Oncogenes and tumor suppressor genes: functions and roles in cancers

Abstract

Cancer, being the most formidable ailment, has had a profound impact on the human health. The disease is primarily associated with genetic mutations that impact oncogenes and tumor suppressor genes (TSGs). Recently, growing evidence have shown that X-linked TSGs have specific role in cancer progression and metastasis as well. Interestingly, our genome harbors around substantial portion of genes that function as tumor suppressors, and the X chromosome alone harbors a considerable number of TSGs. The scenario becomes even more compelling as X-linked TSGs are adaptive to key epigenetic processes such as X chromosome inactivation. Therefore, delineating the new paradigm related to X-linked TSGs, for instance, their crosstalk with autosome and involvement in cancer initiation, progression, and metastasis becomes utmost importance. Considering this, herein, we present a comprehensive discussion of X-linked TSG dysregulation in various cancers as a consequence of genetic variations and epigenetic alterations. In addition, the dynamic role of X-linked TSGs in sex chromosome–autosome crosstalk in cancer genome remodeling is being explored thoroughly. Besides, the functional roles of ncRNAs, role of X-linked TSG in immunomodulation and in gender-based cancer disparities has also been highlighted. Overall, the focal idea of the present article is to recapitulate the findings on X-linked TSG regulation in the cancer landscape and to redefine their role toward improving cancer treatment strategies.

Keywords

cancer signaling / cancer therapy / ncRNAs / tumor suppressor genes (TSGs) / X chromosome–autosome crosstalk / X-chromosome inactivation

References

1	EN Kontomanolis, A Koutras, A Syllaios, et al. Role of oncogenes and tumor-suppressor genes in carcinogenesis: a review. Anticancer Res. 2020;40(11):6009-6015.
2	E Hernández-Lemus, H Reyes-Gopar, J Espinal-Enríquez, S Ochoa. The many faces of gene regulation in cancer: a computational oncogenomics outlook. Genes. 2019;10(11):865.
3	B Dhabhai, A Sharma, J Maciaczyk, TC Dakal. X-linked tumor suppressor genes act as presumed contributors in the sex chromosome-autosome crosstalk in cancers. Cancer Invest. 2022;40(2):103-110.
4	T Kido, Y Li, Y Tanaka, R Dahiya, Y-F Chris Lau. The X-linked tumor suppressor TSPX downregulates cancer-drivers/oncogenes in prostate cancer in a C-terminal acidic domain dependent manner. Oncotarget. 2019;10(15):1491-1506.
5	R Dhakar, TC Dakal, A Sharma. Genetic determinants of lung cancer: Understanding the oncogenic potential of somatic missense mutations. Genomics. 2022;114(4):110401.
6	B Pereira, S-F Chin, OM Rueda, et al. The somatic mutation profiles of 2,433 breast cancers refine their genomic and transcriptomic landscapes. Nat Commun. 2016;7(1):11479.
7	A Sharma, H Liu, F Tobar-Tosse, et al. Ubiquitin carboxyl-terminal hydrolases (UCHs): potential mediators for cancer and neurodegeneration. Int J Mol Sci. 2020;21(11):3910.
8	H Wang, L Yang, M Liu, J Luo. Protein post-translational modifications in the regulation of cancer hallmarks. Cancer Gene Ther. 2023;30(4):529-547.
9	A Sharma, H Liu, MC Herwig-Carl, T Chand Dakal, IGH Schmidt-Wolf. Epigenetic regulatory enzymes: mutation prevalence and coexistence in cancers. Cancer Invest. 2021;39(3):257-273.
10	A Nebbioso, FP Tambaro, C Dell'Aversana, L Altucci. Cancer epigenetics: moving forward. PLos Genet. 2018;14(6):e1007362.
11	GE Parris. The cell clone ecology hypothesis and the cell fusion model of cancer progression and metastasis: history and experimental support. Med Hypotheses. 2006;66(1):76-83.
12	MD Bashyam, S Animireddy, P Bala, A Naz, SA George. The Yin and Yang of cancer genes. Gene. 2019;704:121-133.
13	NJ Dyson. RB1: a prototype tumor suppressor and an enigma. Genes Dev. 2016;30(13):1492-1502.
14	S Kalsoom, M Wasim, S Afzal, et al. Alterations in the RB1 gene in Pakistani patients with retinoblastoma using direct sequencing analysis. Mol Vis. 2015;21:1085-1092.
