang, Y. (Youwen), Tan, S. (Sili), Fiorito, G. (Giovanni), Franke, L. (Lude), Guarrera, S. (Simonetta), Kasela, S. (Silva), Kriebel, J. (Jennifer), Richmond, R.C. (Rebecca C.), Adamo, M. (Marco), Afzal, U. (Uzma), Ala-Korpela, M. (Mika), Albetti, B. (Benedetta), Ammerpohl, O. (Ole), Apperley, J. (Jane), Beekman, M. (Marian), Bertazzi, P.A. (Pier Alberto), Black, S.L. (S. Lucas), Blancher, C. (Christine), Bonder, M.J. (Marc), Brosch, M. (Mario), Carstensen-Kirberg, M. (Maren), Craen, A.J. (Anton) de, Lusignan, S. (Simon) de, Dehghan, A. (Abbas), Elkalaawy, M. (Mohamed), Fischer, K. (Krista), Franco, O.H. (Oscar), Gaunt, T.R. (Tom), Hampe, J. (Jochen), Hashemi, M. (Majid), Isaacs, A.J. (Aaron), Jenkinson, A. (Andrew), Jha, S. (Sujeet), Kato, N. (Norihiro), Krogh, V. (Vittorio), Laffan, M. (Michael), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mok, Z.Y. (Zuan Yu), Motta, V. (Valeria), Ng, H.K. (Hong Kiat), Nikolakopoulou, Z. (Zacharoula), Nteliopoulos, G. (Georgios), Panico, S. (Salvatore), Pervjakova, N. (Natalia), Prokisch, H. (Holger), Rathmann, W. (Wolfgang), Roden, M. (Michael), Rota, F. (Federica), Rozario, M.A. (Michelle Ann), Sandling, J.K. (Johanna), Schafmayer, C. (Clemens), Schramm, K. (Katharina), Siebert, R. (Reiner), Slagboom, P.E. (Eline), Soininen, P. (Pasi), Stolk, L. (Lisette), Strauch, K. (Konstantin), Tai, E.S. (Shyong), Tarantini, L. (Letizia), Thorand, B. (Barbara), Tigchelaar, E.F. (Ettje F.), Tumino, R. (Rosario), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Meurs, J.B.J. (Joyce) van, Vineis, P. (Paolo), Wickremasinghe, A.R. (Ananda), Wijmenga, C. (Cisca), Yang, T.-P. (Tsun-Po), Yuan, W. (Wei), Zhernakova, A. (Alexandra), Batterham, R.L., Smith, A.V. (Davey), Deloukas, P. (Panos), Heijmans, B.T. (Bastiaan T.), Herder, C. (Christian), Hofman, A. (Albert), Lindgren, C.M. (Cecilia M.), Milani, L. (Lili), Harst, P. (Pim) van der, Peters, A. (Annette), Illig, T. (Thomas), Relton, C.L. (Caroline), Waldenberger, M. (Melanie), Jarvelin, M.-R. (Marjo-Riitta), Bollati, V. (Valentina), Soong, R. (Richie), Spector, T.D. (Timothy), Scott, J. (James), McCarthy, M.I. (Mark), Elliott, P. (Paul), Bell, J.T. (Jordana T.), Matullo, G., Gieger, C. (Christian), Kooner, J.S. (Jaspal S.), Grallert, H. (Harald), Chambers, J.C. (John C.), Wahl, S. (Simone), Drong, A. (Alexander), Lehne, B. (Benjamin), Loh, M. (Marie), Scott, W.R. (William R.), Kunze, S. (Sonja), Tsai, P.-C. (Pei-Chien), Ried, J.S. (Janina S.), Zhang, W. (Weihua), Yang, Y. (Youwen), Tan, S. (Sili), Fiorito, G. (Giovanni), Franke, L. (Lude), Guarrera, S. (Simonetta), Kasela, S. (Silva), Kriebel, J. (Jennifer), Richmond, R.C. (Rebecca C.), Adamo, M. (Marco), Afzal, U. (Uzma), Ala-Korpela, M. (Mika), Albetti, B. (Benedetta), Ammerpohl, O. (Ole), Apperley, J. (Jane), Beekman, M. (Marian), Bertazzi, P.A. (Pier Alberto), Black, S.L. (S. Lucas), Blancher, C. (Christine), Bonder, M.J. (Marc), Brosch, M. (Mario), Carstensen-Kirberg, M. (Maren), Craen, A.J. (Anton) de, Lusignan, S. (Simon) de, Dehghan, A. (Abbas), Elkalaawy, M. (Mohamed), Fischer, K. (Krista), Franco, O.H. (Oscar), Gaunt, T.R. (Tom), Hampe, J. (Jochen), Hashemi, M. (Majid), Isaacs, A.J. (Aaron), Jenkinson, A. (Andrew), Jha, S. (Sujeet), Kato, N. (Norihiro), Krogh, V. (Vittorio), Laffan, M. (Michael), Meisinger, C. (Christa), Meitinger, T. (Thomas), Mok, Z.Y. (Zuan Yu), Motta, V. (Valeria), Ng, H.K. (Hong Kiat), Nikolakopoulou, Z. (Zacharoula), Nteliopoulos, G. (Georgios), Panico, S. (Salvatore), Pervjakova, N. (Natalia), Prokisch, H. (Holger), Rathmann, W. (Wolfgang), Roden, M. (Michael), Rota, F. (Federica), Rozario, M.A. (Michelle Ann), Sandling, J.K. (Johanna), Schafmayer, C. (Clemens), Schramm, K. (Katharina), Siebert, R. (Reiner), Slagboom, P.E. (Eline), Soininen, P. (Pasi), Stolk, L. (Lisette), Strauch, K. (Konstantin), Tai, E.S. (Shyong), Tarantini, L. (Letizia), Thorand, B. (Barbara), Tigchelaar, E.F. (Ettje F.), Tumino, R. (Rosario), Uitterlinden, A.G. (André), Duijn, C.M. (Cornelia) van, Meurs, J.B.J. (Joyce) van, Vineis, P. (Paolo), Wickremasinghe, A.R. (Ananda), Wijmenga, C. (Cisca), Yang, T.-P. (Tsun-Po), Yuan, W. (Wei), Zhernakova, A. (Alexandra), Batterham, R.L., Smith, A.V. (Davey), Deloukas, P. (Panos), Heijmans, B.T. (Bastiaan T.), Herder, C. (Christian), Hofman, A. (Albert), Lindgren, C.M. (Cecilia M.), Milani, L. (Lili), Harst, P. (Pim) van der, Peters, A. (Annette), Illig, T. (Thomas), Relton, C.L. (Caroline), Waldenberger, M. (Melanie), Jarvelin, M.-R. (Marjo-Riitta), Bollati, V. (Valentina), Soong, R. (Richie), Spector, T.D. (Timothy), Scott, J. (James), McCarthy, M.I. (Mark), Elliott, P. (Paul), Bell, J.T. (Jordana T.), Matullo, G., Gieger, C. (Christian), Kooner, J.S. (Jaspal S.), Grallert, H. (Harald), and Chambers, J.C. (John C.)

