Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer

Nature Communications

Volumn 6, Issue , 2015, Pages

  Lawrenson, Kate ^a   Li, Qiyuan ^b,c   Kar, Siddhartha ^d   Seo, Ji Heui ^c   Tyrer, Jonathan ^d   Spindler, Tassja J ^a   Lee, Janet ^a   Chen, Yibu ^e   Karst, Alison ^c   Drapkin, Ronny ^c   Aben, Katja K H ^f,g   Anton Culver, Hoda ^h   Antonenkova, Natalia ⁱ   Baker, Helen ^d   Bandera, Elisa V ^j   Bean, Yukie ^k,l   Beckmann, Matthias W ^m   Berchuck, Andrew ⁿ   Bisogna, Maria ^o   Bjorge, Line ^p,q   Bogdanova, Natalia ^r   Brinton, Louise A ^s   Brooks Wilson, Angela ^t,u   Bruinsma, Fiona ^v   Butzow, Ralf ^w,x   Campbell, Ian G ^y,z   Carty, Karen ^aa   Chang Claude, Jenny ^ab   Chenevix Trench, Georgia ^ac   Chen, Anne ^ad   Chen, Zhihua ^ad   Cook, Linda S ^ae   Cramer, Daniel W ^af,ag   Cunningham, Julie M ^ah   Cybulski, Cezary ^ai   Dansonka Mieszkowska, Agnieszka ^ai   Dennis, Joe ^aj   Dicks, Ed ^d   Doherty, Jennifer A ^ak   Dörk, Thilo ^r   Du Bois, Andreas ^al,am   Dürst, Matthias ^an   Eccles, Diana ^ao   Easton, Douglas T ^aj   Edwards, Robert P ^ap,aq   Eilber, Ursula ^ab   Ekici, Arif B ^m   Fasching, Peter A ^m,ar   Fridley, Brooke L ^as   Gao, Yu Tang ^at   Gentry Maharaj, Aleksandra ^au   Giles, Graham G ^v,av   Glasspool, Rosalind ^aa   Goode, Ellen L ^ah   Goodman, Marc T ^aw   Grownwald, Jacek ^ai   Harrington, Patricia ^aj   Harter, Philipp ^al,am   Hasmad, Hanis Nazihah ^ax   Hein, Alexander ^m   Heitz, Florian ^al,am   Hildebrandt, Michelle A T ^ay   Hillemanns, Peter ^r   Hogdall, Estrid ^az,ba   Hogdall, Claus ^ba   Hosono, Satoyo ^bb   Iversen, Edwin S ^bc   Jakubowska, Anna ^ai   James, Paul ^aa   Jensen, Allan ^ba   Ji, Bu Tian ^s   Karlan, Beth Y ^aw   Kjaer, Susanne Kruger ^az,ba   Kelemen, Linda E ^bd   Kellar, Melissa ^k,l   Kelley, Joseph L ^ap   Kiemeney, Lambertus A ^f   Krakstad, Camilla ^p,q   Kupryjanczyk, Jolanta ^ai   Lambrechts, Diether ^be,bf   Lambrechts, Sandrina ^bg   Le, Nhu D ^t   Lee, Alice W ^a   Lele, Shashi ^bh   Leminen, Arto ^w   Lester, Jenny ^aw   Levine, Douglas A ^o   Liang, Dong ^bi   Lissowska, Jolanta ^bj   Lu, Karen ^ay   Lubinski, Jan ^ai   Lundvall, Lene ^ba   Massuger, Leon F A G ^f   Matsuo, Keitaro ^bk   McGuire, Valerie ^bl   McLaughlin, John R ^bm   Nevanlinna, Heli ^w   McNeish, Ian ^bn   Menon, Usha ^au   Modugno, Francesmary ^ap,aq,bo,bp   Moysich, Kirsten B ^bh   Narod, Steven A ^o   Nedergaard, Lotte ^ba   Ness, Roberta B ^bq   Azmi, Mat Adenan Noor ^br   Odunsi, Kunle ^bh   Olson, Sara H ^o   Orlow, Irene ^o   Orsulic, Sandra ^aw   Weber, Rachel Palmieri ^bs   Pearce, Celeste L ^a   Pejovic, Tanja ^k,l   Pelttari, Liisa M ^w   Permuth Wey, Jennifer ^ad   Phelan, Catherine M ^ad   Pike, Malcolm C ^a,ag   Poole, Elizabeth M ^af,ag   Ramus, Susan J ^a   Risch, Harvey A ^bt   Rosen, Barry ^bu,cf   Rossing, Mary Anne ^bv,bw   Rothstein, Joseph H ^bl   Rudolph, Anja ^ab   Runnebaum, Ingo B ^an   Rzepecka, Iwona K ^ai   Salvesen, Helga B ^p,q   Schildkraut, Joellen M ^bx,by   Schwaab, Ira ^by   Sellers, Thomas A ^ad   Shu, Xiao Ou ^bz   Shvetsov, Yurii B ^ca   Siddiqui, Nadeem ^cb   Sieh, Weiva ^bl   Song, Honglin ^d   Southey, Melissa C ^z   Sucheston, Lara ^bh   Tangen, Ingvild L ^p,q   Teo, Soo Hwang ^ax,br   Terry, Kathryn L ^af,ag   Thompson, Pamela J ^aw   Timorek, Agnieszka ^cc   Tsai, Ya Yu ^ad   Tworoger, Shelley S ^af,ag   Van Altena, Anne M ^f   Van Nieuwenhuysen, Els ^bg   Vergote, Ignace ^bg   Vierkant, Robert A ^ah   Wang Gohrke, Shan ^cd   Walsh, Christine ^aw   Wentzensen, Nicolas ^s   Whittemore, Alice S ^bl   Wicklund, Kristine G ^bv   Wilkens, Lynne R ^ca   Woo, Yin Ling ^br   Wu, Xifeng ^ay   Wu, Anna H ^a   Yang, Hannah ^s   Zheng, Wei ^bz   Ziogas, Argyrios ^h   Monteiro, Alvaro ^ad   Pharoah, Paul D ^d   Gayther, Simon A ^a   Freedman, Matthew L ^c   Bowtell, David ^y   Webb, Penelope M ^ac   DeFazio, Anna ^ce   more..

