Integrative bioinformatic analyses of an oncogenomic profile reveal the biology of endometrial cancer and guide drug discovery

Henry Sung Ching Wong, Yung-Shun Juan, Mei-Shin Wu, Yan-Feng Zhang, Yu-Wen Hsu, Huang-Hui Chen, Wei-Min Liu, Wei-Chiao Chang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

A major challenge in personalized cancer medicine is to establish a systematic approach to translate huge oncogenomic datasets to clinical situations and facilitate drug discovery for cancers such as endometrial carcinoma. We performed a genomewide somatic mutation-expression association study in a total of 219 endometrial cancer patients from TCGA database, by evaluating the correlation between ~5,800 somatic mutations to ~13,500 gene expression levels (in total, ~78, 500, 000 pairs). A bioinformatics pipeline was devised to identify expression-associated single nucleotide variations (eSNVs) which are crucial for endometrial cancer progression and patient prognoses. We further prioritized 394 biologically risky mutational candidates which mapped to 275 gene loci and demonstrated that these genes collaborated with expression features were significantly enriched in targets of drugs approved for solid tumors, suggesting the plausibility of drug repurposing. Taken together, we integrated a fundamental endometrial cancer genomic profile into clinical circumstances, further shedding light for clinical implementation of genomic-based therapies and guidance for drug discovery.
Original languageEnglish
Pages (from-to)5909-5923
Number of pages15
JournalOncotarget
Volume7
Issue number5
Publication statusPublished - 2016

Fingerprint

Drug Discovery
Endometrial Neoplasms
Computational Biology
Drug Repositioning
Neoplasms
Precision Medicine
Mutation
Genes
Nucleotides
Databases
Gene Expression
Pharmaceutical Preparations
Therapeutics

Keywords

  • Cancer drivers
  • Cancer drug repurposing
  • Cancer genomics
  • Endometrial cancers
  • Expression-associated somatic mutations

Cite this

Wong, H. S. C., Juan, Y-S., Wu, M-S., Zhang, Y-F., Hsu, Y-W., Chen, H-H., ... Chang, W-C. (2016). Integrative bioinformatic analyses of an oncogenomic profile reveal the biology of endometrial cancer and guide drug discovery. Oncotarget, 7(5), 5909-5923.

Integrative bioinformatic analyses of an oncogenomic profile reveal the biology of endometrial cancer and guide drug discovery. / Wong, Henry Sung Ching; Juan, Yung-Shun; Wu, Mei-Shin; Zhang, Yan-Feng; Hsu, Yu-Wen; Chen, Huang-Hui; Liu, Wei-Min; Chang, Wei-Chiao.

In: Oncotarget, Vol. 7, No. 5, 2016, p. 5909-5923.