Abstract

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10 -7, range P = 9.2 × 10 -8 to 6.0 × 10 -46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10 -6, range P = 5.5 × 10 -6 to 6.1 × 10 -35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10 -54). Our results provide new insights into the biologic pathways influenc

Published
2017
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28. Establishing multiple omics baselines for three Southeast Asian populations in the Singapore Integrative Omics Study

Author

Saw, W-Y, Tantoso, E, Begum, H, Zhou, L, Zou, R, He, C, Chan, SL, Tan, LW-L, Wong, L-P, Xu, W, Kyin, D, Moong, N, Lim, Y, Li, B, Pillai, NE, Peterson, TA, Bielawny, T, Meikle, PJ, Mundra, PA, Lim, W-Y, Luo, M, Chia, K-S, Ong, RT-H, Brunham, LR, Khor, C-C, Too, HP, Soong, R, Wenk, MR, Little, P, Teo, Y-Y, Saw, W-Y, Tantoso, E, Begum, H, Zhou, L, Zou, R, He, C, Chan, SL, Tan, LW-L, Wong, L-P, Xu, W, Kyin, D, Moong, N, Lim, Y, Li, B, Pillai, NE, Peterson, TA, Bielawny, T, Meikle, PJ, Mundra, PA, Lim, W-Y, Luo, M, Chia, K-S, Ong, RT-H, Brunham, LR, Khor, C-C, Too, HP, Soong, R, Wenk, MR, Little, P, and Teo, Y-Y

Abstract

The Singapore Integrative Omics Study provides valuable insights on establishing population reference measurement in 364 Chinese, Malay, and Indian individuals. These measurements include > 2.5 millions genetic variants, 21,649 transcripts expression, 282 lipid species quantification, and 284 clinical, lifestyle, and dietary variables. This concept paper introduces the depth of the data resource, and investigates the extent of ethnic variation at these omics and non-omics biomarkers. It is evident that there are specific biomarkers in each of these platforms to differentiate between the ethnicities, and intra-population analyses suggest that Chinese and Indians are the most biologically homogeneous and heterogeneous, respectively, of the three groups. Consistent patterns of correlations between lipid species also suggest the possibility of lipid tagging to simplify future lipidomics assays. The Singapore Integrative Omics Study is expected to allow the characterization of intra-omic and inter-omic correlations within and across all three ethnic groups through a systems biology approach.The Singapore Genome Variation projects characterized the genetics of Singapore's Chinese, Malay, and Indian populations. The Singapore Integrative Omics Study introduced here goes further in providing multi-omic measurements in individuals from these populations, including genetic, transcriptome, lipidome, and lifestyle data, and will facilitate the study of common diseases in Asian communities.

