Clinical applications of next generation sequencing in cancer: From panels, to exomes, to genomes

Frontiers in Genetics

Volumn 6, Issue JUN, 2015, Pages

  Shen, Tony ^a,b   Pajaro Van de Stadt, Stefan Hans ^a   Yeat, Nai Chien ^a,b   Lin, Jimmy C H ^a  

^a Rare Genomics Institute   (United States)

^b WASHINGTON UNIVERSITY   (United States)

Author keywords

Cancer genomics; Clinical genomics; Exome sequencing; Next generation sequencing (NGS); Non coding DNA

Indexed keywords

APC PROTEIN; B RAF KINASE INHIBITOR; BIOLOGICAL MARKER; BRCA1 PROTEIN; BRCA2 PROTEIN; DNA; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ERBIUM; IMATINIB; PROGESTERONE RECEPTOR; PROTEIN P53; TRASTUZUMAB;

BREAST CANCER; CLINICAL ASSESSMENT; CONTROLLED STUDY; COST UTILITY ANALYSIS; DNA SEQUENCE; EXOME; GENE MUTATION; GENE SEQUENCE; GENETIC DATABASE; GENETIC SCREENING; GENETIC VARIABILITY; GENOME; GENOME ANALYSIS; GENOMIC INSTABILITY; GENOMICS; HUMAN; HUMAN CELL; MELANOMA; METASTATIC MELANOMA; NEOPLASM; NEXT GENERATION SEQUENCING; PANEL STUDY; REVIEW; SENSITIVITY AND SPECIFICITY; TUMOR CELL LINE; ULTRAVIOLET RADIATION;

EID: 84940109321     PISSN: None     EISSN: 16648021     Source Type: Journal    
DOI: 10.3389/fgene.2015.00215     Document Type: Review

References (85)

