KMT2D

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Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and sometimes MLL2 in humans and Mll4 in mice, is a major mammalian histone H3 lysine 4 (H3K4) mono-methyltransferase.[1] It is part of a family of six Set1-like H3K4 methyltransferases that also contains KMT2A (or MLL1), KMT2B (or MLL2), KMT2C (or MLL3), KMT2F (or SET1A), and KMT2G (or SET1B). KMT2D is a large protein over 5,500 amino acids in size and is widely expressed in adult tissues.[2] The protein co-localizes with lineage determining transcription factors on transcriptional enhancers and is essential for cell differentiation and embryonic development.[1] It also plays critical roles in regulating cell fate transition,[1][3][4][5] metabolism,[6][7] and tumor suppression.[8][9][10][11] Mutations in KMT2D have been associated with Kabuki Syndrome,[12] congenital heart disease,[13] and various forms of cancer.[14]

Structure

Gene

In mice, KMT2D is coded by the Kmt2d gene located on chromosome 15F1. Its transcript is 19,823 base pairs long and contains 55 exons and 54 introns.[15] In humans, KMT2D is coded by the KMT2D gene located on chromosome 12q13.12. Its transcript is 19,419 base pairs long and contains 54 exons and 53 introns.[16]

Protein

KMT2D is homologous to Trithorax-related (Trr), which is a Trithorax-group protein.[17] The mouse and human KMT2D proteins are 5,588 and 5,537 amino acids in length, respectively. Both species of the protein weigh about 600 kDa.[15][16] KMT2D contains an enzymatically active C-terminal SET domain that is responsible for its methyltransferase activity and maintaining protein stability in cells.[18] Near the SET domain are a plant homeotic domain (PHD) and FY-rich N/C-terminal (FYRN and FYRC) domains. The protein also contains six N-terminal PHDs, a high mobility group (HMG-I), and nine nuclear receptor interacting motifs (LXXLLs).[14] It was shown that amino acids Y5426 and Y5512 are critical for the enzymatic activity of human KMT2D in vitro.[19] In addition, mutation of Y5477 in mouse KMT2D, which corresponds to Y5426 in human KMT2D, resulted in the inactivation of KMT2D's enzymatic activity in embryonic stem cells.[20] Depletion of cellular H3K4 methylation reduces KMT2D levels, indicating that the protein's stability could be regulated by cellular H3K4 methylation.[19]

Protein complex

Several components of the KMT2D complex were first purified in 2003,[21] and then the entire complex was identified in 2007.[22][23][24][25] Along with KMT2D, the complex also contains ASH2L, RbBP5, WDR5, DPY30, NCOA6, UTX (also known as KDM6A), PA1, and PTIP. WDR5, RbBP5, ASH2L, and DPY30 form the four-subunit sub-complex WRAD, which is critical for H3K4 methyltransferase activity in all mammalian Set1-like histone methyltransferase complexes.[26] WDR5 binds directly with FYRN/FYRC domains of C-terminal SET domain-containing fragments of human KMT2C and KMT2D.[22] UTX, the complex’s H3K27 demethylase, PTIP, and PA1 are subunits that are unique to KMT2C and KMT2D.[22][27][28] KMT2D acts as a scaffold protein within the complex; absence of KMT2D results in destabilization of UTX and collapse of the complex in cells.[1][19]

Enhancer regulation

KMT2D is a major enhancer mono-methyltransferase and has partial functional redundancy with KMT2C.[1][3] The protein selectively binds enhancer regions based on type of cell and stage of differentiation. During differentiation, lineage determining transcription factors recruit KMT2D to establish cell-type specific enhancers. For example, CCAAT/enhancer-binding protein β (C/EBPβ), an early adipogenic transcription factor, recruits and requires KMT2D to establish a subset of adipogenic enhancers during adipogenesis. Depletion of KMT2D prior to differentiation prevents the accumulation of H3K4 mono-methylation (H3K4me1), H3K27 acetylation, the transcriptional coactivator Mediator, and RNA polymerase II on enhancers, resulting in severe defects in gene expression and cell differentiation.[1] KMT2C and KMT2D also identify super-enhancers and are required for formation of super-enhancers during cell differentiation.[29] Mechanistically, KMT2C and KMT2D are required for the binding of H3K27 acetyltransferases CREB-binding protein (CBP) and/or p300 on enhancers, enhancer activation, and enhancer-promotor looping prior to gene transcription.[1][29] Interestingly, the KMT2C and KMT2D proteins, rather than the KMT2C and KMT2D-mediated H3K4me1, control p300 recruitment to enhancers, enhancer activation, and transcription from promoters in embryonic stem cells.[3]