Published
2017

29. Guidance Statement On BRCA1/2 Tumor Testing in Ovarian Cancer Patients

Author

Capoluongo, Ettore Domenico, Ellison, G, Lopez-Guerrero, Ja, Penault-Llorca, F, Ligtenberg, Mjl, Banerjee, S, Singer, C, Friedman, E, Markiefka, B, Schirmacher, P, Buttner, R, van Asperen, Cj, Ray-Coquard, I, Endris, V, Kamel-Reid, S, Percival, N, Bryce, J, Rothlisberger, B, Soong, R, de Castro, Dg, Capoluongo, E (ORCID:0000-0001-9872-0572), Capoluongo, Ettore Domenico, Ellison, G, Lopez-Guerrero, Ja, Penault-Llorca, F, Ligtenberg, Mjl, Banerjee, S, Singer, C, Friedman, E, Markiefka, B, Schirmacher, P, Buttner, R, van Asperen, Cj, Ray-Coquard, I, Endris, V, Kamel-Reid, S, Percival, N, Bryce, J, Rothlisberger, B, Soong, R, de Castro, Dg, and Capoluongo, E (ORCID:0000-0001-9872-0572)

Abstract

The approval, in 2015, of the first poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi; olaparib, Lynparza) for platinum sensitive relapsed high grade ovarian cancer with either germline or somatic BRCA1/2 deleterious mutations is changing the way that BRCA1/2 testing services are offered to patients with ovarian cancer. Ovarian cancer patients are now being referred for BRCA1/2 genetic testing for treatment decisions, in addition to familial risk estimation, and irrespective of a family history of breast or ovarian cancer. Furthermore, testing of tumor samples to identify the estimated 3%-9% of patients with somatic BRCA1/2 mutations who, in addition to germline carriers, could benefit from PARPi therapy is also now being considered. This new testing paradigm poses some challenges, in particular the technical and analytical difficulties of analyzing chemically challenged DNA derived from formalin fixed, paraffin embedded specimens. The current manuscript reviews some of these challenges and technical recommendations to consider when undertaking BRCA1/2 testing in tumor tissue samples to detect both germline and somatic BRCA1/2 mutations. Also provided are considerations for incorporating genetic analysis of ovarian tumor samples into the patient pathway and ethical requirements.

Published
2017

31. Pre-Transplantation Immune Cell Distribution and Early Post-Transplant Fungal Infection Are the Main Risk Factors of Liver Transplantation Recipients in Lower Model of End-Stage Liver Disease

Author

Abdelhamid, N.M., primary, Chen, Y.-C., additional, Wang, Y.-C., additional, Cheng, C.-H., additional, Wu, T.-J., additional, Lee, C.-F., additional, Wu, T.-H., additional, Chou, H.-S., additional, Chan, K.-M., additional, Lee, W.-C., additional, and Soong, R.-S., additional

Published
2017
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33. 149O The National University Cancer Institute, Singapore (NCIS) Integrated Molecular Analysis of Cancer (IMAC) precision oncology programme: Frequency of actionable mutations and outcomes following matched therapy in an Asian Cancer Centre

Author

Syn, N., primary, Heong, V., additional, Lee, X.W., additional, Sapari, N.S., additional, Koh, X.Q., additional, Fazreen, Z., additional, Lim, J.S.Y., additional, Pang, B., additional, Lim, D., additional, Wong, A.L-A., additional, Soo, R.A., additional, Yong, W-P., additional, Chee, C-E., additional, Lee, S-C., additional, Goh, B-C., additional, Soong, R., additional, and Tan, D.S., additional

Published
2016
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36. Gelsolin-mediated activation of PI3K/Akt pathway is crucial for hepatocyte growth factor-induced cell scattering in gastric carcinoma

Author

Huang, B., Deng, S., Loo, S., Datta, A., Yap, Y., Yan, B., Ooi, C., Dinh, T., Zhuo, J., Tochhawng, L., Gopinadhan, S., Jegadeesan, T., Tan, P., Salto-Tellez, M., Yong, W., Soong, R., Yeoh, K., Goh, Y., Lobie, P., Yang, H., Kumar, Alan Prem, Maciver, S., So, J., Yap, C., Huang, B., Deng, S., Loo, S., Datta, A., Yap, Y., Yan, B., Ooi, C., Dinh, T., Zhuo, J., Tochhawng, L., Gopinadhan, S., Jegadeesan, T., Tan, P., Salto-Tellez, M., Yong, W., Soong, R., Yeoh, K., Goh, Y., Lobie, P., Yang, H., Kumar, Alan Prem, Maciver, S., So, J., and Yap, C.

Abstract

In gastric cancer (GC), the main subtypes (diffuse and intestinal types) differ in pathological characteristics, with diffuse GC exhibiting early disseminative and invasive behaviour. A distinctive feature of diffuse GC is loss of intercellular adhesion. Although widely attributed to mutations in the CDH1 gene encoding E-cadherin, a significant percentage of diffuse GC do not harbor CDH1 mutations. We found that the expression of the actin-modulating cytoskeletal protein, gelsolin, is significantly higher in diffuse-type compared to intestinal-type GCs, using immunohistochemical and microarray analysis. Furthermore, in GCs with wild-type CDH1, gelsolin expression correlated inversely with CDH1 gene expression. Downregulating gelsolin using siRNA in GC cells enhanced intercellular adhesion and E-cadherin expression, and reduced invasive capacity. Interestingly, hepatocyte growth factor (HGF) induced increasedgelsolin expression, and gelsolin was essential for HGF-medicated cell scattering and E-cadherin transcriptional repression through Snail, Twist and Zeb2. The HGF-dependent effect on E-cadherin was found to be mediated by interactions between gelsolin and PI3K-Akt signaling. This study reveals for the first time a function of gelsolin in the HGF/cMet oncogenic pathway, which leads to E-cadherin repression and cell scattering in gastric cancer. Our study highlights gelsolin as an important pro-disseminative factor contributing to the aggressive phenotype of diffuse GC.

