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Open Access 01-12-2011 | Review

Genomic sequencing in clinical trials

Authors: Karen K Mestan, Leonard Ilkhanoff, Samdeep Mouli, Simon Lin

Published in: Journal of Translational Medicine | Issue 1/2011

Abstract

Human genome sequencing is the process by which the exact order of nucleic acid base pairs in the 24 human chromosomes is determined. Since the completion of the Human Genome Project in 2003, genomic sequencing is rapidly becoming a major part of our translational research efforts to understand and improve human health and disease. This article reviews the current and future directions of clinical research with respect to genomic sequencing, a technology that is just beginning to find its way into clinical trials both nationally and worldwide. We highlight the currently available types of genomic sequencing platforms, outline the advantages and disadvantages of each, and compare first- and next-generation techniques with respect to capabilities, quality, and cost. We describe the current geographical distributions and types of disease conditions in which these technologies are used, and how next-generation sequencing is strategically being incorporated into new and existing studies. Lastly, recent major breakthroughs and the ongoing challenges of using genomic sequencing in clinical research are discussed.

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Heger M: Next-gen sequencing makes inroads into clinical applications in 2010. [http://www.genomeweb.com/sequencing/next-gen-sequencing-makes-inroads-clinical-applications-2010]

Bhinge AA, Kim J, Euskirchen GM, Snyder M, Iyer VR: Mapping the chromosomal targets of STAT1 by Sequence Tag Analysis of Genomic Enrichment (STAGE). Genome Res. 2007, 17 (6): 910-916. 10.1101/gr.5574907.PubMedCentralCrossRefPubMed

Johnson DS, Mortazavi A, Myers RM, Wold B: Genome-wide mapping of in vivo protein-DNA interactions. Science. 2007, 316 (5830): 1497-1502. 10.1126/science.1141319.CrossRefPubMed

Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B: Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat Methods. 2008, 5 (7): 621-628. 10.1038/nmeth.1226.CrossRefPubMed

Wang ET, Sandberg R, Luo S, Khrebtukova I, Zhang L, Mayr C, Kingsmore SF, Schroth GP, Burge CB: Alternative isoform regulation in human tissue transcriptomes. Nature. 2008, 456 (7221): 470-476. 10.1038/nature07509.PubMedCentralCrossRefPubMed

Harismendy O, Ng PC, Strausberg RL, Wang X, Stockwell TB, Beeson KY, Schork NJ, Murray SS, Topol EJ, Levy S, Frazer KA: Evaluation of next generation sequencing platforms for population targeted sequencing studies. Genome biology. 2009, 10 (3): R32-10.1186/gb-2009-10-3-r32.PubMedCentralCrossRefPubMed

Drmanac R, Sparks AB, Callow MJ, Halpern AL, Burns NL, Kermani BG, Carnevali P, Nazarenko I, Nilsen GB, Yeung G, Dahl F, Fernandez A, Staker B, Pant KP, Baccash J, Borcherding AP, Brownley A, Cedeno R, Chen L, Chernikoff D, Cheung A, Chirita R, Curson B, Ebert JC, Hacker CR, Hartlage R, Hauser B, Huang S, Jiang Y, Karpinchyk V: Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays. Science. 2010, 327 (5961): 78-81. 10.1126/science.1181498.CrossRefPubMed

Hodges E, Xuan Z, Balija V, Kramer M, Molla MN, Smith SW, Middle CM, Rodesch MJ, Albert TJ, Hannon GJ, McCombie WR: Genome-wide in situ exon capture for selective resequencing. Nat Genet. 2007, 39 (12): 1522-1527. 10.1038/ng.2007.42.CrossRefPubMed

Porreca GJ, Zhang K, Li JB, Xie B, Austin D, Vassallo SL, LeProust EM, Peck BJ, Emig CJ, Dahl F, Gao Y, Church GM, Shendure J: Multiplex amplification of large sets of human exons. Nat Methods. 2007, 4 (11): 931-936. 10.1038/nmeth1110.CrossRefPubMed

10.

Kircher M, Kelso J: High-throughput DNA sequencing--concepts and limitations. Bioessays. 2010, 32 (6): 524-536. 10.1002/bies.200900181.CrossRefPubMed

11.

Allison M: Illumina's cut-price genome scan. Nature Biotechnology. 2009, 27:

12.

