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Next-Generation Sequencing and Applications to the Diagnosis and Treatment of Lung Cancer

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Lung Cancer and Personalized Medicine: Novel Therapies and Clinical Management

Abstract

Cancer is a genetic disease characterized by uncontrolled growth of abnormal cells. Over time, somatic mutations accumulate in the cells of an individual due to replication errors, chromosome segregation errors, or DNA damage. When not caught by traditional mechanisms, these somatic mutations can lead to cellular proliferation, the hallmark of cancer. Lung cancer is the leading cause of cancer-related mortality in the United States, accounting for approximately 160,000 deaths annually. Five year survival rates for lung cancer remain low (<50 %) for all stages, with even worse prognosis (<15 %) in late stage cases. Technological advances, including advances in next-generation sequencing (NGS), offer the vision of personalized medicine or precision oncology, wherein an individual’s treatment can be based on his or her individual molecular profile, rather than on historical population-based medicine. Towards this end, NGS has already been used to identify new biomarker candidates for the early diagnosis of lung cancer and is increasingly used to guide personalized treatment decisions. In this review we will provide a high-level overview of NGS technology and summarize its application to the diagnosis and treatment of lung cancer. We will also describe how NGS can drive advances that bring us closer to precision oncology and discuss some of the technical challenges that will need to be overcome in order to realize this ultimate goal.

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References

  1. Stratton MR, Campbell PJ, Futreal PA (2009) The cancer genome. Nature 458:719–724

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Peña-Diaz J et al (2012) Noncanonical mismatch repair as a source of genomic instability in human cells. Mol Cell 47:669–680

    Article  PubMed  CAS  Google Scholar 

  3. Pfeifer GP (2010) Environmental exposures and mutational patterns of cancer genomes. Genome Med 2:54

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Heuvers ME, Wisnivesky J, Stricker BH, Aerts JG (2012) Generalizabliity of results from the National Lung Screening Trial. Eur J Epidemiol 27:669–672

    Article  PubMed  Google Scholar 

  5. National Lung Screening Trial Research Team et al (2011) Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365:395–409

    Article  Google Scholar 

  6. Alexandrov LB et al (2013) Signatures of mutational processes in human cancer. Nature 500:415–421

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Winnick E (2014) Illumina launches two new platforms at JP Morgan Conference; claims $1,000 genome. GenomeWeb 2014. http://www.genomeweb.com/sequencing/illumina-launches-two-new-platforms-jp-morgan-conference-claims-1000-genome. Accessed 27 Jan 2014

  8. Adams MD et al (2012) Global mutational profiling of formalin-fixed human colon cancers from a pathology archive. Mod Pathol 25:1599–1608

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Rehm HL (2013) Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet 14:295–300

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Park JY, Kricka LJ, Fortina P (2013) Next-generation sequencing in the clinic. Nat Biotechnol 31:990–992

    Article  PubMed  CAS  Google Scholar 

  11. Strom SP et al (2014) Assessing the necessity of confirmatory testing for exome-sequencing results in a clinical molecular diagnostics laboratory. Genet Med 16(7):510–515

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Grosu DS et al (2014) Clinical investigational studies for validation of the first next-generation sequencing in vitro diagnostic for cystic fibrosis testing. Expert Rev Mol Diagn 14(5):605–622

    Article  PubMed  CAS  Google Scholar 

  13. Karnes HE, Duncavage EJ, Bernadt CT (2013) Targeted next-generation sequencing using fine-needle aspirates from adenocarcinomas of the lung. Cancer Cytopathol 122(2):104–113

    Article  PubMed  CAS  Google Scholar 

  14. Chen Y, Shi JX, Pan XF, Feng J, Zhao H (2013) Identification of candidate genes for lung cancer somatic mutation test kits. Genet Mol Biol 36:455–464

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Wu K, Huang RS, House L, Cho WC (2013) Next-generation sequencing for lung cancer. Future Oncol 9:1323–1336

    Article  PubMed  CAS  Google Scholar 

  16. Tuononen K et al (2013) Comparison of targeted next-generation sequencing (NGS) and real-time PCR in the detection of EGFR, KRAS, and BRAF mutation on formalin-fixed, paraffin-embedded tumor material of non-small cell lung carcinoma—superiority of NGS. Genes Chromosomes Cancer 52:503–511

    Article  PubMed  CAS  Google Scholar 

  17. Buttitta F et al (2013) Effective assessment of egfr mutation status in bronchoalveolar lavage and pleural fluids by next-generation sequencing. Clin Cancer Res 19:691–698

    Article  PubMed  CAS  Google Scholar 

  18. Evans JP (2010) The human genome project at 10 years: a teachable moment. Genet Med 12:477

    Article  PubMed  Google Scholar 

  19. Lawrence MS et al (2013) Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499:214–218

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Hainaut P, Pfeifer GP (2001) Patterns of p53 G → T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke. Carcinogenesis 22:367–374