Published
2016

38. Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

Author

Kato, N. (Norihiro), Loh, M. (Marie), Takeuchi, F. (Fumihiko), Verweij, N. (Niek), Wang, X. (Xu), Zhang, W. (Weihua), NKelly, T. (Tanika), Saleheen, D., Lehne, B. (Benjamin), Leach, I.M. (Irene Mateo), Drong, A. (Alexander), Abbott, J. (James), Wahl, S. (Simone), Tan, S.-T. (Sian-Tsung), Scott, W.R. (William R.), Campanella, G. (Gianluca), Chadeau-Hyam, M. (Marc), Afzal, U. (Uzma), Ahluwalia, T.S. (Tarunveer Singh), Bonder, M.J. (Marc), Chen, P. (Ping), Dehghan, A. (Abbas), Edwards, T.L. (Todd L.), Esko, T. (Tõnu), Go, M.J. (Min Jin), Harris, S.E. (Sarah), Hartiala, J. (Jaana), Kasela, S. (Silva), Kasturiratne, A. (Anuradhani), Khor, C.C., Kleber, M.E. (Marcus), Li, H. (Huaixing), Mok, Z.Y. (Zuan Yu), Nakatochi, M. (Masahiro), Sapari, N.S. (Nur Sabrina), Saxena, R. (Richa), Stewart, A.F. (Alexandre F.), Stolk, L. (Lisette), Tabara, Y. (Yasuharu), Teh, A.L. (Ai Ling), Wu, Y. (Ying), Wu, J.-Y. (Jer-Yuarn), Zhang, Y. (Yi), Aits, I. (Imke), Da Silva Couto Alves, A. (Alexessander), Das, S. (Shikta), Dorajoo, R. (Rajkumar), CHopewell, J. (Jemma), Kim, Y.K. (Yun Kyoung), WKoivula, R. (Robert), Luan, J. (Jian'An), Lyytikäinen, L.-P. (Leo-Pekka), NNguyen, Q. (Quang), Pereira, M.A. (Mark A), Postmus, D. (Douwe), TRaitakari, O. (Olli), Scannell Bryan, M. (Molly), Scott, R.A. (Robert), Sorice, R., Tragante, V. (Vinicius), Traglia, M. (Michela), White, J. (Jon), Yamamoto, K. (Ken), Zhang, Y. (Yonghong), Adair, L.S. (Linda), Ahmed, A. (Alauddin), Akiyama, K. (Koichi), Asif, R. (Rasheed), Aung, T. (Tin), Barroso, I.E. (Inês), Bjonnes, A. (Andrew), Braun, T.R. (Timothy R.), Cai, H. (Hui), Chang, L.-C. (Li-Ching), Chen, C.-H., Cheng, C-Y. (Ching-Yu), Chong, Y.-S. (Yap-Seng), Collins, F.S. (Francis), Courtney, R. (Regina), Davies, G. (Gail), Delgado, G., Do, L.D. (Loi D.), Doevendans, P.A. (Pieter), Gansevoort, R.T. (Ron), Gao, Y. (Ying), Grammer, T.B. (Tanja B), Grarup, N. (Niels), Grewal, J. (Jagvir), Gu, D. (D.), SWander, G. (Gurpreet), Hartikainen, A.L., Hazen, S.L. (Stanley), He, J. (Jing), Heng, C.K. (Chew-Kiat), Hixso, E.J.A. (E. James Ames), Hofman, A. (Albert), Hsu, C. (Chris), Huang, W. (Wei), Husemoen, L.L.N. (Lise Lotte), Hwang, J.-Y. (Joo-Yeon), Ichihara, S. (Sahoko), Igase, M. (Michiya), Isono, M. (Masato), Justesen, J.M. (Johanne M.), Katsuya, T. (Tomohiro), GKibriya, M. (Muhammad), Kim, Y.J., Kishimoto, M. (Miyako), Koh, W.-P. (Woon-Puay), Kohara, K. (Katsuhiko), Kumari, M. (Meena), Kwek, K. (Kenneth), Lee, N.R. (Nanette), Lee, J. (Jeannette), Liao, J. (Jie), Lieb, W. (Wolfgang), Liewald, D.C.M. (David), Matsubara, T. (Tatsuaki), Matsushita, Y. (Yumi), Meitinger, T. (Thomas), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Mononen, K. (Kari), Müller-Nurasyid, M. (Martina), Nabika, T. (Toru), Nakashima, E. (Eitaro), Ng, H.K. (Hong Kiat), Nikus, K. (Kjell), Nutile, T., Ohkubo, T. (Takayoshi), Ohnaka, K. (Keizo), Parish, S. (Sarah), Paternoster, L. (Lavinia), Peng, H. (Hao), Peters, A. (Annette), TPham, S. (Son), Pinidiyapathirage, M.J. (Mohitha J.), Rahman, M. (Mahfuzar), Rakugi, H. (Hiromi), Rolandsson, O. (Olov), Rozario, M.A. (Michelle Ann), Ruggiero, D., Sala, C. (Cinzia), Sarju, R. (Ralhan), Shimokawa, K. (Kazuro), Snieder, H. (Harold), Sparsø, T. (Thomas), Spiering, W. (Wilko), Starr, J.M. (John), Stott, D.J. (David J.), OStram, D. (Daniel), Sugiyama, T. (Takao), Szymczak, S. (Silke), Tang, W.H.W. (W.H. Wilson), Tong, L. (Lin), Trompet, S. (Stella), Turjanmaa, V. (Väinö), Ueshima, H. (Hirotsugu), Uitterlinden, A.G. (André), Umemura, S. (Satoshi), Vaarasmaki, M. (Marja), Dam, R.M. (Rob Mvan), Gilst, W.H. (Wiek) van, Veldhuisen, D.J. (Dirk) van, Viikari, J. (Jorma), Waldenberger, M. (Melanie), Wang, Y. (Yiqin), Wang, A. (Aili), Wilson, R. (Rory), Wong, T.Y. (Tien Yin), Xiang, Y.