[Frontiers in Bioscience, Landmark, 25, 1825-1835, June 1, 2020]

Beyond the coding genome: non-coding mutations and cancer

Kaivalya Walavalkar1, Dimple Notani1

1Department of Cellular Organization and Signaling, National Centre for Biological Sciences, Tata Institute for Fundamental Research, Bangalore 560065, India


1. Abstract
2. Introduction
3. Link between mutations in enhancers and cancer
4. Mutations in insulators/boundaries
5. Mutations in chromatin architecture proteins
6. Mutations in transcriptional machineries
7. eRNAs in cancer
8. Conclusions
9. Acknowledgments
10. References


Latest advancements in genomics involving individuals from different races and geographical locations has led to the identification of thousands of common as well as rare genetic variants and copy number variations (CNVs). These studies have surprisingly revealed that the majority of genetic variation is not present within the coding region but rather in the non-coding region of the genome, which is also termed as “Medical Genome”. This short review describes how mutations/variations within; regulatory sequences, architectural proteins and transcriptional regulators give rise to the aberrant gene expression profiles that drives cellular transformations and malignancies.


1. Zhang, W., Bojorquez-Gomez, A., Velez, D.O., Xu, G., Sanchez, K.S., Shen, J.P., Chen, K., Licon, K., Melton, C., Olson, K.M. and Yu, M.K. A global transcriptional network connecting noncoding mutations to changes in tumor gene expression. Nat genet, 50(4), 613. (2018)
DOI: 10.1038/s41588-018-0091-2

2. Jolly, M.K., Ware, K.E., Gilja, S., Somarelli, J.A. and Levine, H. EMT and MET: necessary or permissive for metastasis?. Mol Oncol. 11(7):755-769. (2017)
DOI: 10.1002/1878-0261.12083

3. Corradin, O. and Scacheri, P.C. Enhancer variants: evaluating functions in common disease. Genome med, 6(10), p.85 (1-14). (2014)
DOI: 10.1186/s13073-014-0085-3

4. Hazelett, D.J., Rhie, S.K., Gaddis, M., Yan, C., Lakeland, D.L., Coetzee, S.G., Henderson, B.E., Noushmehr, H., Cozen, W., Kote-Jarai, Z. and Eeles, R.A. Comprehensive functional annotation of 77 prostate cancer risk loci. PLoS genet, 10(1), p.e1004102. (2014)
DOI: 10.1371/journal.pgen.1004102

5. Bonifer, C., & Cockerill, P. N. Chromatin priming of genes in development: concepts, mechanisms and consequences. Exp hematol, 49, 1-8. (2017)
DOI: 10.1016/j.exphem.2017.01.003

6. Herz, H. M., Hu, D., & Shilatifard, A. Enhancer malfunction in cancer. Mol cell, 53(6), 859-866. (2014)
DOI: 10.1016/j.molcel.2014.02.033

7. Liu, Q., Thoms, J.A., Nunez, A.C., Huang, Y., Knezevic, K., Packham, D., Poulos, R.C., Williams, R., Beck, D., Hawkins, N.J. and Ward, R.L. Disruption of a− 35 kb Enhancer Impairs CTCF Binding and MLH1 Expression in Colorectal Cells. Clinical Cancer Res, 24(18), pp.4602-4611. (2018)
DOI: 10.1158/1078-0432.CCR-17-3678

8. Gabay, M., Li, Y. and Felsher, D.W. MYC activation is a hallmark of cancer initiation and maintenance. CSH perspectives in medicine, 4(6), p.a014241. (2014)
DOI: 10.1101/cshperspect.a014241

9. Bandopadhayay, P., Ramkissoon, L.A., Jain, P., Bergthold, G., Wala, J., Zeid, R., Schumacher, S.E., Urbanski, L., O'Rourke, R., Gibson, W.J. and Pelton, K. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat genet, 48(3), pp.273-282. (2016)
DOI: 10.1158/1538-7445.AM2016-4372

10. Guo, H., Ahmed, M., Zhang, F., Yao, C.Q., Li, S., Liang, Y., Hua, J., Soares, F., Sun, Y., Langstein, J. and Li, Y. Modulation of long noncoding RNAs by risk SNPs underlying genetic predispositions to prostate cancer. Nat genet, 48(10), pp.1142-1150. (2016)
DOI: 10.1038/ng.3637