^a UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^b XIAMEN UNIVERSITY   (China)

^c DANA FARBER CANCER INSTITUTE   (United States)

^d UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^e UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^f RADBOUD UNIVERSITY MEDICAL CENTER   (Netherlands)

^g Centre the Netherlands   (Netherlands)

^h UNIVERSITY OF CALIFORNIA   (United States)

ⁱ Byelorussian Institute for Oncology and Medical Radiology   (Belarus)

^j RUTGERS CANCER INSTITUTE OF NEW JERSEY   (United States)

^k OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^l OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^m UNIVERSITY HOSPITAL ERLANGEN   (Germany)

ⁿ DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^o MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^p HAUKELAND UNIVERSITY HOSPITAL   (Norway)

^q UNIVERSITY OF BERGEN   (Norway)

^r HANNOVER MEDICAL SCHOOL   (Germany)

^s NATIONAL CANCER INSTITUTE   (United States)

^t BRITISH COLUMBIA CANCER AGENCY   (Canada)

^u SIMON FRASER UNIVERSITY   (Canada)

^v CANCER EPIDEMIOLOGY CENTRE   (Australia)

^w UNIVERSITY OF HELSINKI   (Finland)

^x HELSINKI UNIVERSITY CENTRAL HOSPITAL   (Finland)

^y PETER MACCALLUM CANCER CENTRE   (Australia)

^z UNIVERSITY OF MELBOURNE   (Australia)

^aa BEATSON WEST OF SCOTLAND CANCER CENTRE   (United Kingdom)

^ab GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

^ac QIMR BERGHOFER MEDICAL RESEARCH INSTITUTE   (Australia)

^ad H LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE   (United States)

^ae UNIVERSITY OF NEW MEXICO SCHOOL OF MEDICINE   (United States)

^af HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

^ag HARVARD MEDICAL SCHOOL   (United States)

^ah MAYO CLINIC   (United States)

^ai POMERANIAN MEDICAL UNIVERSITY   (Poland)

^aj UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^ak DARTMOUTH MEDICAL SCHOOL   (United States)

^al KLINIKEN ESSEN MITTE   (Germany)

^am DR HORST SCHMIDT KLINIKEN   (Germany)

^an JENA UNIVERSITY HOSPITAL   (Germany)

^ao UNIVERSITY OF SOUTHAMPTON   (United Kingdom)

^ap UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^aq UNIVERSITY OF PITTSBURGH   (United States)

^ar UNIVERSITY OF CALIFORNIA   (United States)

^as UNIVERSITY OF KANSAS SCHOOL OF MEDICINE   (United States)