-B. (Yong-Bing), Yamaguchi, S. (Shuhei), Ye, X. (Xingwang), Young, R. (Robin), Young, T.L. (Terri), Yuan, J.-M. (Jian-Min), Zhou, X. (Xueya), Asselbergs, F.W. (Folkert), Ciullo, M., Clarke, R. (Robert), Deloukas, P. (Panagiotis), Franke, A. (Andre), Paul, W.F. (W. Frank), Franks, S. (Steve), Friedlander, Y. (Yechiel), Gross, M.D. (Myron D.), Guo, Z. (Zhirong), Hansen, T. (T.), Jarvelin, M.-R. (Marjo-Riitta), Jørgensen, T. (Torben), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kajio, H. (Hiroshi), Kivimaki, M. (Mika), Lee, J.-Y. (Jong-Young), Lehtimäki, T. (Terho), Linneberg, A. (Allan), Miki, T. (Tetsuro), Pedersen, O. (Oluf), Samani, N.J. (Nilesh), Sørensen, T.I.A. (Thorkild), Takayanagi, R. (Ryoichi), Toniolo, D. (Daniela), Ahsan, H. (Habibul), Allayee, H. (Hooman), Chen, Y.-T. (Yuan-Tsong), Danesh, J. (John), Deary, I.J. (Ian), Franco, O.H. (Oscar), Franke, L. (Lude), THeijman, B. (Bastiaan), Holbrook, J.D. (Joanna D.), Isaacs, A.J. (Aaron), Kim, B.-J. (Bong-Jo), Lin, X. (Xu), Liu, J. (Jianjun), März, W. (Winfried), Metspalu, A. (Andres), Mohlke, K.L. (Karen), Sangher, K., Harambir, D. (Dharambir), Shu, X.-O. (Xiao-Ou), Meurs, J.B.J. (Joyce) van, Vithana, E.N. (Eranga), Wickremasinghe, A.R. (Ananda), Wijmenga, C. (Cisca), Wolffenbuttel, B.H.W. (Bruce H.W.), Yokota, M. (Mitsuhiro), Zheng, W. (Wei), Zhu, D. (Dingliang), Vineis, P. (Paolo), Kyrtopoulos, S.A. (Soterios A.), Kleinjans, J.C.S. (Jos C.S.), McCarthy, M.I. (Mark), Soong, R. (Richie), Gieger, C. (Christian), Scott, J. (James), Teo, Y.Y. (Yik Ying), He, J. (Jiang), Elliott, P. (Paul), Tai, E.S. (Shyong), Harst, P. (Pim) van der, Kooner, J.S. (Jaspal S.), Chambers, J.C. (John), Kato, N. (Norihiro), Loh, M. (Marie), Takeuchi, F. (Fumihiko), Verweij, N. (Niek), Wang, X. (Xu), Zhang, W. (Weihua), NKelly, T. (Tanika), Saleheen, D., Lehne, B. (Benjamin), Leach, I.M. (Irene Mateo), Drong, A. (Alexander), Abbott, J. (James), Wahl, S. (Simone), Tan, S.-T. (Sian-Tsung), Scott, W.R. (William R.), Campanella, G. (Gianluca), Chadeau-Hyam, M. (Marc), Afzal, U. (Uzma), Ahluwalia, T.S. (Tarunveer Singh), Bonder, M.J. (Marc), Chen, P. (Ping), Dehghan, A. (Abbas), Edwards, T.L. (Todd L.), Esko, T. (Tõnu), Go, M.J. (Min Jin), Harris, S.E. (Sarah), Hartiala, J. (Jaana), Kasela, S. (Silva), Kasturiratne, A. (Anuradhani), Khor, C.C., Kleber, M.E. (Marcus), Li, H. (Huaixing), Mok, Z.Y. (Zuan Yu), Nakatochi, M. (Masahiro), Sapari, N.S. (Nur Sabrina), Saxena, R. (Richa), Stewart, A.F. (Alexandre F.), Stolk, L. (Lisette), Tabara, Y. (Yasuharu), Teh, A.L. (Ai Ling), Wu, Y. (Ying), Wu, J.-Y. (Jer-Yuarn), Zhang, Y. (Yi), Aits, I. (Imke), Da Silva Couto Alves, A. (Alexessander), Das, S. (Shikta), Dorajoo, R. (Rajkumar), CHopewell, J. (Jemma), Kim, Y.K. (Yun Kyoung), WKoivula, R. (Robert), Luan, J. (Jian'An), Lyytikäinen, L.-P. (Leo-Pekka), NNguyen, Q. (Quang), Pereira, M.A. (Mark A), Postmus, D. (Douwe), TRaitakari, O. (Olli), Scannell Bryan, M. (Molly), Scott, R.A. (Robert), Sorice, R., Tragante, V. (Vinicius), Traglia, M. (Michela), White, J. (Jon), Yamamoto, K. (Ken), Zhang, Y. (Yonghong), Adair, L.S. (Linda), Ahmed, A. (Alauddin), Akiyama, K. (Koichi), Asif, R. (Rasheed), Aung, T. (Tin), Barroso, I.E. (Inês), Bjonnes, A. (Andrew), Braun, T.R. (Timothy R.), Cai, H. (Hui), Chang, L.-C. (Li-Ching), Chen, C.-H., Cheng, C-Y. (Ching-Yu), Chong, Y.