11. Hua, J.T., Ahmed, M., Guo, H., Zhang, Y., Chen, S., Soares, F., Lu, J., Zhou, S., Wang, M., Li, H. and Larson, N.B. Risk SNP-mediated promoter-enhancer switching drives prostate cancer through lncRNA PCAT19. Cell, 174(3), pp.564- 575. (2018)
DOI: 10.1016/j.cell.2018.06.014

12. Hnisz, D., Weintraub, A.S., Day, D.S., Valton, A.L., Bak, R.O., Li, C.H., Goldmann, J., Lajoie, B.R., Fan, Z.P., Sigova, A.A. and Reddy, J. Activation of proto-oncogenes by disruption of chromosome neighborhoods. Science, 351(6280), pp.1454-1458. (2016)
DOI: 10.1126/science.aad9024

13. Campbell, T.M., Castro, M.A., de Santiago, I., Fletcher, M.N., Halim, S., Prathalingam, R., Ponder, B.A. and Meyer, K.B. FGFR2 risk SNPs confer breast cancer risk by augmenting oestrogen responsiveness. Carcinogenesis, 37(8), pp.741-750. (2016)
DOI: 10.1093/carcin/bgw065

14. Hill, V.K., Kim, J.S. and Waldman, T. Cohesin mutations in human cancer. Biochimica Et Biophysica Acta (BBA)-Reviews on Cancer, 1866(1), pp.1- 11. (2016)
DOI: 10.1016/j.bbcan.2016.05.002

15. Rovnak, J., Brewster, C.D. and Quackenbush, S.L. Retroviral cyclin enhances cyclin-dependent kinase-8 activity. Journal of virol, 86(10), pp.5742- 5751. (2012)
DOI: 10.1128/JVI.07006-11

16. Guo X.1. and Wang X.F. A mediator lost in the war on cancer. Cell. 21;151(5), pp. 927-9299. (2012)
DOI: 10.1016/j.cell.2012.11.003

17. Meng, F.L., Du, Z., Federation, A., Hu, J., Wang, Q., Kieffer-Kwon, K.R., Meyers, R.M., Amor, C., Wasserman, C.R., Neuberg, D. and Casellas, R. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell, 159(7), pp.1538-1548. (2014)
DOI: 10.1016/j.cell.2014.11.014

18. Mansour, M.R., Abraham, B.J., Anders, L., Berezovskaya, A., Gutierrez, A., Durbin, A.D., Etchin, J., Lawton, L., Sallan, S.E., Silverman, L.B. and Loh, M.L. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science, 346(6215), pp.1373-1377. (2014)
DOI: 10.1126/science.1259037

19. Huang, Q., Whitington, T., Gao, P., Lindberg, J.F., Yang, Y., Sun, J., Väisänen, M.R., Szulkin, R., Annala, M., Yan, J. and Egevad, L.A. A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nat genet, 46(2), pp.126-135. (2014)
DOI: 10.1038/ng.2862

20. Zhang, J., Ding, L., Holmfeldt, L., Wu, G., Heatley, S.L., Payne-Turner, D., Easton, J., Chen, X., Wang, J., Rusch, M. and Lu, C. The genetic basis of early T- cell precursor acute lymphoblastic leukaemia. Nature, 481(7380), pp.157-163. (2012)

21. Tuupanen, S., Yan, J., Turunen, M., Gylfe, A.E., Kaasinen, E., Li, L., Eng, C., Culver, D.A., Kalady, M.F., Pennison, M.J. and Pasche, B. Characterization of the colorectal cancer-associated enhancer MYC-335 at 8q24: the role of rs67491583. Cancer genet, 205(1-2), pp.25-33. (2012)
DOI: 10.1016/j.cancergen.2012.01.005

22. He, H., Li, W., Liyanarachchi, S., Srinivas, M., Wang, Y., Akagi, K., Wang, Y., Wu, D., Wang, Q., Jin, V. and Symer, D.E. Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer. PNAS, 112(19), pp.6128-6133. (2015)
DOI: 10.1073/pnas.1506255112

23. French, J.D., Ghoussaini, M., Edwards, S.L., Meyer, K.B., Michailidou, K., Ahmed, S., Khan, S., Maranian, M.J., O'Reilly, M., Hillman, K.M. and Betts, J.A. Functional variants at the 11q13 risk locus for breast cancer regulate cyclin D1 expression through long-range enhancers. AJHG, 92(4), pp.489-503. (2013)