Research output: Contribution to journalArticle

Wong, Henry Sung Ching ; Juan, Yung-Shun ; Wu, Mei-Shin ; Zhang, Yan-Feng ; Hsu, Yu-Wen ; Chen, Huang-Hui ; Liu, Wei-Min ; Chang, Wei-Chiao. / Integrative bioinformatic analyses of an oncogenomic profile reveal the biology of endometrial cancer and guide drug discovery. In: Oncotarget. 2016 ; Vol. 7, No. 5. pp. 5909-5923.
@article{73426375fa1442e59549d4d496c42066,
title = "Integrative bioinformatic analyses of an oncogenomic profile reveal the biology of endometrial cancer and guide drug discovery",
abstract = "A major challenge in personalized cancer medicine is to establish a systematic approach to translate huge oncogenomic datasets to clinical situations and facilitate drug discovery for cancers such as endometrial carcinoma. We performed a genomewide somatic mutation-expression association study in a total of 219 endometrial cancer patients from TCGA database, by evaluating the correlation between ~5,800 somatic mutations to ~13,500 gene expression levels (in total, ~78, 500, 000 pairs). A bioinformatics pipeline was devised to identify expression-associated single nucleotide variations (eSNVs) which are crucial for endometrial cancer progression and patient prognoses. We further prioritized 394 biologically risky mutational candidates which mapped to 275 gene loci and demonstrated that these genes collaborated with expression features were significantly enriched in targets of drugs approved for solid tumors, suggesting the plausibility of drug repurposing. Taken together, we integrated a fundamental endometrial cancer genomic profile into clinical circumstances, further shedding light for clinical implementation of genomic-based therapies and guidance for drug discovery.",
keywords = "Cancer drivers, Cancer drug repurposing, Cancer genomics, Endometrial cancers, Expression-associated somatic mutations",
author = "Wong, {Henry Sung Ching} and Yung-Shun Juan and Mei-Shin Wu and Yan-Feng Zhang and Yu-Wen Hsu and Huang-Hui Chen and Wei-Min Liu and Wei-Chiao Chang",
note = "Export Date: 6 April 2016 通訊地址: Chang, W.-C.; Taipei Medical University, School of PharmacyTaiwan; 電子郵件: wcc@tmu.edu.tw 參考文獻: Siegel, R.L., Miller, K.D., Jemal, A., Cancer statistics, 2015 (2015) CA Cancer J Clin, 65 (1), pp. 5-29; Westin, S.N., Broaddus, R.R., Personalized therapy in endometrial cancer: challenges and opportunities (2012) Cancer Biol Ther, 13 (1), pp. 1-13; Gupta, S.C., Sung, B., Prasad, S., Webb, L.J., Aggarwal, B.B., Cancer drug discovery by repurposing: teaching new tricks to old dogs (2013) Trends Pharmacol Sci, 34 (9), pp. 508-517; Gelijns, A.C., Rosenberg, N., Moskowitz, A.J., Capturing the unexpected benefits of medical research (1998) N Engl J Med, 339 (10), pp. 693-698; Cancer Genome Atlas Research, N., Kandoth, C., Schultz, N., Cherniack, A.D., Akbani, R., Liu, Y., Shen, H., Laird, P.W., Integrated genomic characterization of endometrial carcinoma (2013) Nature, 497 (7447), pp. 67-73; Le Gallo, M., Bell, D.W., The emerging genomic landscape of endometrial cancer (2014) Clin Chem, 60 (1), pp. 98-110; Banno, K., Kisu, I., Yanokura, M., Masuda, K., Ueki, A., Kobayashi, Y., Susumu, N., Aoki, D., Epigenetics and genetics in endometrial cancer: new carcinogenic mechanisms and relationship with clinical practice (2012) Epigenomics, 4 (2), pp. 147-162; Liu, Y., Patel, L., Mills, G.B., Lu, K.H., Sood, A.K., Ding, L., Kucherlapati, R., Zhang, W., Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma (2014) J Natl Cancer Inst, 106, p. 9; Wishart, D.S., Knox, C., Guo, A.C., Shrivastava, S., Hassanali, M., Stothard, P., Chang, Z., Woolsey, J., DrugBank: a comprehensive resource for in silico drug discovery and exploration (2006) Nucleic Acids Res, 34 (DATABASE ISSUE), pp. D668-D672; Chen, X., Ji, Z.L., Chen, Y.Z., TTD: Therapeutic Target Database (2002) Nucleic Acids Res, 30 (1), pp. 412-415; Zhu, F., Shi, Z., Qin, C., Tao, L., Liu, X., Xu, F., Zhang, L., Chen, Y., Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery (2012) Nucleic Acids Res, 40 (DATABASE ISSUE), pp. D1128-D1136; Turnbull, C., Rapley, E.A., Seal, S., Pernet, D., Renwick, A., Hughes, D., Ricketts, M., Easton, D.F., Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer (2010) Nat Genet, 42 (7), pp. 604-607; Caceres-Gorriti, K.Y., Carmona, E., Barres, V., Rahimi, K., Letourneau, I.J., Tonin, P.N., Provencher, D., Mes-Masson, A.M., RAN nucleo-cytoplasmic transport and mitotic spindle assembly partners XPO7 and TPX2 are new prognostic biomarkers in serous epithelial ovarian cancer (2014) PLoS One, 9 (3); Aghajanian, C., Sill, M.W., Darcy, K.M., Greer, B., McMeekin, D.S., Rose, P.G., Rotmensch, J., Leslie, K.K., Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study (2011) J Clin Oncol, 29 (16), pp. 259-265; Grisham, R.N., Adaniel, C., Hyman, D.M., Ma, W., Iasonos, A., Aghajanian, C., Konner, J., Gemcitabine for advanced endometrial cancer: a retrospective study of the Memorial sloan-Kettering Cancer Center experience (2012) Int J Gynecol Cancer, 22 (5), pp. 807-811; Brown, J., Smith, J.A., Ramondetta, L.M., Sood, A.K., Ramirez, P.T., Coleman, R.L., Levenback, C.F., Wolf, J.K., Combination of gemcitabine and cisplatin is highly active in women with endometrial carcinoma: results of a prospective phase 2 trial (2010) Cancer, 116 (21), pp. 4973-4979; Hasegawa, M., Sakamoto, H., Deng, X., Ige, Y., Shirakawa, T., Ohtani, K., Takami, M., Satoh, K., Estramustine phosphate, estrogen conjugated with nitrogen mustard inhibits the growth of endometrial cancer cells in vitro (1995) Nihon Sanka Fujinka Gakkai Zasshi, 47 (5), pp. 479-485; Thigpen, T., Brady, M.F., Homesley, H.D., Soper, J.T., Bell, J., Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study (2001) J Clin Oncol, 19 (2), pp. 364-367; Zhu, Y., Qiu, P., Ji, Y., TCGA-assembler: open-source software for retrieving and processing TCGA data (2014) Nat Methods, 11 (6), pp. 599-600; Hou, J.P., Ma, J., DawnRank: discovering personalized driver genes in cancer (2014) Genome Med, 6 (7), p. 56; Li, Q., Seo, J.H., Stranger, B., McKenna, A., Pe'er, I., Laframboise, T., Brown, M., Freedman, M.L., Integrative eQTL-based analyses reveal the biology of breast cancer risk loci (2013) Cell, 152 (3), pp. 633-641; Yu, G., Wang, L.G., Han, Y., He, Q.Y., clusterProfiler: an R package for comparing biological themes among gene clusters (2012) OMICS, 16 (5), pp. 284-287; Zhang, H.M., Chen, H., Liu, W., Liu, H., Gong, J., Wang, H., Guo, A.Y., AnimalTFDB: a comprehensive animal transcription factor database (2012) Nucleic Acids Res, 40 (DATABASE ISSUE), pp. D144-D149; Heagerty, P.J., Zheng, Y., Survival model predictive accuracy and ROC curves (2005) Biometrics, 61 (1), pp. 92-105; Okada, Y., Wu, D., Trynka, G., Raj, T., Terao, C., Ikari, K., Kochi, Y., Ortmann, W., Genetics of rheumatoid arthritis contributes to biology and drug discover (2014) Nature, 506 (7488), pp. 376-381; Wishart, D.S., Knox, C., Guo, A.C., Cheng, D., Shrivastava, S., Tzur, D., Gautam, B., Hassanali, M., DrugBank: a knowledgebase for drugs, drug actions and drug targets (2008) Nucleic Acids Res, 36 (DATABASE ISSUE), pp. D901-D906",
year = "2016",
language = "English",
volume = "7",
pages = "5909--5923",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",
number = "5",