-S. (Yap-Seng), Collins, F.S. (Francis), Courtney, R. (Regina), Davies, G. (Gail), Delgado, G., Do, L.D. (Loi D.), Doevendans, P.A. (Pieter), Gansevoort, R.T. (Ron), Gao, Y. (Ying), Grammer, T.B. (Tanja B), Grarup, N. (Niels), Grewal, J. (Jagvir), Gu, D. (D.), SWander, G. (Gurpreet), Hartikainen, A.L., Hazen, S.L. (Stanley), He, J. (Jing), Heng, C.K. (Chew-Kiat), Hixso, E.J.A. (E. James Ames), Hofman, A. (Albert), Hsu, C. (Chris), Huang, W. (Wei), Husemoen, L.L.N. (Lise Lotte), Hwang, J.-Y. (Joo-Yeon), Ichihara, S. (Sahoko), Igase, M. (Michiya), Isono, M. (Masato), Justesen, J.M. (Johanne M.), Katsuya, T. (Tomohiro), GKibriya, M. (Muhammad), Kim, Y.J., Kishimoto, M. (Miyako), Koh, W.-P. (Woon-Puay), Kohara, K. (Katsuhiko), Kumari, M. (Meena), Kwek, K. (Kenneth), Lee, N.R. (Nanette), Lee, J. (Jeannette), Liao, J. (Jie), Lieb, W. (Wolfgang), Liewald, D.C.M. (David), Matsubara, T. (Tatsuaki), Matsushita, Y. (Yumi), Meitinger, T. (Thomas), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Mononen, K. (Kari), Müller-Nurasyid, M. (Martina), Nabika, T. (Toru), Nakashima, E. (Eitaro), Ng, H.K. (Hong Kiat), Nikus, K. (Kjell), Nutile, T., Ohkubo, T. (Takayoshi), Ohnaka, K. (Keizo), Parish, S. (Sarah), Paternoster, L. (Lavinia), Peng, H. (Hao), Peters, A. (Annette), TPham, S. (Son), Pinidiyapathirage, M.J. (Mohitha J.), Rahman, M. (Mahfuzar), Rakugi, H. (Hiromi), Rolandsson, O. (Olov), Rozario, M.A. (Michelle Ann), Ruggiero, D., Sala, C. (Cinzia), Sarju, R. (Ralhan), Shimokawa, K. (Kazuro), Snieder, H. (Harold), Sparsø, T. (Thomas), Spiering, W. (Wilko), Starr, J.M. (John), Stott, D.J. (David J.), OStram, D. (Daniel), Sugiyama, T. (Takao), Szymczak, S. (Silke), Tang, W.H.W. (W.H. Wilson), Tong, L. (Lin), Trompet, S. (Stella), Turjanmaa, V. (Väinö), Ueshima, H. (Hirotsugu), Uitterlinden, A.G. (André), Umemura, S. (Satoshi), Vaarasmaki, M. (Marja), Dam, R.M. (Rob Mvan), Gilst, W.H. (Wiek) van, Veldhuisen, D.J. (Dirk) van, Viikari, J. (Jorma), Waldenberger, M. (Melanie), Wang, Y. (Yiqin), Wang, A. (Aili), Wilson, R. (Rory), Wong, T.Y. (Tien Yin), Xiang, Y.-B. (Yong-Bing), Yamaguchi, S. (Shuhei), Ye, X. (Xingwang), Young, R. (Robin), Young, T.L. (Terri), Yuan, J.-M. (Jian-Min), Zhou, X. (Xueya), Asselbergs, F.W. (Folkert), Ciullo, M., Clarke, R. (Robert), Deloukas, P. (Panagiotis), Franke, A. (Andre), Paul, W.F. (W. Frank), Franks, S. (Steve), Friedlander, Y. (Yechiel), Gross, M.D. (Myron D.), Guo, Z. (Zhirong), Hansen, T. (T.), Jarvelin, M.-R. (Marjo-Riitta), Jørgensen, T. (Torben), Jukema, J.W. (Jan Wouter), Kähönen, M. (Mika), Kajio, H. (Hiroshi), Kivimaki, M. (Mika), Lee, J.-Y. (Jong-Young), Lehtimäki, T. (Terho), Linneberg, A. (Allan), Miki, T. (Tetsuro), Pedersen, O. (Oluf), Samani, N.J. (Nilesh), Sørensen, T.I.A. (Thorkild), Takayanagi, R. (Ryoichi), Toniolo, D. (Daniela), Ahsan, H. (Habibul), Allayee, H. (Hooman), Chen, Y.-T. (Yuan-Tsong), Danesh, J. (John), Deary, I.J. (Ian), Franco, O.H. (Oscar), Franke, L. (Lude), THeijman, B. (Bastiaan), Holbrook, J.D. (Joanna D.), Isaacs, A.J. (Aaron), Kim, B.-J. (Bong-Jo), Lin, X. (Xu), Liu, J. (Jianjun), März, W. (Winfried), Metspalu, A. (Andres), Mohlke, K.L. (Karen), Sangher, K., Harambir, D. (Dharambir), Shu, X.-O. (Xiao-Ou), Meurs, J.B.J. (Joyce) van, Vithana, E.N. (Eranga), Wickremasinghe, A.R. (Ananda), Wijmenga, C. (Cisca), Wolffenbuttel, B.H.W. (Bruce H.W.), Yokota, M. (Mitsuhiro), Zheng, W. (Wei), Zhu, D. (Dingliang), Vineis, P. (Paolo), Kyrtopoulos, S.A. (Soterios A.), Kleinjans, J.C.S. (Jos C.S.), McCarthy, M.I. (Mark), Soong, R. (Richie), Gieger, C. (Christian), Scott, J. (James), Teo, Y.Y. (Yik Ying), He, J. (Jiang), Elliott, P. (Paul), Tai, E.S. (Shyong), Harst, P. (Pim) van der, Kooner, J.S. (Jaspal S.), and Chambers, J.C. (John)