15	L Chen, S Liu, Y Tao. Regulating tumor suppressor genes: post-translational modifications. Signal Transduct Target Ther. 2020;5(1):90.
16	L Soucek, JR Whitfield, NM Sodir, et al. Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev. 2013;27(5):504-513.
17	AG Knudson Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68(4):820-823.
18	AJ Levine, CA Finlay, PW Hinds. P53 is a tumor suppressor gene. Cell. 2004;116(2):S67-S69. Suppl.
19	S Wang, J Gao, Q Lei, et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell. 2003;4(3):209-221.
20	RE Buller, AK Sood, T Lallas, T Buekers, JS Skilling. Association between nonrandom X-chromosome inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer. J Natl Cancer Inst. 1999;91(4):339-346.
21	DJ Liao, Q-Q Du, BW Yu, D Grignon, FH Sarkar. Novel perspective: focusing on the X chromosome in reproductive cancers: ESSAY. Cancer Invest. 2003;21(4):641-658.
22	Y Liu, L Wang, P Zheng. X-linked tumor suppressors: perplexing inheritance, a unique therapeutic opportunity. Trends Genet. 2010;26(6):260-265.
23	L Wang, R Liu, W Li, et al. Somatic single hits inactivate the X-linked tumor suppressor FOXP3 in the prostate. Cancer Cell. 2009;16(4):336-346.
24	T Zuo, L Wang, C Morrison, et al. FOXP3 is an X-linked breast cancer suppressor gene and an important repressor of the HER-2/ErbB2 oncogene. Cell. 2007;129(7):1275-1286.
25	EY Lee, WJ Muller. Oncogenes and tumor suppressor genes. Cold Spring Harb Perspect Biol. 2010;2(10):a003236.
26	P Chandrashekar, N Ahmadinejad, J Wang, et al. Somatic selection distinguishes oncogenes and tumor suppressor genes. Bioinformatics. 2020;36(6):1712-1717.
27	J Downward. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3(1):11-22.
28	R Nahta, GN Hortobagyi, FJ Esteva. Growth factor receptors in breast cancer: potential for therapeutic intervention. Oncologist. 2003;8(1):5-17.
29	KV Desai, N Xiao, W Wang, et al. Initiating oncogenic event determines gene-expression patterns of human breast cancer models. Proc Natl Acad Sci USA. 2002;99(10):6967-6972.
30	R Jan, GE Chaudhry. Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull. 2019;9(2):205-218.
31	A Klinakis, M Szabolcs, K Politi, H Kiaris, S Artavanis-Tsakonas, A Efstratiadis. Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice. Proc Natl Acad Sci USA. 2006;103(24):9262-9267.
32	S Hutter, S Bolin, H Weishaupt, FJ Swartling. Modeling and targeting MYC genes in childhood brain tumors. Genes (Basel). 2017;8(4):107.
33	X Ji, Y Wang, G Liu. Expression analysis of MYC genes from Tamarix hispida in response to different abiotic stresses. Int J Mol Sci. 2012;13(2):1300-1313.
34	C Osborne, P Wilson, D Tripathy. Oncogenes and tumor suppressor genes in breast cancer: potential diagnostic and therapeutic applications. Oncologist. 2004;9(4):361-377.
35	RM Hudziak, GD Lewis, M Winget, BM Fendly, HM Shepard, A Ullrich. p185 HER2 monoclonal antibody has antiproliferative effects in vitro and sensitizes human breast tumor cells to tumor necrosis factor. Mol Cell Biol. 1989;9(3):1165-1172.
36	P Carter, L Presta, CM Gorman, et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA. 1992;89(10):4285-4289.
37	RA Clynes, TL Towers, LG Presta, JV Ravetch. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med. 2000;6(4):443-446.
38	CL Vogel, MA Cobleigh, D Tripathy, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2023;41(9):1638-1645.
39	MA Cobleigh, CL Vogel, D Tripathy, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17(9):2639-2639.
40	J Baselga, D Tripathy, J Mendelsohn, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996;14(3):737-744.
41	DJ Slamon, B Leyland-Jones, S Shak, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792.
42	AG Knudson Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA. 1971;68(4):820-823.
43	Z Liu, A Turkoz, EN Jackson, et al. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. J Clin Invest. 2011;121(2):800-808.