1. Bardeesy, N., and Depinho, R. A. (2002). Pancreatic cancer biology and genetics. Nat. Rev. Cancer 2, 897-909. doi: 10.1038/nrc949.
2. Bastos, D. A., Dzik, C., Rathkopf, D., and Scher, H. I. (2014). Expanding androgen-and androgen receptor signaling-directed therapies for castration-resistant prostate cancer. Oncology (Williston Park, NY) 28, 693-699.
3. Beshnova, D. A., Cherstvy, A. G., Vainshtein, Y., and Teif, V. B. (2014). Regulation of the nucleosome repeat length in vivo by the DNA sequence, protein concentrations and long-range interactions. PLoS Comput. Biol. 10:e1003698. doi: 10.1371/journal.pcbi.1003698.
4. Biegel, J. A., Zhou, J.-Y., Rorke, L. B., Stenstrom, C., Wainwright, L. M., and Fogelgren, B. (1999). Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59, 74-79.
5. Brose, M. S., Volpe, P., Feldman, M., Kumar, M., Rishi, I., Gerrero, R., et al. (2002). BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res. 62, 6997-7000.
6. Brunicardi, F. C., Gibbs, R. A., Wheeler, D. A., Nemunaitis, J., Fisher, W., Goss, J., et al. (2011). Overview of the development of personalized genomic medicine and surgery. World J. Surg. 35, 1693-1699. doi: 10.1007/s00268-011-1056-0.
7. Buchanan, J., Wordsworth, S., and Schuh, A. (2013). Issues surrounding the health economic evaluation of genomic technologies. Pharmacogenomics 14, 1833-1847. doi: 10.2217/pgs.13.183.
8. Cherstvy, A. G., and Teif, V. B. (2014). Electrostatic effect of H1-histone protein binding on nucleosome repeat length. Phys. Biol. 11:044001. doi: 10.1088/1478-3975/11/4/044001.
9. Cheung, C. C., Carydis, B., Ezzat, S., Bedard, Y. C., and Asa, S. L. (2001). Analysis of ret/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer. J. Clin. Endocrinol. Metab. 86, 2187-2190. doi: 10.1210/jcem.86.5.7504.
10. Chin, C.-S., Alexander, D. H., Marks, P., Klammer, A. A., Drake, J., Heiner, C., et al. (2013). Nonhybrid, finished microbial genome assemblies from long-read SMRT sequencing data. Nat. Methods 10, 563-569. doi: 10.1038/nmeth.2474.
11. Chmielecki, J., and Meyerson, M. (2014). DNA sequencing of cancer: what have we learned? Annu. Rev. Med. 65, 63-79. doi: 10.1146/annurev-med-060712-200152.
12. Dahia, P. L. M., Marsh, D. J., Zheng, Z., Zedenius, J., Komminoth, P., Frisk, T., et al. (1997). Somatic deletions and mutations in the cowden disease gene, PTEN, in sporadic thyroid tumors. Cancer Res. 57, 4710-4713.
13. Dawson, S.-J., Tsui, D. W., Murtaza, M., Biggs, H., Rueda, O. M., Chin, S.-F., et al. (2013). Analysis of circulating tumor DNA to monitor metastatic breast cancer. N. Engl. J. Med. 368, 1199-1209. doi: 10.1056/NEJMoa1213261.
14. De Ligt, J., Willemsen, M. H., Van Bon, B. W., Kleefstra, T., Yntema, H. G., Kroes, T., et al. (2012). Diagnostic exome sequencing in persons with severe intellectual disability. N. Engl. J. Med. 367, 1921-1929. doi: 10.1056/NEJMoa1206524.
15. Desmedt, C., Voet, T., Sotiriou, C., and Campbell, P. J. (2012). Next-generation sequencing in breast cancer: first take home messages. Curr. Opin. Oncol. 24, 597-604. doi: 10.1097/CCO.0b013e328359554e.
16. Devita, V. T., and Rosenberg, S. A. (2012). Two hundred years of cancer research. N. Engl. J. Med. 366, 2207-2214. doi: 10.1056/NEJMra1204479.
17. Dewey, F. E., Grove, M. E., Pan, C., Goldstein, B. A., Bernstein, J. A., Chaib, H., et al. (2014). Clinical interpretation and implications of whole-genome sequencing. JAMA 311, 1035-1045. doi: 10.1001/jama.2014.1717.
18. Diehl, F., Schmidt, K., Choti, M. A., Romans, K., Goodman, S., Li, M., et al. (2007). Circulating mutant DNA to assess tumor dynamics. Nat. Med. 14, 985-990. doi: 10.1038/nm.1789.