Abstract

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10 -11 to 5.0 × 10 -21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10 -6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.

Published
2015
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39. The prognostic value of the stem-like group in colorectal cancer using a panel of immunohistochemistry markers

Author

Ong, C., Chong, P., McArt, D., Chan, J., Tan, H., Kumar, Alan Prem, Chung, M., Clément, M., Soong, R., Van Schaeybroeck, S., Waugh, D., Johnston, P., Dunne, P., Salto-Tellez, M., Ong, C., Chong, P., McArt, D., Chan, J., Tan, H., Kumar, Alan Prem, Chung, M., Clément, M., Soong, R., Van Schaeybroeck, S., Waugh, D., Johnston, P., Dunne, P., and Salto-Tellez, M.

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the Western world. It is becoming increasingly clear that CRC is a diverse disease, as exemplified by the identification of subgroups of CRC tumours that are driven by distinct biology. Recently, a number of studies have begun to define panels of diagnostically relevant markers to align patients into individual subgroups in an attempt to give information on prognosis and treatment response. We examined the immunohistochemical expression profile of 18 markers, each representing a putative role in cancer development, in 493 primary colorectal carcinomas using tissue microarrays. Through unsupervised clustering in stage II cancers, we identified two cluster groups that are broadly defined by inflammatory or immune-related factors (CD3, CD8, COX-2 and FOXP3) and stem-like factors (CD44, LGR5, SOX2, OCT4). The expression of the stem-like group markers was associated with a significantly worse prognosis compared to cases with lower expression. In addition, patients classified in the stem-like subgroup displayed a trend towards a benefit from adjuvant treatment. The biologically relevant and poor prognostic stem-like group could also be identified in early stage I cancers, suggesting a potential opportunity for the identification of aggressive tumors at a very early stage of the disease.

Published
2015

40. Phase I and biomarker study of OPB-51602, a novel signal transducer and activator of transcription (STAT) 3 inhibitor, in patients with refractory solid malignancies

Author

Wong, A., Soo, R., Tan, D., Lee, S., Lim, J., Marban, P., Kong, L., Lee, Y., Wang, L., Thuya, W., Soong, R., Yee, M., Chin, T., Cordero, M., Asuncion, B., Pang, B., Pervaiz, Shazib, Hirpara, J., Sinha, A., Xu, W., Yuasa, M., Tsunoda, T., Motoyama, M., Yamauchi, T., Goh, B., Wong, A., Soo, R., Tan, D., Lee, S., Lim, J., Marban, P., Kong, L., Lee, Y., Wang, L., Thuya, W., Soong, R., Yee, M., Chin, T., Cordero, M., Asuncion, B., Pang, B., Pervaiz, Shazib, Hirpara, J., Sinha, A., Xu, W., Yuasa, M., Tsunoda, T., Motoyama, M., Yamauchi, T., and Goh, B.