44	DW Goodrich. The retinoblastoma tumor-suppressor gene, the exception that proves the rule. Oncogene. 2006;25(38):5233-5243.
45	YI Leiderman, S Kiss, S Mukai. Molecular genetics of RB1–the retinoblastoma gene. Semin Ophthalmol. 2007;22(4):247-254.
46	V Mendonca, AC Evangelista, BP Matta, et al. Molecular alterations in retinoblastoma beyond RB1. Exp Eye Res. 2021;211:108753.
47	B Vogelstein, KW Kinzler. Cancer genes and the pathways they control. Nat Med. 2004;10(8):789-799.
48	F Kerangueven, L Essioux, A Dib, et al. Loss of heterozygosity and linkage analysis in breast carcinoma: indication for a putative third susceptibility gene on the short arm of chromosome 8. Oncogene. 1995;10(5):1023-1026.
49	W Burke, M Daly, J Garber, et al. Recommendations for follow-up care of individuals with an inherited predisposition to cancer: II. BRCA1 and BRCA2. JAMA. 1997;277(12):997-1003.
50	GB Mills, Y Lu, X Fang, et al. The role of genetic abnormalities of PTEN and the phosphatidylinositol 3-kinase pathway in breast and ovarian tumorigenesis, prognosis, and therapy. Seminars in oncology: 2001. Elsevier; 2001:125-141.
51	MR Nelen, WC van Staveren, EA Peeters, et al. Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet. 1997;6(8):1383-1387.
52	DW Bell, JM Varley, TE Szydlo, et al. Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome. Science. 1999;286(5449):2528-2531.
53	P Vahteristo, J Bartkova, H Eerola, et al. A CHEK2 genetic variant contributing to a substantial fraction of familial breast cancer. Am Hum Genet. 2002;71(2):432-438.
54	Y Shiloh. ATM and related protein kinases: safeguarding genome integrity. Nat Rev Cancer. 2003;3(3):155-168.
55	KK Khanna. Cancer risk and the ATM gene: a continuing debate. J Natl Cancer Inst. 2000;92(10):795-802.
56	S Park, F Supek, B Lehner. Higher order genetic interactions switch cancer genes from two-hit to one-hit drivers. Nat Commun. 2021;12(1):7051.
57	X Wang, W Hu, X Li, et al. Single-hit inactivation drove tumor suppressor genes out of the X chromosome during evolution. Cancer Res. 2022;82(8):1482-1491.
58	J Lipsick. A history of cancer research: tumor suppressor genes. Cold Spring Harb Perspect Biol. 2020;12(2):a035907.
59	SM Rothenberg, J Settleman. Discovering tumor suppressor genes through genome-wide copy number analysis. Curr Genomics. 2010;11(5):297-310.
60	GJ Pageau, LL Hall, S Ganesan, DM Livingston, JB Lawrence. The disappearing Barr body in breast and ovarian cancers. Nat Rev Cancer. 2007;7(8):628-633.
61	TE Buekers, TA Lallas, RE Buller. Xp22. 2–3 loss of heterozygosity is associated with germline BRCA1 mutation in ovarian cancer. Gynecol Oncol. 2000;76(3):418-422.
62	C Choi, S Cho, I Horikawa, et al. Loss of heterozygosity at chromosome segment Xq25-26.1 in advanced human ovarian carcinomas. Genes Chromosomes Cancer. 1997;20(3):234-242.
63	N Wang, E Cedrone, GR Skuse, R Insel, J Dry. Two identical active X chromosomes in human mammary carcinoma cells. Cancer Genet Cytogenet. 1990;46(2):271-280.
64	ML Loupart, S Adams, JA Armour, R Walker, W Brammar, J Varley. Loss of heterozygosity on the X chromosome in human breast cancer. Genes Chromosomes Cancer. 1995;13(4):229-238.
65	C Choi, MH Kim, SW Juhng. Loss of heterozygosity on chromosome XP22. 2-p22. 13 and Xq26. 1-q27. 1 in human breast carcinomas. J Korean Med Sci. 1998;13(3):311-316.
66	SM Sirchia, L Ramoscelli, FR Grati, et al. Loss of the inactive X chromosome and replication of the active X in BRCA1-defective and wild-type breast cancer cells. Cancer Res. 2005;65(6):2139-2146.