Functions

Development

Whole-body knockout of Kmt2d in mice results in early embryonic lethality.[1] Targeted knockout of Kmt2d in precursors cells of brown adipocytes and myocytes results in decreases in brown adipose tissue and muscle mass in mice, indicating that KMT2D is required for adipose and muscle tissue development.[1] In the hearts of mice, a single copy of the Kmt2d gene is sufficient for normal heart development.[30] Complete loss of Kmt2d in cardiac precursors and myocardium leads to severe cardiac defects and early embryonic lethality. KMT2D mediated mono- and di-methylation is required for maintaining necessary gene expression programs during heart development. Knockout studies in mice also show that KMT2D is required for proper B-cell development.[8]

Cell fate transition

KMT2D is partially functionally redundant with KMT2C and is required for cell differentiation in culture.[1][3] KMT2D regulates the induction of adipogenic and myogenic genes and is required for cell-type specific gene expression during differentiation. KMT2C and KMT2D are essential for adipogenesis and myogenesis.[1] Similar functions are seen in neuronal and osteoblast differentiation.[4][5] KMT2D facilitates cell fate transition by priming enhancers (through H3K4me1) for p300-mediated activation. For p300 to bind the enhancer, the physical presence of KMT2D, and not just the KMT2D-mediated H3K4me1, is required. However, KMT2D is dispensable for maintaining embryonic stem cell and somatic cell identity.[3]

Metabolism

KMT2D is partially functionally redundant with KMT2C in the liver as well. Heterozygous Kmt2d+/- mice exhibit enhanced glucose tolerance and insulin sensitivity and increased serum bile acid.[6] KMT2C and KMT2D are significant epigenetic regulators of the hepatic circadian clock and are co-activators of the circadian transcription factors retinoid-related orphan receptor (ROR)-α and -γ.[6] In mice, KMT2D also acts as a coactivator of PPARγ within the liver to direct over-nutrition induced steatosis. Heterozygous Kmt2d+/- mice exhibit resistance to over-nutrition induced hepatic steatosis.[7]

Tumor suppression

KMT2C and KMT2D along with NCOA6 act as coactivators of p53, a well-established tumor suppressor and transcription factor, and are necessary for endogenous expression of p53 in response to doxorubicin, a DNA damaging agent.[9] KMT2C and KMT2D have also been implicated with tumor suppressor roles in acute myeloid leukemia, follicular lymphoma, and diffuse large B cell lymphoma.[8][10][11] Knockout of Kmt2d in mice negatively affects the expression of tumor suppressor genes TNFAIP3, SOCS3, and TNFRSF14.[11]

Conversely, KMT2D deficiency in several breast and colon cancer cell lines leads to reduced proliferation.[31][32][33] Increased KMT2D was shown to facilitate chromatin opening and recruitment of transcription factors, including estrogen receptor (ER), in ER-positive breast cancer cells.[34] Thus, KMT2D may have diverse effects on tumor suppression in different cell types.