Abstract

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.Background: The aim of this study was to determine the maximum-tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of OPB-51602, an oral, direct signal transduction activator of transcription 3 (STAT3) inhibitor, in patients with refractory solid tumors. Patients and methods: Three cohorts were studied: cohort A, a sequential dose escalation of OPB-51602 administered intermittently (days 1-14 every 21 days); cohort B, an expansion cohort evaluating the dose lower than the MTD; cohort C, evaluating continuous daily dosing. Results: Fifty-one patients were studied at 2, 4, and 5 mg per day dosing. The MTD was 5 mg; first-cycle dose-limiting toxicities (DLTs) were grade 3 hyponatremia in one patient, and grade 3 dehydration in another. Intermittent dosing of both 2 and 4 mg doses were tolerable, and the recommended phase II dose was 4 mg. Cohort B investigated 4 mg intermittently, whereas cohort C investigated 4 mg continuously. Common toxicities included fatigue, nausea/vomiting, diarrhea, anorexia, and early-onset peripheral neuropathy. Drug-induced pneumonitis occurred in two patients in cohort C. Continuous dosing was associated with a higher incidence of peripheral neuropathy and a lower mean relative dose intensity, compared with intermittent dosing. Steady-state pharmacokinetics was characterized by high oral clearance, mean elimination half-life ranging from 44 to 61 h, and a large terminal-phase volume of distribution. An active metabolite, OPB-51822, accumulated to a greater extent than OPB-51602. Flow cytometry of peripheral blood mononuclear cells demonstrated pSTAT3 (Tyr705) inhibition following exposure. Two patients achieved partial responses at 5 mg intermittently and 4 mg continuously; both had epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCL

Published
2015

44. Etablierung eines murinen Tumormodells zur prospektiven Responsebeurteilung target-orientierter Therapieformen beim Lungenkarzinom

Author

Merk, Johannes, Rolff, J., Becker, M., Soong, R., Klemm, W., Fichtner, I., and Leschber, G.

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Einleitung: Die Wert der adjuvanten Therapie beim operierten, nicht-kleinzelligen Lungenkarzinom (NSCLC) ist inzwischen auch in frühen Tumorstadien für platinbasierte Chemotherapien durch Multicenterstudien belegt. Weitere Therapieformen, wie die targetorientierten Verfahren, sollten -basierend[for full text, please go to the a.m. URL], 16. Jahrestagung der Deutschen Gesellschaft für Thoraxchirurgie

Published
2010

46. Patients with colorectal tumors with microsatellite instability and large deletions in HSP110 T17 have improved response to 5-fluorouracil-based chemotherapy

Author

Collura, A., Lagrange, A., Svrcek, M., Marisa, L., Buhard, O., Guilloux, A., Wanherdrick, K., Dorard, C., Taieb, A., Saget, A., Loh, M., Soong, R., Zeps, Nikolajs, Platell, C., Mews, A., Iacopetta, B., De Thonel, A., Seigneuric, R., Marcion, G., Chapusot, C., Lepage, C., Bouvier, A., Gaub, M., Milano, G., Selves, J., Senet, P., Delarue, P., Arzouk, H., Lacoste, C., Coquelle, A., Bengrine-Lefèvre, L., Tournigand, C., Lefèvre, J., Parc, Y., Biard, D., Fléjou, J., Garrido, C., Duval, A., Collura, A., Lagrange, A., Svrcek, M., Marisa, L., Buhard, O., Guilloux, A., Wanherdrick, K., Dorard, C., Taieb, A., Saget, A., Loh, M., Soong, R., Zeps, Nikolajs, Platell, C., Mews, A., Iacopetta, B., De Thonel, A., Seigneuric, R., Marcion, G., Chapusot, C., Lepage, C., Bouvier, A., Gaub, M., Milano, G., Selves, J., Senet, P., Delarue, P., Arzouk, H., Lacoste, C., Coquelle, A., Bengrine-Lefèvre, L., Tournigand, C., Lefèvre, J., Parc, Y., Biard, D., Fléjou, J., Garrido, C., and Duval, A.

Abstract

Background & Aims: Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil–based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Methods: We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T17 affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II–III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T17.Results: HSP110 and HSP110DE9 interacted in a 1:1 ratio. Tumor cells with large deletions in T17 had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T17 were mostly biallelic in primary tumor samples with MSI. Patients with stage II–III cancer who received chemotherapy and had large HSP110 T17 deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012–0.8; P = .03). We found a significant interaction between chemotherapy and T17 deletion (P = .009). Conclusions: About 25% of patients with stages II–III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T17 intron repeat of HSP110 in tumor DNA.

Published
2014

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