^at SHANGHAI CANCER INSTITUTE   (China)

^au UNIVERSITY COLLEGE LONDON   (United Kingdom)

^av UNIVERSITY OF MELBOURNE   (Australia)

^aw CEDARS SINAI MEDICAL CENTER   (United States)

^ax CANCER RESEARCH INITIATIVES FOUNDATION   (Malaysia)

^ay UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER   (United States)

^az DANISH CANCER SOCIETY RESEARCH CENTER   (Denmark)

^ba UNIVERSITY OF COPENHAGEN   (Denmark)

^bb AICHI CANCER CENTER HOSPITAL   (Japan)

^bc Duke University   (United States)

^bd MEDICAL UNIVERSITY OF SOUTH CAROLINA   (United States)

^be DEPARTMENT OF PLANT SYSTEMS BIOLOGY   (Belgium)

^bf UNIVERSITY OF LEUVEN   (Belgium)

^bg UNIVERSITY HOSPITALS LEUVEN   (Belgium)

^bh ROSWELL PARK CANCER INSTITUTE   (United States)

^bi TEXAS SOUTHERN UNIVERSITY   (United States)

^bj INSTITUTE OF ONCOLOGY   (Poland)

^bk KYUSHU UNIVERSITY   (Japan)

^bl STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^bm MOUNT SINAI HOSPITAL   (Canada)

^bn UNIVERSITY OF GLASGOW   (United Kingdom)

^bo UNIVERSITY OF PITTSBURGH   (United States)

^bp UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH   (United States)

^bq UNIVERSITY OF TEXAS SCHOOL OF PUBLIC HEALTH   (United States)

^br UNIVERSITY MALAYA MEDICAL CENTRE   (Malaysia)

^bs DUKE UNIVERSITY MEDICAL CENTER   (United States)

^bt YALE UNIVERSITY   (United States)

^bu PRINCESS MARGARET HOSPITAL   (Canada)

^bv Fred Hutchinson Cancer Research Center   (United States)

^bw UNIVERSITY OF WASHINGTON   (United States)

^bx DUKE CANCER INSTITUTE   (United States)

^by Institut Für Humangenetik Wiesbaden   (Germany)

^bz VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^ca UNIVERSITY OF HAWAII CANCER CENTER   (United States)

^cb GLASGOW ROYAL INFIRMARY   (United Kingdom)

^cc Brodnowski Hospital Warsaw   (Poland)

^cd UNIVERSITY OF ULM   (Germany)

^ce UNIVERSITY OF SYDNEY   (Australia)

^cf UNIVERSITY OF TORONTO   (Canada)

more..

Author keywords

[No Author keywords available]

Indexed keywords

CANCER; CELLS AND CELL COMPONENTS; CHROMOSOME; GENE EXPRESSION; GENETIC ANALYSIS; GENOMICS; PROTEIN; RNA; WOMENS HEALTH;

ANCHORAGE INDEPENDENT GROWTH; ARTICLE; CANCER GRADING; CANCER STEM CELL; CHROMOSOME 1P; CHROMOSOME 2Q; FEMALE; GENE EXPRESSION; GENE OVEREXPRESSION; GENETIC ASSOCIATION; GENETIC RISK; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HOXD9 GENE; HUMAN; HUMAN CELL; NONHUMAN; OVARY CARCINOMA; PROMOTER REGION; QUANTITATIVE TRAIT LOCUS; SINGLE NUCLEOTIDE POLYMORPHISM; TRANSCRIPTOMICS; GENE EXPRESSION REGULATION; GENETIC ASSOCIATION STUDY; GENETIC PREDISPOSITION; GENETICS; METABOLISM; NEOPLASM; NUCHAL CORD; OVARY TUMOR; TUMOR CELL LINE;

HOMEODOMAIN PROTEIN; HOXD9 PROTEIN, HUMAN; PROTEIN BINDING; TUMOR PROTEIN;

CELL LINE, TUMOR; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; GENETIC ASSOCIATION STUDIES; GENETIC PREDISPOSITION TO DISEASE; HOMEODOMAIN PROTEINS; HUMANS; NEOPLASM PROTEINS; NEOPLASMS, GLANDULAR AND EPITHELIAL; NUCHAL CORD; OVARIAN NEOPLASMS; PROTEIN BINDING; QUANTITATIVE TRAIT LOCI;

EID: 84942455970     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms9234     Document Type: Article

References (62)