}

TY - JOUR

T1 - Integrative bioinformatic analyses of an oncogenomic profile reveal the biology of endometrial cancer and guide drug discovery

AU - Wong, Henry Sung Ching

AU - Juan, Yung-Shun

AU - Wu, Mei-Shin

AU - Zhang, Yan-Feng

AU - Hsu, Yu-Wen

AU - Chen, Huang-Hui

AU - Liu, Wei-Min

AU - Chang, Wei-Chiao

N1 - Export Date: 6 April 2016 通訊地址: Chang, W.-C.; Taipei Medical University, School of PharmacyTaiwan; 電子郵件: wcc@tmu.edu.tw 參考文獻: Siegel, R.L., Miller, K.D., Jemal, A., Cancer statistics, 2015 (2015) CA Cancer J Clin, 65 (1), pp. 5-29; Westin, S.N., Broaddus, R.R., Personalized therapy in endometrial cancer: challenges and opportunities (2012) Cancer Biol Ther, 13 (1), pp. 1-13; Gupta, S.C., Sung, B., Prasad, S., Webb, L.J., Aggarwal, B.B., Cancer drug discovery by repurposing: teaching new tricks to old dogs (2013) Trends Pharmacol Sci, 34 (9), pp. 508-517; Gelijns, A.C., Rosenberg, N., Moskowitz, A.J., Capturing the unexpected benefits of medical research (1998) N Engl J Med, 339 (10), pp. 693-698; Cancer Genome Atlas Research, N., Kandoth, C., Schultz, N., Cherniack, A.D., Akbani, R., Liu, Y., Shen, H., Laird, P.W., Integrated genomic characterization of endometrial carcinoma (2013) Nature, 497 (7447), pp. 67-73; Le Gallo, M., Bell, D.W., The emerging genomic landscape of endometrial cancer (2014) Clin Chem, 60 (1), pp. 98-110; Banno, K., Kisu, I., Yanokura, M., Masuda, K., Ueki, A., Kobayashi, Y., Susumu, N., Aoki, D., Epigenetics and genetics in endometrial cancer: new carcinogenic mechanisms and relationship with clinical practice (2012) Epigenomics, 4 (2), pp. 147-162; Liu, Y., Patel, L., Mills, G.B., Lu, K.H., Sood, A.K., Ding, L., Kucherlapati, R., Zhang, W., Clinical significance of CTNNB1 mutation and Wnt pathway activation in endometrioid endometrial carcinoma (2014) J Natl Cancer Inst, 106, p. 9; Wishart, D.S., Knox, C., Guo, A.C., Shrivastava, S., Hassanali, M., Stothard, P., Chang, Z., Woolsey, J., DrugBank: a comprehensive resource for in silico drug discovery and exploration (2006) Nucleic Acids Res, 34 (DATABASE ISSUE), pp. D668-D672; Chen, X., Ji, Z.L., Chen, Y.Z., TTD: Therapeutic Target Database (2002) Nucleic Acids Res, 30 (1), pp. 412-415; Zhu, F., Shi, Z., Qin, C., Tao, L., Liu, X., Xu, F., Zhang, L., Chen, Y., Therapeutic target database update 2012: a resource for facilitating target-oriented drug discovery (2012) Nucleic Acids Res, 40 (DATABASE ISSUE), pp. D1128-D1136; Turnbull, C., Rapley, E.A., Seal, S., Pernet, D., Renwick, A., Hughes, D., Ricketts, M., Easton, D.F., Variants near DMRT1, TERT and ATF7IP are associated with testicular germ cell cancer (2010) Nat Genet, 42 (7), pp. 604-607; Caceres-Gorriti, K.Y., Carmona, E., Barres, V., Rahimi, K., Letourneau, I.J., Tonin, P.N., Provencher, D., Mes-Masson, A.M., RAN nucleo-cytoplasmic transport and mitotic spindle assembly partners XPO7 and TPX2 are new prognostic biomarkers in serous epithelial ovarian cancer (2014) PLoS One, 9 (3); Aghajanian, C., Sill, M.W., Darcy, K.M., Greer, B., McMeekin, D.S., Rose, P.G., Rotmensch, J., Leslie, K.K., Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study (2011) J Clin Oncol, 29 (16), pp. 259-265; Grisham, R.N., Adaniel, C., Hyman, D.M., Ma, W., Iasonos, A., Aghajanian, C., Konner, J., Gemcitabine for advanced endometrial cancer: a retrospective study of the Memorial sloan-Kettering Cancer Center experience (2012) Int J Gynecol Cancer, 22 (5), pp. 807-811; Brown, J., Smith, J.A., Ramondetta, L.M., Sood, A.K., Ramirez, P.T., Coleman, R.L., Levenback, C.F., Wolf, J.K., Combination of gemcitabine and cisplatin is highly active in women with endometrial carcinoma: results of a prospective phase 2 trial (2010) Cancer, 116 (21), pp. 4973-4979; Hasegawa, M., Sakamoto, H., Deng, X., Ige, Y., Shirakawa, T., Ohtani, K., Takami, M., Satoh, K., Estramustine phosphate, estrogen conjugated with nitrogen mustard inhibits the growth of endometrial cancer cells in vitro (1995) Nihon Sanka Fujinka Gakkai Zasshi, 47 (5), pp. 479-485; Thigpen, T., Brady, M.F., Homesley, H.D., Soper, J.T., Bell, J., Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study (2001) J Clin Oncol, 19 (2), pp. 364-367; Zhu, Y., Qiu, P., Ji, Y., TCGA-assembler: open-source software for retrieving and processing TCGA data (2014) Nat Methods, 11 (6), pp. 599-600; Hou, J.P., Ma, J., DawnRank: discovering personalized driver genes in cancer (2014) Genome Med, 6 (7), p. 56; Li, Q., Seo, J.H., Stranger, B., McKenna, A., Pe'er, I., Laframboise, T., Brown, M., Freedman, M.L., Integrative eQTL-based analyses reveal the biology of breast cancer risk loci (2013) Cell, 152 (3), pp. 633-641; Yu, G., Wang, L.G., Han, Y., He, Q.Y., clusterProfiler: an R package for comparing biological themes among gene clusters (2012) OMICS, 16 (5), pp. 284-287; Zhang, H.M., Chen, H., Liu, W., Liu, H., Gong, J., Wang, H., Guo, A.Y., AnimalTFDB: a comprehensive animal transcription factor database (2012) Nucleic Acids Res, 40 (DATABASE ISSUE), pp. D144-D149; Heagerty, P.J., Zheng, Y., Survival model predictive accuracy and ROC curves (2005) Biometrics, 61 (1), pp. 92-105; Okada, Y., Wu, D., Trynka, G., Raj, T., Terao, C., Ikari, K., Kochi, Y., Ortmann, W., Genetics of rheumatoid arthritis contributes to biology and drug discover (2014) Nature, 506 (7488), pp. 376-381; Wishart, D.S., Knox, C., Guo, A.C., Cheng, D., Shrivastava, S., Tzur, D., Gautam, B., Hassanali, M., DrugBank: a knowledgebase for drugs, drug actions and drug targets (2008) Nucleic Acids Res, 36 (DATABASE ISSUE), pp. D901-D906