Clinical significance

Loss of function mutations in KMT2D, also known as MLL2 in humans, have been identified in Kabuki syndrome,[12] with mutational occurrence rates between 56% and 75%.[35][36][37] Congenital heart disease has been associated with an excess of mutations in genes that regulate H3K4 methylation, including KMT2D.[13]

Frameshift and nonsense mutations in the SET and PHD domains affect 37% and 60%, respectively, of the total KMT2D mutations in cancers.[14] Cancers with somatic mutations in KMT2D occur most commonly in the brain, lymph nodes, blood, lungs, large intestine, and endometrium.[14] These cancers include medulloblastoma,[38][39][40] pheochromocytoma,[41] non-Hodgkin lymphoma,[42] diffuse large B-cell lymphoma,[43][44] cutaneous T-cell lymphoma, Sézary syndrome,[45] bladder, lung, and endometrial carcinomas,[46] esophageal squamous cell carcinoma,[47][48][49] pancreatic cancer,[50] and prostate cancer.[51]

Notes


References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Lee JE, Wang C, Xu S, Cho YW, Wang L, Feng X, et al. (December 2013). "H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation". eLife. 2: e01503. doi:10.7554/eLife.01503. PMID 24368734.
  2. ↑ Prasad R, Zhadanov AB, Sedkov Y, Bullrich F, Druck T, Rallapalli R, et al. (July 1997). "Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax". Oncogene. 15 (5): 549–60. doi:10.1038/sj.onc.1201211. PMID 9247308.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Wang C, Lee JE, Lai B, Macfarlan TS, Xu S, Zhuang L, Liu C, Peng W, Ge K (October 2016). "Enhancer priming by H3K4 methyltransferase MLL4 controls cell fate transition". Proceedings of the National Academy of Sciences of the United States of America. 113 (42): 11871–11876. doi:10.1073/pnas.1606857113. PMID 27698142.
  4. ↑ 4.0 4.1 Dhar SS, Lee SH, Kan PY, Voigt P, Ma L, Shi X, Reinberg D, Lee MG (December 2012). "Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4". Genes & Development. 26 (24): 2749–62. doi:10.1101/gad.203356.112. PMID 23249737.
  5. ↑ 5.0 5.1 Munehira Y, Yang Z, Gozani O (October 2016). "Systematic Analysis of Known and Candidate Lysine Demethylases in the Regulation of Myoblast Differentiation". Journal of Molecular Biology. doi:10.1016/j.jmb.2016.10.004. PMID 27732873.
  6. ↑ 6.0 6.1 6.2 Kim DH, Rhee JC, Yeo S, Shen R, Lee SK, Lee JW, Lee S (March 2015). "Crucial roles of mixed-lineage leukemia 3 and 4 as epigenetic switches of the hepatic circadian clock controlling bile acid homeostasis in mice". Hepatology. 61 (3): 1012–23. doi:10.1002/hep.27578. PMID 25346535.
  7. ↑ 7.0 7.1 Kim DH, Kim J, Kwon JS, Sandhu J, Tontonoz P, Lee SK, Lee S, Lee JW (November 2016). "Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2". Cell Reports. 17 (6): 1671–1682. doi:10.1016/j.celrep.2016.10.023. PMID 27806304.
  8. ↑ 8.0 8.1 8.2 Zhang J, Dominguez-Sola D, Hussein S, Lee JE, Holmes AB, Bansal M, et al. (October 2015). "Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis". Nature Medicine. 21 (10): 1190–8. doi:10.1038/nm.3940. PMID 26366712.
  9. ↑ 9.0 9.1 Lee J, Kim DH, Lee S, Yang QH, Lee DK, Lee SK, Roeder RG, Lee JW (May 2009). "A tumor suppressive coactivator complex of p53 containing ASC-2 and histone H3-lysine-4 methyltransferase MLL3 or its paralogue MLL4". Proceedings of the National Academy of Sciences of the United States of America. 106 (21): 8513–8. doi:10.1073/pnas.0902873106. PMID 19433796.