19. Eid, J., Fehr, A., Gray, J., Luong, K., Lyle, J., Otto, G., et al. (2009). Real-time DNA sequencing from single polymerase molecules. Science 323, 133-138. doi: 10.1126/science.1162986.
20. English, A. C., Richards, S., Han, Y., Wang, M., Vee, V., Qu, J., et al. (2012). Mind the gap: upgrading genomes with Pacific Biosciences RS long-read sequencing technology. PLoS ONE 7:e47768. doi: 10.1371/journal.pone.0047768.
21. Frampton, G. M., Fichtenholtz, A., Otto, G. A., Wang, K., Downing, S. R., He, J., et al. (2013). Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat. Biotechnol. 31, 1023-1031. doi: 10.1038/nbt.2696.
22. Fugazzola, L., Pierotti, M. A., Vigano, E., Pacini, F., Vorontsova, T. V., and Bongarzone, I. (1996). Molecular and biochemical analysis of RET/PTC4, a novel oncogenic rearrangement between RET and ELE1 genes, in a post-Chernobyl papillary thyroid cancer. Oncogene 13, 1093-1097.
23. Garraway, L. A., Widlund, H. R., Rubin, M. A., Getz, G., Berger, A. J., Ramaswamy, S., et al. (2005). Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117-122. doi: 10.1038/nature03664.
24. Gilissen, C., Hehir-Kwa, J. Y., Thung, D. T., van de Vorst, M., van Bon, B. W. M., Willemsen, M. H., et al. (2014). Genome sequencing identifies major causes of severe intellectual disability. Nature 511, 344-347. doi: 10.1038/nature13394.
25. GLOBOCAN (2012). Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2012. Available online at: http://globocan.iarc.fr/Pages/fact_sheets_population.aspx.
26. Gormally, E., Caboux, E., Vineis, P., and Hainaut, P. (2007). Circulating free DNA in plasma or serum as biomarker of carcinogenesis: practical aspects and biological significance. Mutat. Res. 635, 105-117. doi: 10.1016/j.mrrev.2006.11.002.
27. Gottlieb, B., Alvarado, C., Wang, C., Gharizadeh, B., Babrzadeh, F., Richards, B., et al. (2013). Making sense of intratumor genetic heterogeneity: altered frequency of androgen receptor CAG repeat length variants in breast cancer tissues. Hum. Mutat. 34, 610-618. doi: 10.1002/humu.22287.
28. Hodis, E., Watson, I. R., Kryukov, G. V., Arold, S. T., Imielinski, M., Theurillat, J. P., et al. (2012). A landscape of driver mutations in melanoma. Cell 150, 251-263. doi: 10.1016/j.cell.2012.06.024.
29. Hon, G. C., Hawkins, R. D., Caballero, O. L., Lo, C., Lister, R., Pelizzola, M., et al. (2012). Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer. Genome Res. 22, 246-258. doi: 10.1101/gr.125872.111.
30. Huang, F. W., Hodis, E., Xu, M. J., Kryukov, G. V., Chin, L., and Garraway, L. A. (2013). Highly recurrent TERT promoter mutations in human melanoma. Science 339, 957-959. doi: 10.1126/science.1229259.
31. Jones, S., Zhang, X., Parsons, D. W., Lin, J. C.-H., Leary, R. J., Angenendt, P., et al. (2008). Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801-1806. doi: 10.1126/science.1164368.
32. Kanamori, Y., Matsushima, M., Minaguchi, T., Kobayashi, K., Sagae, S., Kudo, R., et al. (1999). Correlation between expression of the matrix metalloproteinase-1 gene in ovarian cancers and an insertion/deletion polymorphism in its promoter region. Cancer Res. 59, 4225-4227.
33. Kim, T.-M., Laird, P. W., and Park, P. J. (2013). The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155, 858-868. doi: 10.1016/j.cell.2013.10.015.
34. Kleinman, C. L., Gerges, N., Papillon-Cavanagh, S., Sin-Chan, P., Pramatarova, A., Quang, D.-A. K., et al. (2014). Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR. Nat. Genet. 46, 39-44. doi: 10.1038/ng.2849.