24. Pomerantz, M.M., Ahmadiyeh, N., Jia, L., Herman, P., Verzi, M.P., Doddapaneni, H., Beckwith, C.A., Chan, J.A., Hills, A., Davis, M. and Yao, K. The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat genet, 41(8), pp.882-884. (2009)
DOI: 10.1038/ng.403

25. Takeda, D.Y., Spisák, S., Seo, J.H., Bell, C., O'Connor, E., Korthauer, K., Ribli, D., Csabai, I., Solymosi, N., Szállási, Z. and Stillman, D.R. A somatically acquired enhancer of the androgen receptor is a noncoding driver in advanced prostate cancer. Cell, 174(2), pp.422-432. (2018)
DOI: 10.1016/j.cell.2018.05.037

26. Zeid, R., Lawlor, M.A., Poon, E., Reyes, J.M., Fulciniti, M., Lopez, M.A., Scott, T.G., Nabet, B., Erb, M.A., Winter, G.E. and Jacobson, Z. Enhancer invasion shapes MYCN-dependent transcriptional amplification in neuroblastoma. Nat genet, 50(4), pp.515-523. (2018)
DOI: 10.1038/s41588-018-0044-9

27. Zimmerman, M.W., Liu, Y., He, S., Durbin, A.D., Abraham, B.J., Easton, J., Shao, Y., Xu, B., Zhu, S., Zhang, X. and Li, Z. MYC drives a subset of high-risk pediatric neuroblastomas and is activated through mechanisms including enhancer hijacking and focal enhancer amplification. Cancer disc, 8(3), pp.320-335. (2018)
DOI: 10.1158/2159-8290.CD-17-0993

28. Drier, Y., Cotton, M.J., Williamson, K.E., Gillespie, S.M., Ryan, R.J., Kluk, M.J., Carey, C.D., Rodig, S.J., Sholl, L.M., Afrogheh, A.H. and Faquin, W.C. An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma. Nat genet, 48(3), p.265. (2016)
DOI: 10.1038/ng.3502

29. Zhang, X., Zhou, L., Fu, G., Sun, F., Shi, J., Wei, J., Lu, C., Zhou, C., Yuan, Q. and Yang, M. The identification of an ESCC susceptibility SNP rs920778 that regulates the expression of lncRNA HOTAIR via a novel intronic enhancer. Carcinogenesis, 35(9), pp.2062-2067. (2014)
DOI: 10.1093/carcin/bgu103

30. Visser, M., Palstra, R.J. and Kayser, M. Allele-specific transcriptional regulation of IRF4 in melanocytes is mediated by chromatin looping of the intronic rs12203592 enhancer to the IRF4 promoter. Human mol genet, 24(9), pp.2649-2661. (2015)
DOI: 10.1093/hmg/ddv029

31. Dwight, T., Flynn, A., Amarasinghe, K., Benn, D.E., Lupat, R., Li, J., Cameron, D.L., Hogg, A., Balachander, S., Candiloro, I.L. and Wong, S.Q. TERT structural rearrangements in metastatic pheochromocytomas. Endocrine-related cancer, 25(1), pp.1-9. (2018)
DOI: 10.1530/ERC-17-0306

32. Havelange, V., Pekarsky, Y., Nakamura, T., Palamarchuk, A., Alder, H., Rassenti, L., Kipps, T. and Croce, C.M. IRF4 mutations in chronic lymphocytic leukemia. Blood, 118(10), pp.2827-2829. (2011)
DOI: 10.1182/blood-2011-04-350579

33. Delhommeau, F., Dupont, S., Valle, V.D., James, C., Trannoy, S., Masse, A., Kosmider, O., Le Couedic, J.P., Robert, F., Alberdi, A. and Lecluse, Y. Mutation in TET2 in myeloid cancers. NEJM, 360(22), pp.2289-2301. (2009)
DOI: 10.1056/NEJMoa0810069

34. Nikoloski, G., Langemeijer, S.M., Kuiper, R.P., Knops, R., Massop, M., Tönnissen, E.R., Van der Heijden, A., Scheele, T.N., Vandenberghe, P., de Witte, T. and van der Reijden, B.A. Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nat genet, 42(8), pp.665-667. (2010)
DOI: 10.1038/ng.620