  10. ↑ 10.0 10.1 Chen C, Liu Y, Rappaport AR, Kitzing T, Schultz N, Zhao Z, Shroff AS, Dickins RA, Vakoc CR, Bradner JE, Stock W, LeBeau MM, Shannon KM, Kogan S, Zuber J, Lowe SW (May 2014). "MLL3 is a haploinsufficient 7q tumor suppressor in acute myeloid leukemia". Cancer Cell. 25 (5): 652–65. doi:10.1016/j.ccr.2014.03.016. PMID 24794707.
  11. ↑ 11.0 11.1 11.2 Ortega-Molina A, Boss IW, Canela A, Pan H, Jiang Y, Zhao C, et al. (October 2015). "The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development". Nature Medicine. 21 (10): 1199–208. doi:10.1038/nm.3943. PMID 26366710.
  12. ↑ 12.0 12.1 Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. (September 2010). "Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome". Nature Genetics. 42 (9): 790–3. doi:10.1038/ng.646. PMID 20711175.
  13. ↑ 13.0 13.1 Zaidi S, Choi M, Wakimoto H, Ma L, Jiang J, Overton JD, et al. (June 2013). "De novo mutations in histone-modifying genes in congenital heart disease". Nature. 498 (7453): 220–3. doi:10.1038/nature12141. PMID 23665959.
  14. ↑ 14.0 14.1 14.2 14.3 Rao RC, Dou Y (June 2015). "Hijacked in cancer: the KMT2 (MLL) family of methyltransferases". Nature Reviews. Cancer. 15 (6): 334–46. doi:10.1038/nrc3929. PMID 25998713.
  15. ↑ 15.0 15.1 "Transcript: Kmt2d-001 (ENSMUST00000023741.15) - Summary - Mus musculus - Ensembl genome browser 88". www.ensembl.org.
  16. ↑ 16.0 16.1 "Transcript: KMT2D-001 (ENST00000301067.11) - Summary - Homo sapiens - Ensembl genome browser 88". www.ensembl.org.
  17. ↑ Mohan M, Herz HM, Smith ER, Zhang Y, Jackson J, Washburn MP, Florens L, Eissenberg JC, Shilatifard A (November 2011). "The COMPASS family of H3K4 methylases in Drosophila". Molecular and Cellular Biology. 31 (21): 4310–8. doi:10.1128/MCB.06092-11. PMID 21875999.
  18. ↑ Ruthenburg AJ, Allis CD, Wysocka J (January 2007). "Methylation of lysine 4 on histone H3: intricacy of writing and reading a single epigenetic mark". Molecular Cell. 25 (1): 15–30. doi:10.1016/j.molcel.2006.12.014. PMID 17218268.
  19. ↑ 19.0 19.1 19.2 Jang Y, Wang C, Zhuang L, Liu C, Ge K (December 2016). "H3K4 Methyltransferase Activity Is Required for MLL4 Protein Stability". Journal of Molecular Biology. doi:10.1016/j.jmb.2016.12.016. PMID 28013028.
  20. ↑ Dorighi KM, Swigut T, Henriques T, Bhanu NV, Scruggs BS, Nady N, Still CD, Garcia BA, Adelman K, Wysocka J (May 2017). "Mll3 and Mll4 Facilitate Enhancer RNA Synthesis and Transcription from Promoters Independently of H3K4 Monomethylation". Molecular Cell. doi:10.1016/j.molcel.2017.04.018. PMID 28483418.
  21. ↑ Goo YH, Sohn YC, Kim DH, Kim SW, Kang MJ, Jung DJ, Kwak E, Barlev NA, Berger SL, Chow VT, Roeder RG, Azorsa DO, Meltzer PS, Suh PG, Song EJ, Lee KJ, Lee YC, Lee JW (January 2003). "Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins". Molecular and Cellular Biology. 23 (1): 140–9. PMID 12482968.
  22. ↑ 22.0 22.1 22.2 Cho YW, Hong T, Hong S, Guo H, Yu H, Kim D, Guszczynski T, Dressler GR, Copeland TD, Kalkum M, Ge K (July 2007). "PTIP associates with MLL3- and MLL4-containing histone H3 lysine 4 methyltransferase complex". The Journal of Biological Chemistry. 282 (28): 20395–406. doi:10.1074/jbc.M701574200. PMID 17500065.
  23. ↑ Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM, Nakamura T, Mazo A, Eisenbach L, Canaani E (March 2007). "Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth". Molecular and Cellular Biology. 27 (5): 1889–903. doi:10.1128/MCB.01506-06. PMID 17178841.