67	S Ganesan, DP Silver, RA Greenberg, et al. BRCA1 supports XIST RNA concentration on the inactive X chromosome. Cell. 2002;111(3):393-405.
68	M Kristiansen, GPS Knudsen, P Maguire, et al. High incidence of skewed X chromosome inactivation in young patients with familial non-BRCA1/BRCA2 breast cancer. J Med Genet. 2005;42(11):877-880.
69	AL Richardson, ZC Wang, A De Nicolo, et al. X chromosomal abnormalities in basal-like human breast cancer. Cancer Cell. 2006;9(2):121-132.
70	S Knuutila, Y Aalto, K Autio, et al. DNA copy number losses in human neoplasms. Am J Pathol. 1999;155(3):683-694.
71	JO Indsto, NT Nassif, RF Kefford, GJ Mann. Frequent loss of heterozygosity targeting the inactive X chromosome in melanoma. Clin Cancer Res. 2003;9(17):6476-6482.
72	F Jiang, J Richter, P Schraml, et al. Chromosomal imbalances in papillary renal cell carcinoma: genetic differences between histological subtypes. Am J Pathol. 1998;153(5):1467-1473.
73	M Mathur, S Das, HH Samuels. PSF-TFE3 oncoprotein in papillary renal cell carcinoma inactivates TFE3 and p53 through cytoplasmic sequestration. Oncogene. 2003;22(32):5031-5044.
74	L Bottarelli, C Azzoni, F Necchi, et al. Sex chromosome alterations associate with tumor progression in sporadic colorectal carcinomas. Clin Cancer Res. 2007;13(15):4365-4370. Pt 1.
75	T D'Adda, L Bottarelli, C Azzoni, et al. Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors. Mod Pathol. 2005;18(6):795-805.
76	S Pizzi, T D'Adda, C Azzoni, et al. Ireland: Malignancy-associated allelic losses on the X-chromosome in foregut but not in midgut endocrine tumours. J Pathol. 2002;196(4):401-407.
77	YJ Chen, A Vortmeyer, Z Zhuang, F Gibril, RT Jensen. X-chromosome loss of heterozygosity frequently occurs in gastrinomas and is correlated with aggressive tumor growth. Cancer. 2004;100(7):1379-1387.
78	C Azzoni, L Bottarelli, S Pizzi, T D'adda, G Rindi, C Bordi. Xq25 and Xq26 identify the common minimal deletion region in malignant gastroenteropancreatic endocrine carcinomas. Virchows Arch. 2006;448(2):119-126.
79	Y Jiao, C Shi, BH Edil, et al. DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science. 2011;331(6021):1199-1203.
80	M Zhao, J Sun, Z Zhao. TSGene: a web resource for tumor suppressor genes. Nucleic Acids Res. 2013;41(D1):D970-D976.
81	J Lever, EY Zhao, J Grewal, MR Jones, SJM Jones. CancerMine: a literature-mined resource for drivers, oncogenes and tumor suppressors in cancer. Nat Methods. 2019;16(6):505-507.
82	J Lyu, JJ Li, J Su, et al. DORGE: Discovery of Oncogenes and tumoR suppressor genes using Genetic and Epigenetic features. Sci Adv. 2020;6(46):eaba6784.
83	JS Chen, WS Hung, HH Chan, SJ Tsai, HS Sun. In silico identification of oncogenic potential of fyn-related kinase in hepatocellular carcinoma. Bioinformatics. 2013;29(4):420-427.
84	Y Yang, LM Fu. TSGDB: a database system for tumor suppressor genes. Bioinformatics. 2003;19(17):2311-2312.
85	M Zhao, J Sun, Z Zhao. TSGene: a web resource for tumor suppressor genes. Nucleic Acids Res. 2013;41(Database issue):D970-D976.
86	SA Forbes, N Bindal, S Bamford, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 2011;39(Database issue):D945-D950.
87	M Uhlen, L Fagerberg, BM Hallstrom, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419.
88	E Cerami, J Gao, U Dogrusoz, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401-404.
89	A Thakur, H Xu, Y Wang, A Bollig, H Biliran, JD Liao. The role of X-linked genes in breast cancer. Breast Cancer Res Treat. 2005;93(2):135-143.
90	CD Hurst, O Alder, FM Platt, et al. Genomic subtypes of non-invasive bladder cancer with distinct metabolic profile and female gender bias in KDM6A mutation frequency. Cancer Cell. 2017;32(5):701-715. .e707.