35. Koboldt, D. C., Fulton, R. S., Mclellan, M. D., Schmidt, H., Kalicki-Veizer, J., Mcmichael, J. F., et al. (2012). Comprehensive molecular portraits of human breast tumours. Nature 490, 61-70. doi: 10.1038/nature11412.
36. Kosaka, T., Yatabe, Y., Endoh, H., Kuwano, H., Takahashi, T., and Mitsudomi, T. (2004). Mutations of the epidermal growth factor receptor gene in lung cancer: biological and clinical implications. Cancer Res. 64, 8919-8923. doi: 10.1158/0008-5472.CAN-04-2818.
37. Krauthammer, M., Kong, Y., Ha, B. H., Evans, P., Bacchiocchi, A., McCusker, J. P., et al. (2012). Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat. Genet. 44, 1006-1014. doi: 10.1038/ng.2359.
38. Kunz, M., Dannemann, M., and Kelso, J. (2013). High-throughput sequencing of the melanoma genome. Exp. Dermatol. 22, 10-17. doi: 10.1111/exd.12054.
39. Kurian, A. W., Hare, E. E., Mills, M. A., Kingham, K. E., Mcpherson, L., Whittemore, A. S., et al. (2014). Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J. Clin. Oncol. 32, 2001-2009. doi: 10.1200/JCO.2013.53.6607.
40. Kuroda, S., Tam, J., Roth, J. A., Sokolov, K., and Ramesh, R. (2014). EGFR-targeted plasmonic magnetic nanoparticles suppress lung tumor growth by abrogating G2/M cell-cycle arrest and inducing DNA damage. Int. J. Nanomed. 9, 3825. doi: 10.2147/IJN.S65990.
41. Lee, H., Deignan, J. L., Dorrani, N., Strom, S. P., Kantarci, S., Quintero-Rivera, F., et al. (2014). Clinical exome sequencing for genetic identification of rare mendelian disorders. JAMA 312, 1880-1887. doi: 10.1001/jama.2014.14604.
42. Ley, T. J., Mardis, E. R., Ding, L., Fulton, B., Mclellan, M. D., Chen, K., et al. (2008). DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature 456, 66-72. doi: 10.1038/nature07485.
43. Ley, T. J., Minx, P. J., Walter, M. J., Ries, R. E., Sun, H., Mclellan, M., et al. (2003). A pilot study of high-throughput, sequence-based mutational profiling of primary human acute myeloid leukemia cell genomes. Proc. Natl. Acad. Sci. U.S.A. 100, 14275-14280. doi: 10.1073/pnas.2335924100.
44. Lipson, D., Capelletti, M., Yelensky, R., Otto, G., Parker, A., Jarosz, M., et al. (2012). Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat. Med. 18, 382-384. doi: 10.1038/nm.2673.
45. Liu, L., Li, Y., Li, S., Hu, N., He, Y., Pong, R., et al. (2012). Comparison of next-generation sequencing systems. J. Biomed. Biotechnol. 2012, 11. doi: 10.1155/2012/251364.
46. Lohr, J. G., Adalsteinsson, V. A., Cibulskis, K., Choudhury, A. D., Rosenberg, M., Cruz-Gordillo, P., et al. (2014). Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer. Nat. Biotechnol. 32, 479-484. doi: 10.1038/nbt.2892.
47. Mardis, E. R. (2013). Next-generation sequencing platforms. Annu. Rev. Anal. Chem. (Palo. Alto Calif). 6, 287-303. doi: 10.1146/annurev-anchem-062012-092628.
48. Martin, H. C., Kim, G. E., Pagnamenta, A. T., Murakami, Y., Carvill, G. L., Meyer, E., et al. (2014). Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum. Mol. Genet. 23, 3200-3211. doi: 10.1093/hmg/ddu030.
49. Meldrum, C., Doyle, M. A., and Tothill, R. W. (2011). Next-generation sequencing for cancer diagnostics: a practical perspective. Clin. Biochem. Rev. 32, 177-195.
50. Miki, Y., Nishisho, I., Horii, A., Miyoshi, Y., Utsunomiya, J., Kinzler, K. W., et al. (1992). Disruption of the APC gene by a retrotransposal insertion of L1 sequence in a colon cancer. Cancer Res. 52, 643-645.
51. Moller, P., Evans, D. G., Reis, M. M., Gregory, H., Anderson, E., Maehle, L., et al. (2007). Surveillance for familial breast cancer: differences in outcome according to BRCA mutation status. Int. J. Cancer 121, 1017-1020. doi: 10.1002/ijc.22789.