  24. ↑ Lee MG, Villa R, Trojer P, Norman J, Yan KP, Reinberg D, Di Croce L, Shiekhattar R (October 2007). "Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination". Science. 318 (5849): 447–50. doi:10.1126/science.1149042. PMID 17761849.
  25. ↑ Patel A, Vought VE, Dharmarajan V, Cosgrove MS (November 2008). "A conserved arginine-containing motif crucial for the assembly and enzymatic activity of the mixed lineage leukemia protein-1 core complex". The Journal of Biological Chemistry. 283 (47): 32162–75. doi:10.1074/jbc.M806317200. PMID 18829457.
  26. ↑ Ernst P, Vakoc CR (May 2012). "WRAD: enabler of the SET1-family of H3K4 methyltransferases". Briefings in Functional Genomics. 11 (3): 217–26. doi:10.1093/bfgp/els017. PMID 22652693.
  27. ↑ Cho YW, Hong S, Ge K (2012). "Affinity purification of MLL3/MLL4 histone H3K4 methyltransferase complex". Methods in Molecular Biology. 809: 465–72. doi:10.1007/978-1-61779-376-9_30. PMID 22113294.
  28. ↑ Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K (November 2007). "Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases". Proceedings of the National Academy of Sciences of the United States of America. 104 (47): 18439–44. doi:10.1073/pnas.0707292104. PMID 18003914.
  29. ↑ 29.0 29.1 Lai B, Lee JE, Jang Y, Wang L, Peng W, Ge K (April 2017). "MLL3/MLL4 are required for CBP/p300 binding on enhancers and super-enhancer formation in brown adipogenesis". Nucleic Acids Research. doi:10.1093/nar/gkx234. PMID 28398509.
  30. ↑ Ang SY, Uebersohn A, Spencer CI, Huang Y, Lee JE, Ge K, Bruneau BG (March 2016). "KMT2D regulates specific programs in heart development via histone H3 lysine 4 di-methylation". Development. 143 (5): 810–21. doi:10.1242/dev.132688. PMID 26932671.
  31. ↑ Guo C, Chen LH, Huang Y, Chang CC, Wang P, Pirozzi CJ, et al. (November 2013). "KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation". Oncotarget. 4 (11): 2144–53. doi:10.18632/oncotarget.1555. PMID 24240169.
  32. ↑ Kim JH, Sharma A, Dhar SS, Lee SH, Gu B, Chan CH, Lin HK, Lee MG (March 2014). "UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells". Cancer Research. 74 (6): 1705–17. doi:10.1158/0008-5472.CAN-13-1896. PMID 24491801.
  33. ↑ Mo R, Rao SM, Zhu YJ (June 2006). "Identification of the MLL2 complex as a coactivator for estrogen receptor alpha". The Journal of Biological Chemistry. 281 (23): 15714–20. doi:10.1074/jbc.M513245200. PMID 16603732.
  34. ↑ Toska E, Osmanbeyoglu HU, Castel P, Chan C, Hendrickson RC, Elkabets M, Dickler MN, Scaltriti M, Leslie CS, Armstrong SA, Baselga J (March 2017). "PI3K pathway regulates ER-dependent transcription in breast cancer through the epigenetic regulator KMT2D". Science. 355 (6331): 1324–1330. doi:10.1126/science.aah6893. PMID 28336670.
  35. ↑ Bögershausen N, Wollnik B (March 2013). "Unmasking Kabuki syndrome". Clinical Genetics. 83 (3): 201–11. doi:10.1111/cge.12051. PMID 23131014.
  36. ↑ Li Y, Bögershausen N, Alanay Y, Simsek Kiper PO, Plume N, Keupp K, et al. (December 2011). "A mutation screen in patients with Kabuki syndrome". Human Genetics. 130 (6): 715–24. doi:10.1007/s00439-011-1004-y. PMID 21607748.
  37. ↑ Paulussen AD, Stegmann AP, Blok MJ, Tserpelis D, Posma-Velter C, Detisch Y, et al. (February 2011). "MLL2 mutation spectrum in 45 patients with Kabuki syndrome". Human Mutation. 32 (2): E2018–25. doi:10.1002/humu.21416. PMID 21280141.