    Article  PubMed  CAS  Google Scholar 

  21. Pfeifer GP, Besaratinia A (2009) Mutational spectra of human cancer. Hum Genet 125:493–506

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Paez JG et al (2004) EGFR mutations in lung cancer: correlation with clinical response to gefitibin therapy. Science 304:1497–1500

    Article  PubMed  CAS  Google Scholar 

  23. Pao W et al (2004) EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306–13311

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Kwak EL et al (2010) Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 363:1693–1703

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Choi K, Creighton CJ, Stivers D, Fujimoto N, Kurie JM (2007) Transcriptional profiling of non-small cell lung cancer cells activating EGFR somatic mutations. PLoS One 11, e1226

    Article  CAS  Google Scholar 

  26. Ding C, Li R, Peng J, Guo Z (2012) A polymorphism at the miR-502 binding site in the 3′ untranslated region of the SET8 gene is associated with the outcome of small-cell lung cancer. Exp Ther Med 3:689–692

    PubMed  PubMed Central  CAS  Google Scholar 

  27. Qian Q et al (2014) Methylated +58CpG site decreases DCN mRNA expression and enhances TGF-β/Smad signaling in NSCLC cells with high metastatic potential. Int J Oncol 44:874–882

    PubMed  CAS  Google Scholar 

  28. Zhao Y et al (2014) Identification of somatic alterations in stage I lung adenocarcinomas by next-generation sequencing. Genes Chromosomes Cancer 53(4):289–298

    Article  PubMed  CAS  Google Scholar 

  29. Vogelstein B et al (2013) Cancer genome landscapes. Science 339:1546–1558

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Thomas A, Rajan A, Lopez-Chavez A, Wang Y, Giaccone G (2013) From targets to targeted therapies and molecular profiling in non-small cell lung carcinoma. Ann Oncol 24:577–585

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Zhang J et al (2013) Exome profiling of primary, metastatic and recurrent ovarian carcinomas in a BRCA1-positive patient. BMC Cancer 13:146

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Vignot S et al (2013) Next-generation sequencing reveals high concordance of recurrent somatic alterations between primary tumor and metastases from patients with non-small-cell lung cancer. J Clin Oncol 31:2167–2172

    Article  PubMed  CAS  Google Scholar 

  33. De Mattow-Arruda L et al (2013) Establishing the origin of metastatic deposits in the setting of multiple primary malignancies: the role of massively parallel sequencing. Mol Oncol 8(1):150–158

    Article  CAS  Google Scholar 

  34. Zhang J et al (2013) Identifying driver mutations from sequencing data of heterogeneous tumors in the era of personalized genome sequencing. Brief Bioinform 15(2):244–255

    Article  PubMed  CAS  Google Scholar 

  35. Kismidou V et al (2013) Tumor heterogeneity revealed by KRAS, BRAF, and PIK3CA pyrosequencing: KRAS and PIK3CA intratumour mutation profile differences and their therapeutic implications. Hum Mutat 35(3):329–340

    Article  CAS  Google Scholar 

  36. Ni X et al (2013) Reproducible copy number variation patterns among single circulating tumor cells of lung cancer patients. Proc Natl Acad Sci U S A 110:1083–1088

    Article  Google Scholar 

  37. Lecomte T, Ceze N, Dorval E, Laurent-Luig P (2010) Circulating free tumor DNA and colorectal cancer. Gasteoenterol Clin Biol 34:662–681

    Article  CAS  Google Scholar 

  38. Dawson SJ et al (2013) Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 368:1199–1209

    Article  PubMed  CAS  Google Scholar 

  39. The Cancer Genome Atlas Network (2013) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330–337

    Google Scholar 

  40. The Cancer Genome Atlas Research Network (2013) The cancer genome atlas pan-cancer analysis project. Nat Gen 45:1113–1120

    Article  CAS  Google Scholar 

  41. Pantel K, Alix-Panabieres C (2013) Real-time liquid biopsy in cancer patients: fact or fiction? Cancer Res 73:6384–6388

    Article  PubMed  CAS  Google Scholar 

  42. Schwarzenback H (2013) Circulating nucleic acids as biomarkers in breast cancer. Breast Cancer Res 15:211

    Article  CAS  Google Scholar 

  43. Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A (2013) Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 10:472–484

    Article  PubMed  CAS  Google Scholar 

  44. Heitzer E et al (2013) Complex tumor genomes inferred from single circulating tumor cells by array-CGH and next-generation sequencing. Cancer Res 73:2965–2975