Bennett ST, Barnes C, Cox A, Davies L, Brown C: Toward the 1,000 dollars human genome. Pharmacogenomics. 2005, 6 (4): 373-382. 10.1517/14622416.6.4.373.CrossRefPubMed

13.

Schadt EE, Turner S, Kasarskis A: A window into third-generation sequencing. Human molecular genetics. 2010, 19 (R2): R227-240. 10.1093/hmg/ddq416.CrossRefPubMed

14.

Rasko DA, Webster DR, Sahl JW, Bashir A, Boisen N, Scheutz F, Paxinos EE, Sebra R, Chin CS, Iliopoulos D, Klammer A, Peluso P, Lee L, Kislyuk AO, Bullard J, Kasarskis A, Wang S, Eid J, Rank D, Redman JC, Steyert SR, Frimodt-Moller J, Struve C, Petersen AM, Krogfelt KA, Nataro JP, Schadt EE, Waldor MK: Origins of the E. coli strain causing an outbreak of hemolytic-uremic syndrome in Germany. N Engl J Med. 2011, 365 (8): 709-717. 10.1056/NEJMoa1106920.PubMedCentralCrossRefPubMed

15.

Biesecker LG, Mullikin JC, Facio FM, Turner C, Cherukuri PF, Blakesley RW, Bouffard GG, Chines PS, Cruz P, Hansen NF, Teer JK, Maskeri B, Young AC, Manolio TA, Wilson AF, Finkel T, Hwang P, Arai A, Remaley AT, Sachdev V, Shamburek R, Cannon RO, Green ED: The ClinSeq Project: piloting large-scale genome sequencing for research in genomic medicine. Genome Res. 2009, 19 (9): 1665-1674. 10.1101/gr.092841.109.PubMedCentralCrossRefPubMed

16.

Xu G, Fewell C, Taylor C, Deng N, Hedges D, Wang X, Zhang K, Lacey M, Zhang H, Yin Q, Cameron J, Lin Z, Zhu D, Flemington EK: Transcriptome and targetome analysis in MIR155 expressing cells using RNA-seq. Rna. 2010, 16 (8): 1610-1622. 10.1261/rna.2194910.PubMedCentralCrossRefPubMed

17.

Mardis ER, Ding L, Dooling DJ, Larson DE, McLellan MD, Chen K, Koboldt DC, Fulton RS, Delehaunty KD, McGrath SD, Fulton LA, Locke DP, Magrini VJ, Abbott RM, Vickery TL, Reed JS, Robinson JS, Wylie T, Smith SM, Carmichael L, Eldred JM, Harris CC, Walker J, Peck JB, Du F, Dukes AF, Sanderson GE, Brummett AM, Clark E, McMichael JF: Recurring mutations found by sequencing an acute myeloid leukemia genome. N Engl J Med. 2009, 361 (11): 1058-1066. 10.1056/NEJMoa0903840.PubMedCentralCrossRefPubMed

18.

Thompson JF, Reifenberger JG, Giladi E, Kerouac K, Gill J, Hansen E, Kahvejian A, Kapranov P, Knope T, Lipson D, Steinmann KE, Milos PM: Single-step capture and sequencing of natural DNA for detection of BRCA1 mutations. Genome Res. 2011

19.

Greulich H: The genomics of lung adenocarcinoma: opportunities for targeted therapies. Genes Cancer. 2010, 1 (12): 1200-1210. 10.1177/1947601911407324.PubMedCentralCrossRefPubMed

20.

Mele C, Iatropoulos P, Donadelli R, Calabria A, Maranta R, Cassis P, Buelli S, Tomasoni S, Piras R, Krendel M, Bettoni S, Morigi M, Delledonne M, Pecoraro C, Abbate I, Capobianchi MR, Hildebrandt F, Otto E, Schaefer F, Macciardi F, Ozaltin F, Emre S, Ibsirlioglu T, Benigni A, Remuzzi G, Noris M: MYO1E Mutations and Childhood Familial Focal Segmental Glomerulosclerosis. N Engl J Med. 2011

21.

Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ: Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006, 38 (5): 561-565. 10.1038/ng1775.CrossRefPubMed

22.

Amberger J, Bocchini C, Hamosh A: A new face and new challenges for Online Mendelian Inheritance in Man (OMIM(R)). Hum Mutat. 2011, 32 (5): 564-567. 10.1002/humu.21466.CrossRefPubMed

23.