1. Ahmadiyeh, N. et al. 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc. Natl Acad. Sci. USA 107, 9742-9746 (2010).
2. Grisanzio, C. et al. Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis. Proc. Natl Acad. Sci. USA 109, 11252-11257 (2012).
3. Pomerantz, M. M. et al. Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis. PLoS Genet. 6, e1001204 (2010).
4. French, J. D. et al. Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers. Am. J. Hum. Genet. 92, 489-503 (2013).
5. Bojesen, S. E. et al. Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer. Nat. Genet. 45, 371-384 384e1-2 (2013).
6. Hazelett, D. J. et al. Comprehensive functional annotation of 77 prostate cancer risk loci. PLoS Genet. 10, e1004102 (2014).
7. Pomerantz, M. M. et al. The 8q24 cancer risk variant rs6983267 shows longrange interaction with MYC in colorectal cancer. Nat. Genet. 41, 882-884 (2009).
8. Smemo, S. et al. Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 507, 371-375 (2014).
9. Song, H. et al. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat. Genet. 41, 996-1000 (2009).
10. Pharoah, P. D. et al. GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer. Nat. Genet. 45, 362-370 370e1-2 (2013).
11. Permuth-Wey, J. et al. Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. Nat. Commun. 4, 1627 (2013).
12. Goode, E. L. et al. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat. Genet. 42, 874-879 (2010).
13. Bolton, K. L. et al. Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat. Genet. 42, 880-884 (2010).
14. Shen, H. et al. Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nat. Commun. 4, 1628 (2013).
15. Li, Q. et al. Integrative eQTL-based analyses reveal the biology of breast cancer risk loci. Cell 152, 633-641 (2013).
16. Li, Q. et al. Expression QTL-based analyses reveal candidate causal genes and loci across five tumor types. Hum. Mol. Genet. 23, 5294-5302 (2014).
17. Westra, H. J. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat. Genet. 45, 1238-1243 (2013).
18. Permuth-Wey, J. et al. LIN28B polymorphisms influence susceptibility to epithelial ovarian cancer. Cancer Res. 71, 3896-3903 (2011).
19. Kuchenbaecker, K. B. et al. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat. Genet. 47, 164-171 (2015).
20. Network, C.G.A.R. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609-615 (2011).
21. Ahmed, A. A. et al. Driver mutations in TP53 are ubiquitous in high grade serous carcinoma of the ovary. J. Pathol. 221, 49-56 (2010).
22. Karst, A. M., Levanon, K. & Drapkin, R. Modeling high-grade serous ovarian carcinogenesis from the fallopian tube. Proc. Natl Acad. Sci. USA 108, 7547-7552 (2011).
23. Lawrenson, K. et al. Senescent fibroblasts promote neoplastic transformation of partially transformed ovarian epithelial cells in a three-dimensional model of early stage ovarian cancer. Neoplasia 12, 317-325 (2010).
24. Fletcher, M. N. et al. Master regulators of FGFR2 signalling and breast cancer risk. Nat. Commun. 4, 2464 (2013).
25. Small, K. S. et al. Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes. Nat. Genet. 43, 561-564 (2011).
26. Schork, A. J. et al. All SNPs are not created equal: genome-wide association studies reveal a consistent pattern of enrichment among functionally annotated SNPs. PLoS Genet. 9, e1003449 (2013).
27. Silverman, E. K. & Loscalzo, J. Network medicine approaches to the genetics of complex diseases. Discov. Med. 14, 143-152 (2012).
28. Ideker, T., Ozier, O., Schwikowski, B. & Siegel, A. F. Discovering regulatory and signalling circuits in molecular interaction networks. Bioinformatics 18 (Suppl 1): S233-S240 (2002).
29. Kanehisa, M. & Goto, S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28, 27-30 (2000).
30. Stranger, B. E. et al. Patterns of cis regulatory variation in diverse human populations. PLoS Genet. 8, e1002639 (2012).
31. Shah, N. & Sukumar, S. The Hox genes and their roles in oncogenesis. Nat. Rev. Cancer 10, 361-371 (2010).
32. Kelemen, L. M. et al. Genome-wide significant risk associations for mucinous ovarian carcinoma. Nat. Genet. 47, 888-897 (2015).
33. Coetzee, S. G. et al. Cell type specific enrichment of risk associated regulatory elements at ovarian cancer susceptibility loci. Hum. Mol. Genet. 24, 3595-3607 (2015).