    Article  PubMed  CAS  Google Scholar 

  45. Kim SY, Speed TP (2013) Comparing somatic variant callers: beyond Venn diagrams. BMC Bioinformatics 10:189

    Article  Google Scholar 

  46. 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 Biol. 2009;10(3):R32. doi: 10.1186/gb-2009-10-3-r32. Epub 2009 Mar 27. PMID: 19327155

    Google Scholar 

  47. Ivahkno S et al (2010) CNAseg—a novel framework for identification of copy number changes in cancer from second-generation sequencing data. Bioinformatics 26:3051–3058

    Article  CAS  Google Scholar 

  48. Xie C, Tammi MT (2009) CNV-seq, a new method to detect copy number variation using high-throughput sequencing. BMC Bioinformatics 10:80

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Escaramís G et al (2013) PeSV-Fisher: identification of somatic and non-somatic structural variants using next generation sequencing data. PLoS One 8, e63377

    Article  PubMed  PubMed Central  Google Scholar 

  50. Chen K et al (2009) BreakDancer: an algorithm for high-resolution mapping of genomic structural variation. Nat Methods 6:677–681

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Chan KC et al (2013) Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing. Proc Natl Acad Sci U S A 110:18761–18768

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucl Acids Res 31:3812–3814

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Adzhubei IA et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Sherry ST, Ward M, Sirotkin K (1999) DbSNP-database for single nucleotide polymorphisms and other classes of minor genetic variation. Genome Res 9:677–679

    PubMed  CAS  Google Scholar 

  55. Bamford S et al (2004) The COSMIC (catalogue of somatic mutations in cancer) database and website. Br J Cancer 91:355–358

    PubMed  PubMed Central  CAS  Google Scholar 

  56. Hamosh A, Scott AF, Amberger J, Valle D, McKusick VA (2000) Online Mendelian Inheritance in Man (OMIM). Hum Mutat 15:57–61

    Article  PubMed  CAS  Google Scholar 

  57. International HapMap Consortium (2003) The International HapMap project. Nature 426:789–796

    Article  CAS  Google Scholar 

  58. Gonzalez-Perez A, Lopez-Bigas N (2012) Functional impact bias reveals cancer drivers. Nucl Acids Res 40, e169

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Hodis E et al (2012) A landscape of driver mutations in melanoma. Cell 150:251–263

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Reimand J, Bader GD (2013) Systematic analysis of somatic mutations in phosphorylation signaling predicts novel cancer drivers. Mol Sys Biol 9:637

    Article  CAS  Google Scholar 

  61. Gonzalez-Perez A et al (2013) Computational approaches to identify functional genetic variants in cancer genomes. Nat Methods 10:723–729

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Hartzler A et al (2013) Stakeholder engagement: a key component of integrating genomic information into electronic health records. Genet Med 15:792–801

    Article  PubMed  PubMed Central  Google Scholar 

  63. Gottesman O et al (2013) The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future. Genet Med 15:761–771

    Article  PubMed  PubMed Central  Google Scholar 

  64. Kho AN et al (2013) Practical challenges in integrating genomic data into the electronic health record. Genet Med 15:772–778

    Article  PubMed  PubMed Central  Google Scholar 

  65. Ury AG (2013) Storing and interpreting genomic information in widely deployed electronic health record systems. Genet Med 15:779–785

    Article  PubMed  Google Scholar 

  66. Hazin R et al (2013) Ethical, legal, and social implications of incorporating genomic information into electronic health records. Genet Med 15:810–816

    Article  PubMed  PubMed Central  Google Scholar 

  67. Tarczy-Hornoch P et al (2013) A survey of informatics approaches to whole-exome and whole-genome clinical reporting in the electronic health record. Genet Med 15:824–832

    Article  PubMed  PubMed Central  Google Scholar 

  68. Lo YM et al (1999) Rapid clearance of fetal DNA from maternal plasma. Am J Hum Genet 64:218–224

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Jackson L, Goldsmith L, O’Connor A, Skirton H (2012) Incidental findings in genetic research and clinical diagnostic tests: a systematic review. Am J Med Genet A 158A:3159–3167

    Article  PubMed  Google Scholar 

  70. Presidential Commission for the Study of Bioethical Issues (2012) Privacy and progress in whole genome sequencing. Presidential Commission for the Study of Bioethical Issues 2012. Washington, DC. http://bioethics.gov/sites/default/files/PrivacyProgress508_1.pdf. Accessed 27 Jan 2014

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Correspondence to Frank S. Ong M.D. .

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Kruglyak, K.M., Lin, E., Ong, F.S. (2016). Next-Generation Sequencing and Applications to the Diagnosis and Treatment of Lung Cancer. In: Ahmad, A., Gadgeel, S. (eds) Lung Cancer and Personalized Medicine: Novel Therapies and Clinical Management. Advances in Experimental Medicine and Biology, vol 890. Springer, Cham. https://doi.org/10.1007/978-3-319-24932-2_7

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