Ku CS, Naidoo N, Pawitan Y: Revisiting Mendelian disorders through exome sequencing. Hum Genet. 2011, 129 (4): 351-370. 10.1007/s00439-011-0964-2.CrossRefPubMed

24.

Buckingham KJ, Lee C, Bigham AW, Tabor HK, Dent KM, Huff CD, Shannon PT, Jabs EW, Nickerson DA, Shendure J, Bamshad MJ: Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010, 42 (1): 30-35. 10.1038/ng.499.PubMedCentralCrossRefPubMed

25.

Zhao Q, Kirkness EF, Caballero OL, Galante PA, Parmigiani RB, Edsall L, Kuan S, Ye Z, Levy S, Vasconcelos AT, Ren B, de Souza SJ, Camargo AA, Simpson AJ, Strausberg RL: Systematic detection of putative tumor suppressor genes through the combined use of exome and transcriptome sequencing. Genome Biol. 2010, 11 (11): R114-10.1186/gb-2010-11-11-r114.PubMedCentralCrossRefPubMed

26.

Rios J, Stein E, Shendure J, Hobbs HH, Cohen JC: Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia. Hum Mol Genet. 2010, 19 (22): 4313-4318. 10.1093/hmg/ddq352.PubMedCentralCrossRefPubMed

27.

Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S: Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. The New England journal of medicine. 2010, 363 (23): 2220-2227. 10.1056/NEJMoa1002926.PubMedCentralCrossRefPubMed

28.

Vilarino-Guell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI, Cobb SA, Wilhoite GJ, Bacon JA, Behrouz B, Melrose HL, Hentati E, Puschmann A, Evans DM, Conibear E, Wasserman WW, Aasly JO, Burkhard PR, Djaldetti R, Ghika J, Hentati F, Krygowska-Wajs A, Lynch T, Melamed E, Rajput A, Rajput AH, Solida A, Wu RM, Uitti RJ: VPS35 Mutations in Parkinson Disease. Am J Hum Genet. 2011, 89 (1): 162-167. 10.1016/j.ajhg.2011.06.001.PubMedCentralCrossRefPubMed

29.

Zimprich A, Benet-Pages A, Struhal W, Graf E, Eck SH, Offman MN, Haubenberger D, Spielberger S, Schulte EC, Lichtner P, Rossle SC, Klopp N, Wolf E, Seppi K, Pirker W, Presslauer S, Mollenhauer B, Katzenschlager R, Foki T, Hotzy C, Reinthaler E, Harutyunyan A, Kralovics R, Peters A, Zimprich F, Brucke T, Poewe W, Auff E, Trenkwalder C, Rost B: A Mutation in VPS35, Encoding a Subunit of the Retromer Complex, Causes Late-Onset Parkinson Disease. Am J Hum Genet. 2011, 89 (1): 168-175. 10.1016/j.ajhg.2011.06.008.PubMedCentralCrossRefPubMed

30.

Betancur C: Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res. 2011, 1380: 42-77.CrossRefPubMed

31.

O'Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE: Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet. 2011, 43 (6): 585-589. 10.1038/ng.835.PubMedCentralCrossRefPubMed

32.

Heger M: Transcriptome Sequencing Becoming Key Approach to Study Disease and Guide Treatment. [http://www.genomeweb.com/sequencing/transcriptome-sequencing-becoming-key-approach-study-disease-and-guide-treatment]

33.

Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A, Delaney A, Gelmon K, Guliany R, Senz J, Steidl C, Holt RA, Jones S, Sun M, Leung G, Moore R, Severson T, Taylor GA, Teschendorff AE, Tse K, Turashvili G, Varhol R, Warren RL, Watson P, Zhao Y, Caldas C, Huntsman D, Hirst M, Marra MA, Aparicio S: Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009, 461 (7265): 809-813. 10.1038/nature08489.CrossRefPubMed

34.

Hawkins SM, Creighton CJ, Han DY, Zariff A, Anderson ML, Gunaratne PH, Matzuk MM: Functional microRNA involved in endometriosis. Mol Endocrinol. 2011, 25 (5): 821-832. 10.1210/me.2010-0371.PubMedCentralCrossRefPubMed

35.