34. Bayarsaihan, D. et al. Expression of BEN, a member of TFII-I family of transcription factors, during mouse pre-and postimplantation development. Gene Expr. Patterns 3, 579-589 (2003).
35. Bayarsaihan, D. et al. Homez, a homeobox leucine zipper gene specific to the vertebrate lineage. Proc. Natl Acad. Sci. USA 100, 10358-10363 (2003).
36. Raines, A. M. et al. Recombineering-based dissection of flanking and paralogous Hox gene functions in mouse reproductive tracts. Development 140, 2942-2952 (2013).
37. Chen, F. & Capecchi, M. R. Paralogous mouse Hox genes, Hoxa9, Hoxb9, and Hoxd9, function together to control development of the mammary gland in response to pregnancy. Proc. Natl Acad. Sci. USA 96, 541-546 (1999).
38. Tabuse, M. et al. Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells. Mol. Cancer 10, 60 (2011).
39. Deinnocentes, P., Perry, A. L., Graff, E. C., Lutful Kabir, F. M. & Curtis Bird, R. Characterization of HOX gene expression in canine mammary tumour cell lines from spontaneous tumours. Vet. Comp. Oncol. 13, 322-336 (2015).
40. Purrington, K. S. et al. Genetic variation in mitotic regulatory pathway genes is associated with breast tumor grade. Hum. Mol. Genet. 23, 6034-6046 (2014).
41. Peng, C., Zhang, X., Yu, H., Wu, D. & Zheng, J. Wnt5a as a predictor in poor clinical outcome of patients and a mediator in chemoresistance of ovarian cancer. Int. J. Gynecol. Cancer 21, 280-288 (2011).
42. Doherty, J. A. et al. ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study. Cancer Epidemiol. Biomarkers Prev. 19, 245-250 (2010).
43. Pearce, C. L. et al. Genetic variation in insulin-like growth factor 2 may play a role in ovarian cancer risk. Hum. Mol. Genet. 20, 2263-2272 (2011).
44. Sood, A. K. et al. Biological significance of focal adhesion kinase in ovarian cancer: role in migration and invasion. Am. J. Pathol. 165, 1087-1095 (2004).
45. Stengel, K. & Zheng, Y. Cdc42 in oncogenic transformation, invasion, and tumorigenesis. Cell Signal. 23, 1415-1423 (2011).
46. Perets, R. et al. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in brca;tp53;pten models. Cancer Cell 24, 751-765 (2013).
47. Auersperg, N. Ovarian surface epithelium as a source of ovarian cancers: unwarranted speculation or evidence-based hypothesis? Gynecol. Oncol. 130, 246-251 (2013).
48. Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G. R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955-959 (2012).
49. Howie, B. N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009).
50. Xing, G., Lin, C. Y., Wooding, S. P. & Xing, C. Blindly using Wald's test can miss rare disease-causal variants in case-control association studies. Ann. Hum. Genet. 76, 168-177 (2012).
51. Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904-909 (2006).
52. Li, N. F. et al. A modified medium that significantly improves the growth of human normal ovarian surface epithelial (OSE) cells in vitro. Lab. Invest. 84, 923-931 (2004).
53. Dekker, J. The three 'C' s of chromosome conformation capture: controls, controls, controls. Nat. Methods 3, 17-21 (2006).
54. Miele, A., Gheldof, N., Tabuchi, T. M., Dostie, J. & Dekker, J. Mapping chromatin interactions by chromosome conformation capture. Curr. Protoc. Mol. Biol. Chapter 21, Unit 21. 11 (2006).
55. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545-15550 (2005).
56. Shannon, P. et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 13, 2498-2504 (2003).
57. Khurana, E., Fu, Y., Chen, J. & Gerstein, M. Interpretation of genomic variants using a unified biological network approach. PLoS Comput. Biol. 9, e1002886 (2013).
58. Lage, K. et al. A human phenome-interactome network of protein complexes implicated in genetic disorders. Nat. Biotechnol. 25, 309-316 (2007).
59. Das, J. & Yu, H. HINT: high-quality protein interactomes and their applications in understanding human disease. BMC Syst. Biol. 6, 92 (2012).
60. Kanehisa, M. et al. Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res. 42, D199-D205 (2014).
61. Sales, G., Calura, E., Cavalieri, D. & Romualdi, C. graphite-a bioconductor package to convert pathway topology to gene network. BMC Bioinformatics 13, 20 (2012).
62. Huang, d. W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44-57 (2009).