35. Ley, T.J., Ding, L., Walter, M.J., McLellan, M.D., Lamprecht, T., Larson, D.E., Kandoth, C., Payton, J.E., Baty, J., Welch, J. and Harris, C.C. DNMT3A mutations in acute myeloid leukemia. NEJM, 363(25), pp.2424-2433. (2010)

36. Smith, M.J., O'Sullivan, J., Bhaskar, S.S., Hadfield, K.D., Poke, G., Caird, J., Sharif, S., Eccles, D., Fitzpatrick, D., Rawluk, D. and du Plessis, D. Loss- of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat genet, 45(3), pp.295-298. (2013)
DOI: 10.1038/ng.2552

37. Kadoch, C., Hargreaves, D.C., Hodges, C., Elias, L., Ho, L., Ranish, J. and Crabtree, G.R. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat genet, 45(6), pp.592-601. (2013)
DOI: 10.1038/ng.2628

38. Xia, W., Nagase, S., Montia, A.G., Kalachikov, S.M., Keniry, M., Su, T., Memeo, L., Hibshoosh, H. and Parsons, R. BAF180 is a critical regulator of p21 induction and a tumor suppressor mutated in breast cancer. Cancer res, 68(6), pp.1667-1674. (2008)
DOI: 10.1158/0008-5472.CAN-07-5276

39. Varela, I., Tarpey, P., Raine, K., Huang, D., Ong, C.K., Stephens, P., Davies, H., Jones, D., Lin, M.L., Teague, J. and Bignell, G. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature, 469(7331), pp.539-542. (2011)

40. Koschmann, C., Calinescu, A.A., Nunez, F.J., Mackay, A., Fazal-Salom, J., Thomas, D., Mendez, F., Kamran, N., Dzaman, M., Mulpuri, L. and Krasinkiewicz, J. ATRX loss promotes tumor growth and impairs nonhomologous end joining DNA repair in glioma. Science transl med, 8(328), pp. (1-11). (2016)
DOI: 10.1126/scitranslmed.aac8228

41. Bernt, K.M., Zhu, N., Sinha, A.U., Vempati, S., Faber, J., Krivtsov, A.V., Feng, Z., Punt, N., Daigle, A., Bullinger, L. and Pollock, R.M. MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer cell, 20(1), pp.66-78. (2011)
DOI: 10.1016/j.ccr.2011.06.010

42. Parsons, D.W., Li, M., Zhang, X., Jones, S., Leary, R.J., Lin, J.C.H., Boca, S.M., Carter, H., Samayoa, J., Bettegowda, C. and Gallia, G.L. The genetic landscape of the childhood cancer medulloblastoma. Science, 331(6016), pp.435- 439. (2011)
DOI: 10.1126/science.1198056

43. Wang, G.G., Cai, L., Pasillas, M.P. and Kamps, M.P. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat cell biol, 9(7), pp.804-812. (2007)
DOI: 10.1038/ncb1608

44. Papaemmanuil, E., Doehner, H. and Campbell, P.J., Genomic Classification in Acute Myeloid Leukemia. NEJM, 375(9), pp.900-901. (2016)
DOI: 10.1056/NEJMc1608739

45. Hashizume, R., Andor, N., Ihara, Y., Lerner, R., Gan, H., Chen, X., Fang, D., Huang, X., Tom, M.W., Ngo, V. and Solomon, D. Pharmacologic inhibition of histone demethylation as a therapy for pediatric brainstem glioma. Nat med, 20(12), pp.1394-1396. (2014)
DOI: 10.1038/nm.3716

46. Asangani, I.A., Dommeti, V.L., Wang, X., Malik, R., Cieslik, M., Yang, R., Escara-Wilke, J., Wilder-Romans, K., Dhanireddy, S., Engelke, C. and Iyer, M.K. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature, 510(7504), 278. (2014)
DOI: 10.1038/nature13229

47. Gao, Y.B., Chen, Z.L., Li, J.G., Hu, X.D., Shi, X.J., Sun, Z.M., Zhang, F., Zhao, Z.R., Li, Z.T., Liu, Z.Y. and Zhao, Y.D. Genetic landscape of esophageal squamous cell carcinoma. Nat genet, 46(10), pp.1097-1102. (2014)
DOI: 10.1038/ng.3076