Kannan K, Wang L, Wang J, Ittmann MM, Li W, Yen L: Recurrent chimeric RNAs enriched in human prostate cancer identified by deep sequencing. Proc Natl Acad Sci USA. 2011, 108 (22): 9172-9177. 10.1073/pnas.1100489108.PubMedCentralCrossRefPubMed

36.

Martens-Uzunova ES, Jalava SE, Dits NF, van Leenders GJ, Moller S, Trapman J, Bangma CH, Litman T, Visakorpi T, Jenster G: Diagnostic and prognostic signatures from the small non-coding RNA transcriptome in prostate cancer. Oncogene. 2011

37.

ClinicalTrials.gov: A service of the U.S. National Institutes of Health. [http://www.clinicaltrials.gov]

38.

Campbell PJ, Stephens PJ, Pleasance ED, O'Meara S, Li H, Santarius T, Stebbings LA, Leroy C, Edkins S, Hardy C, Teague JW, Menzies A, Goodhead I, Turner DJ, Clee CM, Quail MA, Cox A, Brown C, Durbin R, Hurles ME, Edwards PA, Bignell GR, Stratton MR, Futreal PA: Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing. Nat Genet. 2008, 40 (6): 722-729. 10.1038/ng.128.PubMedCentralCrossRefPubMed

39.

Chapman MA, Lawrence MS, Keats JJ, Cibulskis K, Sougnez C, Schinzel AC, Harview CL, Brunet JP, Ahmann GJ, Adli M, Anderson KC, Ardlie KG, Auclair D, Baker A, Bergsagel PL, Bernstein BE, Drier Y, Fonseca R, Gabriel SB, Hofmeister CC, Jagannath S, Jakubowiak AJ, Krishnan A, Levy J, Liefeld T, Lonial S, Mahan S, Mfuko B, Monti S, Perkins LM: Initial genome sequencing and analysis of multiple myeloma. Nature. 2011, 471 (7339): 467-472. 10.1038/nature09837.PubMedCentralCrossRefPubMed

40.

Lee W, Jiang Z, Liu J, Haverty PM, Guan Y, Stinson J, Yue P, Zhang Y, Pant KP, Bhatt D, Ha C, Johnson S, Kennemer MI, Mohan S, Nazarenko I, Watanabe C, Sparks AB, Shames DS, Gentleman R, de Sauvage FJ, Stern H, Pandita A, Ballinger DG, Drmanac R, Modrusan Z, Seshagiri S, Zhang Z: The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature. 2010, 465 (7297): 473-477. 10.1038/nature09004.CrossRefPubMed

41.

Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, Dooling D, Dunford-Shore BH, McGrath S, Hickenbotham M, Cook L, Abbott R, Larson DE, Koboldt DC, Pohl C, Smith S, Hawkins A, Abbott S, Locke D, Hillier LW, Miner T, Fulton L, Magrini V, Wylie T, Glasscock J, Conyers J, Sander N, Shi X, Osborne JR, Minx P: DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008, 456 (7218): 66-72. 10.1038/nature07485.PubMedCentralCrossRefPubMed

42.

Allen C, Foulkes WD: Qualitative thematic analysis of consent forms used in cancer genome sequencing. BMC Med Ethics. 2011, 12: 14-10.1186/1472-6939-12-14.PubMedCentralCrossRefPubMed

43.

Clayton EW, Ross LF: Implications of disclosing individual results of clinical research. Jama. 2006, 295 (1): 37-author reply 37-38PubMed

44.

Shalowitz DI, Miller FG: Disclosing individual results of clinical research: implications of respect for participants. Jama. 2005, 294 (6): 737-740. 10.1001/jama.294.6.737.CrossRefPubMed

45.

Fernald GH, Capriotti E, Daneshjou R, Karczewski KJ, Altman RB: Bioinformatics challenges for personalized medicine. Bioinformatics. 2011, 27 (13): 1741-1748. 10.1093/bioinformatics/btr295.PubMedCentralCrossRefPubMed

46.

Aldhous P: Where robots labour to overcome genetic disease. NewScientist. 2011, 14:

Title: Genomic sequencing in clinical trials
Authors: Karen K Mestan
Leonard Ilkhanoff
Samdeep Mouli
Simon Lin
Publication date: 01-12-2011
Publisher: BioMed Central
Published in: Journal of Translational Medicine / Issue 1/2011
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/1479-5876-9-222

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