PY - 2016

Y1 - 2016

N2 - A major challenge in personalized cancer medicine is to establish a systematic approach to translate huge oncogenomic datasets to clinical situations and facilitate drug discovery for cancers such as endometrial carcinoma. We performed a genomewide somatic mutation-expression association study in a total of 219 endometrial cancer patients from TCGA database, by evaluating the correlation between ~5,800 somatic mutations to ~13,500 gene expression levels (in total, ~78, 500, 000 pairs). A bioinformatics pipeline was devised to identify expression-associated single nucleotide variations (eSNVs) which are crucial for endometrial cancer progression and patient prognoses. We further prioritized 394 biologically risky mutational candidates which mapped to 275 gene loci and demonstrated that these genes collaborated with expression features were significantly enriched in targets of drugs approved for solid tumors, suggesting the plausibility of drug repurposing. Taken together, we integrated a fundamental endometrial cancer genomic profile into clinical circumstances, further shedding light for clinical implementation of genomic-based therapies and guidance for drug discovery.

AB - A major challenge in personalized cancer medicine is to establish a systematic approach to translate huge oncogenomic datasets to clinical situations and facilitate drug discovery for cancers such as endometrial carcinoma. We performed a genomewide somatic mutation-expression association study in a total of 219 endometrial cancer patients from TCGA database, by evaluating the correlation between ~5,800 somatic mutations to ~13,500 gene expression levels (in total, ~78, 500, 000 pairs). A bioinformatics pipeline was devised to identify expression-associated single nucleotide variations (eSNVs) which are crucial for endometrial cancer progression and patient prognoses. We further prioritized 394 biologically risky mutational candidates which mapped to 275 gene loci and demonstrated that these genes collaborated with expression features were significantly enriched in targets of drugs approved for solid tumors, suggesting the plausibility of drug repurposing. Taken together, we integrated a fundamental endometrial cancer genomic profile into clinical circumstances, further shedding light for clinical implementation of genomic-based therapies and guidance for drug discovery.

KW - Cancer drivers

KW - Cancer drug repurposing

KW - Cancer genomics

KW - Endometrial cancers

KW - Expression-associated somatic mutations

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-84958068829&origin=resultslist&sort=plf-f&src=s&st1=Integrative+bioinformatic+analyses+of+an+oncogenomic+profile+reveal+the+biology+of+endometrial+cancer+and+guide+drug+discovery&st2=&sid=f7406710445d5f5e159a54bfa092811f&sot=b&sdt=b&sl=141&s=TITLE-ABS-KEY%28Integrative+bioinformatic+analyses+of+an+oncogenomic+profile+reveal+the+biology+of+endometrial+cancer+and+guide+drug+discovery%29&relpos=0&citeCnt=1&searchTerm=

UR - https://www.scopus.com/results/citedbyresults.uri?sort=plf-f&cite=2-s2.0-84958068829&src=s&imp=t&sid=b2db5930ac99f916747c59b1e3a5e954&sot=cite&sdt=a&sl=0&origin=recordpage&editSaveSearch=&txGid=99bccf022cf9b6e2484e26ad5257d50e

M3 - Article

VL - 7

SP - 5909

EP - 5923

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 5

ER -