52. Montagna, M., Palma, M. D., Menin, C., Agata, S., De Nicolo, A., Chieco-Bianchi, L., et al. (2003). Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum. Mol. Genet. 12, 1055-1061. doi: 10.1093/hmg/ddg120.
53. Morgan, J. E., Carr, I. M., Sheridan, E., Chu, C. E., Hayward, B., Camm, N., et al. (2010). Genetic diagnosis of familial breast cancer using clonal sequencing. Hum. Mutat. 31, 484-491. doi: 10.1002/humu.21216.
54. Murtaza, M., Dawson, S.-J., Tsui, D. W., Gale, D., Forshew, T., Piskorz, A. M., et al. (2013). Non-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA. Nature 497, 108-112. doi: 10.1038/nature12065.
55. Nguyen, U. T. T., Bittoval, L., Muller, M. M., Fierz, B., David, Y., Houck-Loomis, B., et al. (2014). Accelerated chromatin biochemistry using DNA-barcoded nucteosome libraries. Nat. Methods 11, 834-840. doi: 10.1038/nmeth.3022.
56. Pacific Biosciences Investor Relations. (2013). Pacific Biosciences Announces Agreement With Roche Diagnostics to Develop and Supply DNA Sequencing-Based Products for Clinical Diagnostics. Available online at: http://investor.pacificbiosciences.com/releasedetail.cfm?ReleaseID=793199.
57. Park, J. Y., Kricka, L. J., Clark, P., Londin, E., and Fortina, P. (2014). Clinical genomics: when whole genome sequencing is like a whole-body CT scan. Clin. Chem. 60, 1390-1392. doi: 10.1373/clinchem.2014.230276.
58. Raley, C., Munroe, D., Jones, K., Tsai, Y.-C., Guo, Y., Tran, B., et al. (2014). Preparation of next-generation DNA sequencing libraries from ultra-low amounts of input DNA: application to single-molecule, real-time (SMRT) Sequencing on the pacific biosciences RS II. bioRxiv. doi: 10.1101/003566.
59. Rheinbay, E., Louis, D. N., Bernstein, B. E., and Suvà, M. L. (2012). A tell-tail sign of chromatin: histone mutations drive pediatric glioblastoma. Cancer Cell 21, 329-331. doi: 10.1016/j.ccr.2012.03.001.
60. Riahi, A., Kharrat, M., Ghourabi, M. E., Khomsi, F., Gamoudi, A., Lariani, I., et al. (2014). Mutation spectrum and prevalence of BRCA1 and BRCA2 genes in patients with familial and early-onset breast/ovarian cancer from Tunisia. Clin. Genet. 87, 155-160. doi: 10.1111/cge.12337.
61. Schroeder, C., Stutzmann, F., Weber, B. H., Riess, O., and Bonin, M. (2010). High-throughput resequencing in the diagnosis of BRCA1/2 mutations using oligonucleotide resequencing microarrays. Breast Cancer Res. Treat. 122, 287-297. doi: 10.1007/s10549-009-0639-z.
62. Sellner, L. N., and Taylor, G. R. (2004). MLPA and MAPH: new techniques for detection of gene deletions. Hum. Mutat. 23, 413-419. doi: 10.1002/humu.20035.
63. Shah, S. P., Roth, A., Goya, R., Oloumi, A., Ha, G., Zhao, Y., et al. (2012). The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395-399. doi: 10.1038/nature10933.
64. Sjöblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., et al. (2006). The consensus coding sequences of human breast and colorectal cancers. Science 314, 268-274. doi: 10.1126/science.1133427.
65. Smith, C. C., Wang, Q., Chin, C.-S., Salerno, S., Damon, L. E., Levis, M. J., et al. (2012). Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature 485, 260-263. doi: 10.1038/nature11016.
66. Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., et al. (2007). Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561-566. doi: 10.1038/nature05945.
67. Stephens, P. J., Mcbride, D. J., Lin, M.-L., Varela, I., Pleasance, E. D., Simpson, J. T., et al. (2009). Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005-1010. doi: 10.1038/nature08645.