  38. ↑ Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, et al. (August 2012). "Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations". Nature. 488 (7409): 106–10. doi:10.1038/nature11329. PMID 22820256.
  39. ↑ Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC, et al. (January 2011). "The genetic landscape of the childhood cancer medulloblastoma". Science. 331 (6016): 435–9. doi:10.1126/science.1198056. PMID 21163964.
  40. ↑ Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, et al. (August 2012). "Dissecting the genomic complexity underlying medulloblastoma". Nature. 488 (7409): 100–5. doi:10.1038/nature11284. PMID 22832583.
  41. ↑ Juhlin CC, Stenman A, Haglund F, Clark VE, Brown TC, Baranoski J, et al. (September 2015). "Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene". Genes, Chromosomes & Cancer. 54 (9): 542–54. doi:10.1002/gcc.22267. PMID 26032282.
  42. ↑ Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, et al. (July 2011). "Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma". Nature. 476 (7360): 298–303. doi:10.1038/nature10351. PMID 21796119.
  43. ↑ Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A, Wells VA, Grunn A, Messina M, Elliot O, Chan J, Bhagat G, Chadburn A, Gaidano G, Mullighan CG, Rabadan R, Dalla-Favera R (July 2011). "Analysis of the coding genome of diffuse large B-cell lymphoma". Nature Genetics. 43 (9): 830–7. doi:10.1038/ng.892. PMID 21804550.
  44. ↑ Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al. (March 2012). "Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing". Proceedings of the National Academy of Sciences of the United States of America. 109 (10): 3879–84. doi:10.1073/pnas.1121343109. PMID 22343534.
  45. ↑ da Silva Almeida AC, Abate F, Khiabanian H, Martinez-Escala E, Guitart J, Tensen CP, Vermeer MH, Rabadan R, Ferrando A, Palomero T (December 2015). "The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome". Nature Genetics. 47 (12): 1465–70. doi:10.1038/ng.3442. PMID 26551667.
  46. ↑ Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. (October 2013). "Mutational landscape and significance across 12 major cancer types". Nature. 502 (7471): 333–9. doi:10.1038/nature12634. PMID 24132290.
  47. ↑ Gao YB, Chen ZL, Li JG, Hu XD, Shi XJ, Sun ZM, et al. (October 2014). "Genetic landscape of esophageal squamous cell carcinoma". Nature Genetics. 46 (10): 1097–102. doi:10.1038/ng.3076. PMID 25151357.
  48. ↑ Lin DC, Hao JJ, Nagata Y, Xu L, Shang L, Meng X, Sato Y, Okuno Y, Varela AM, Ding LW, Garg M, Liu LZ, Yang H, Yin D, Shi ZZ, Jiang YY, Gu WY, Gong T, Zhang Y, Xu X, Kalid O, Shacham S, Ogawa S, Wang MR, Koeffler HP (May 2014). "Genomic and molecular characterization of esophageal squamous cell carcinoma". Nature Genetics. 46 (5): 467–73. doi:10.1038/ng.2935. PMID 24686850.
  49. ↑ Song Y, Li L, Ou Y, Gao Z, Li E, Li X, et al. (May 2014). "Identification of genomic alterations in oesophageal squamous cell cancer". Nature. 509 (7498): 91–5. doi:10.1038/nature13176. PMID 24670651.
  50. ↑ Sausen M, Phallen J, Adleff V, Jones S, Leary RJ, Barrett MT, et al. (July 2015). "Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients". Nature Communications. 6: 7686. doi:10.1038/ncomms8686. PMID 26154128.
  51. ↑ Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. (July 2012). "The mutational landscape of lethal castration-resistant prostate cancer". Nature. 487 (7406): 239–43. doi:10.1038/nature11125. PMID 22722839.

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