48. Gocho, Y., Kiyokawa, N., Ichikawa, H., Nakabayashi, K., Osumi, T., Ishibashi, T., Ueno, H., Terada, K., Oboki, K., Sakamoto, H. and Shioda, Y. A novel recurrent EP300-ZNF384 gene fusion in B-cell precursor acute lymphoblastic leukemia. Leukemia, 29(12), pp.2445-2448. (2015)
DOI: 10.1038/leu.2015.111

49. Gruhn, B., Naumann, T., Gruner, D., Walther, M., Wittig, S., Becker, S., Beck, J.F. and Sonnemann, J. The expression of histone deacetylase 4 is associated with prednisone poor-response in childhood acute lymphoblastic leukemia. Leukemia res, 37(10), pp.1200-1207. (2013)
DOI: 10.1016/j.leukres.2013.07.016

50. Wang, Q. and Cheng, T. Evidences for mutations in the histone modifying gene SETD2 as critical drivers in leukemia development. Science China Life Sciences, 57(9), pp.944-946. (2014)
DOI: 10.1007/s11427-014-4702-6

51. Figueroa, M.E., Chen, S.C., Andersson, A.K., Phillips, L.A., Li, Y., Sotzen, J., Kundu, M., Downing, J.R., Melnick, A. and Mullighan, C.G. Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia. The Journal of clin invest, 123(7), pp.3099-3111. (2013)
DOI: 10.1172/JCI66203

52. Dolnik, A., Engelmann, J.C., Scharfenberger-Schmeer, M., Mauch, J., Kelkenberg- Schade, S., Haldemann, B., Fries, T., Krönke, J., Kühn, M.W., Paschka, P. and Kayser, S. Commonly altered genomic regions in acute myeloid leukemia are enriched for somatic mutations involved in chromatin remodeling and splicing. Blood, 120(18), pp.e83-e92. (2012)
DOI: 10.1182/blood-2011-12-401471

53. Solomon, D.A., Kim, T., Diaz-Martinez, L.A., Fair, J., Elkahloun, A.G., Harris, B.T., Toretsky, J.A., Rosenberg, S.A., Shukla, N., Ladanyi, M. and Samuels, Y. Mutational inactivation of STAG2 causes aneuploidy in human cancer. Science, 333(6045), pp.1039-1043. (2011)
DOI: 10.1126/science.1203619

54. Kon, A., Shih, L.Y., Minamino, M., Sanada, M., Shiraishi, Y., Nagata, Y., Yoshida, K., Okuno, Y., Bando, M., Nakato, R. and Ishikawa, S. Recurrent mutations in multiple components of the cohesin complex in myeloid neoplasms. Nat genet, 45(10), pp.1232-1237. (2013)
DOI: 10.1038/ng.2731

55. Wu, J., Qin, W., Wang, Y., Sadik, A., Liu, J., Wang, Y., Song, P., Wang, X., Sun, K., Zeng, J. and Wang, L., SPDEF is overexpressed in gastric cancer and triggers cell proliferation by forming a positive regulation loop with FoxM1. Journal of cellular biochem, 119(11), pp.9042-9054. (2018)
DOI: 10.1002/jcb.27161

56. Kalkat, M., De Melo, J., Hickman, K., Lourenco, C., Redel, C., Resetca, D., Tamachi, A., Tu, W. and Penn, L. MYC deregulation in primary human cancers. Genes, 8(6), p.151 (1-30). (2017)
DOI: 10.3390/genes8060151

Abbreviations: CNVs- Copy number variations, WGS- Whole-genome sequencing, DHS- DNase hypersensitivity, ChIP- Chromatin immunoprecipitation, GRO-Global run-on, ChIA-PET- Chromatin Interaction Analysis by Paired-End Tag, 3C- Chromatin conformation capture, GWAS- Genome-wide association study, SNP- Single nucleotide polymorphism, TF-Transcription factor, TAD- Topologically associating domain and DSB- Double strand break.

Key Words: Genome, Mutation, Enhancer, Cancer, SNP, Oncogene, GWAS, eRNA, Insulator, Boundary, TAD, CTCF, Chromatin architecture, Enhanceropathy and Review.

Send correspondence to: Dimple Notani, 1National Centre for Biological Sciences, Bangalore, India, Tel: 080 2366 6664, E-mail: dnotani@ncbs.res.in