68. Taylor, R. W., Pyle, A., Griffin, H., Blakely, E. L., Duff, J., He, L., et al. (2014). Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA 312, 68-77. doi: 10.1001/jama.2014.7184.
69. Ting, D. T., Lipson, D., Paul, S., Brannigan, B. W., Akhavanfard, S., Coffman, E. J., et al. (2011). Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers. Science 331, 593-596. doi: 10.1126/science.1200801.
70. Tseng, T.-L., Shih, Y.-P., Huang, Y.-C., Wang, C.-K., Chen, P.-H., Chang, J.-G., et al. (2003). Genotypic and phenotypic characterization of a putative tumor susceptibility gene, GNMT, in liver cancer. Cancer Res. 63, 647-654.
71. Tsimberidou, A.-M., Wen, S., Hong, D. S., Wheler, J. J., Falchook, G. S., Fu, S., et al. (2014). Personalized medicine for patients with advanced cancer in the phase I program at MD Anderson: validation and landmark analyses. Clin. Cancer Res. 20, 4827-4836. doi: 10.1158/1078-0432.CCR-14-0603.
72. Van De Vijver, M. J., He, Y. D., van 't Veer, L. J., Dai, H., Hart, A. A. M., Voskuil, D. W., et al. (2002). A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999-2009. doi: 10.1056/NEJMoa021967.
73. Van't Veer, L. J., Dai, H., Van De Vijver, M. J., He, Y. D., Hart, A. A., Mao, M., et al. (2002). Gene expression profiling predicts clinical outcome of breast cancer. Nature 415, 530-536. doi: 10.1038/415530a.
74. Vogelstein, B., and Kinzler, K. W. (2004). Cancer genes and the pathways they control. Nat. Med. 10, 789-799. doi: 10.1038/nm1087.
75. Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., and Kinzler, K. W. (2013). Cancer genome landscapes. Science 339, 1546-1558. doi: 10.1126/science.1235122.
76. Walsh, T., Casadei, S., Coats, K., Swisher, E., Stray, S. M., Higgins, J., et al. (2006). Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA 295, 1379-1388. doi: 10.1001/jama.295.12.1379.
77. Wang, J., Gotway, G., Pascual, J. M., and Park, J. Y. (2014a). DIagnostic yield of clinical next-generation sequencing panels for epilepsy. JAMA Neurol. 71, 650-651. doi: 10.1001/jamaneurol.2014.405.
78. Wang, L., and Wheeler, D. A. (2014). Genomic sequencing for cancer diagnosis and therapy. Annu. Rev. Med. 65, 33-48. doi: 10.1146/annurev-med-120811-171056.
79. Wang, Y., Waters, J., Leung, M. L., Unruh, A., Roh, W., Shi, X., et al. (2014b). Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature 512, 155-160. doi: 10.1038/nature13600.
80. Wei, G., Hu, G., Cui, K., and Zhao, K. (2012). "Chapter thirteen-genome-wide mapping of nucleosome occupancy, histone modifications, and gene expression using next-generation sequencing technology," in Methods in Enzymology, eds W. Carl and C. D. Allis (San Diego, CA: Academic Press), 297-313.
81. Wei, X., Walia, V., Lin, J. C., Teer, J. K., Prickett, T. D., Gartner, J., et al. (2011). Exome sequencing identifies GRIN2A as frequently mutated in melanoma. Nat. Genet. 43, 442-446. doi: 10.1038/ng.810.
82. Wood, L. D., Parsons, D. W., Jones, S., Lin, J., Sjöblom, T., Leary, R. J., et al. (2007). The genomic landscapes of human breast and colorectal cancers. Science 318, 1108-1113. doi: 10.1126/science.1145720.
83. Yang, Y., Muzny, D. M., Reid, J. G., Bainbridge, M. N., Willis, A., Ward, P. A., et al. (2013). Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Engl. J. Med. 369, 1502-1511. doi: 10.1056/NEJMoa1306555.
84. Yang, Y., Muzny, D. M., Xia, F., Niu, Z., Person, R., Ding, Y., et al. (2014). Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312, 1870-1879. doi: 10.1001/jama.2014.14601.
85. Zhu, Q., Pao, G. M., Huynh, A. M., Suh, H., Tonnu, N., Nederlof, P. M., et al. (2011). BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature 477, 179-184. doi: 10.1038/nature10371.