91	ML Nickerson, GM Dancik, KM Im, et al. Concurrent alterations in TERT, KDM6A, and the BRCA pathway in bladder cancer. Clin Cancer Res. 2014;20(18):4935-4948.
92	K Koike, A Kasamatsu, M Iyoda, et al. High prevalence of epigenetic inactivation of the human four and a half LIM domains 1 gene in human oral cancer. Int J Oncol. 2013;42(1):141-150.
93	A Sharma, MA Jamil, N Nuesgen, et al. Detailed methylation map of LINE-1 5′-promoter region reveals hypomethylated CpG hotspots associated with tumor tissue specificity. Mol Genet Genomic Med. 2019;7(5):e601.
94	A Sharma, O Kaut, A Pavlova, et al. Skewed X-chromosome inactivation and XIST locus methylation levels do not contribute to the lower prevalence of Parkinson's disease in females. Neurobiol Aging. 2017;57:248.e241-248.e245.
95	A Sharma, H Liu, F Tobar-Tosse, et al. Genome organization in proximity to the BAP1 locus appears to play a pivotal role in a variety of cancers. Cancer Sci. 2020;111(4):1385-1391.
96	WM White, HF Willard, DL Van Dyke, DJ Wolff. The spreading of X inactivation into autosomal material of an x;autosome translocation: evidence for a difference between autosomal and X-chromosomal DNA. Am J Hum Genet. 1998;63(1):20-28.
97	MD Simon, SF Pinter, R Fang, et al. High-resolution Xist binding maps reveal two-step spreading during X-chromosome inactivation. Nature. 2013;504(7480):465-469.
98	DW Bellott, H Skaletsky, T Pyntikova, et al. Convergent evolution of chicken Z and human X chromosomes by expansion and gene acquisition. Nature. 2010;466(7306):612-616.
99	JL Mueller, H Skaletsky, LG Brown, et al. Independent specialization of the human and mouse X chromosomes for the male germ line. Nat Genet. 2013;45(9):1083-1087.
100	JA Graves. Sex chromosome specialization and degeneration in mammals. Cell. 2006;124(5):901-914.
101	X Wang, KC Douglas, JL Vandeberg, AG Clark, PB Samollow. Chromosome-wide profiling of X-chromosome inactivation and epigenetic states in fetal brain and placenta of the opossum, Monodelphis domestica. Genome Res. 2014;24(1):70-83.
102	AM Livernois, JA Graves, PD Waters. The origin and evolution of vertebrate sex chromosomes and dosage compensation. Heredity (Edinb). 2012;108(1):50-58.
103	M Escamilla-Del-Arenal, ST da Rocha, E Heard. Evolutionary diversity and developmental regulation of X-chromosome inactivation. Hum Genet. 2011;130(2):307-327.
104	J Grant, SK Mahadevaiah, P Khil, et al. Rsx is a metatherian RNA with Xist-like properties in X-chromosome inactivation. Nature. 2012;487(7406):254-258.
105	L Duret, C Chureau, S Samain, J Weissenbach, P Avner. The Xist RNA gene evolved in eutherians by pseudogenization of a protein-coding gene. Science. 2006;312(5780):1653-1655.
106	A Spatz, C Borg, J Feunteun. X-chromosome genetics and human cancer. Nat Rev Cancer. 2004;4(8):617-629.
107	E Yildirim, JE Kirby, DE Brown, et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell. 2013;152(4):727-742.
108	HS Leong, K Chen, Y Hu, et al. Epigenetic regulator Smchd1 functions as a tumor suppressor. Cancer Res. 2013;73(5):1591-1599.
109	AV Gendrel, YA Tang, M Suzuki, et al. Epigenetic functions of smchd1 repress gene clusters on the inactive X chromosome and on autosomes. Mol Cell Biol. 2013;33(16):3150-3165.
110	H Royo, H Seitz, E ElInati, AH Peters, MB Stadler, JM Turner. Silencing of X-linked MicroRNAs by meiotic sex chromosome inactivation. PLoS Genet. 2015;11(10):e1005461.
111	JT Lee. Epigenetic regulation by long noncoding RNAs. Science. 2012;338(6113):1435-1439.
112	J Zhao, BK Sun, JA Erwin, JJ Song, JT Lee. Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science. 2008;322(5902):750-756.
113	Y Jeon, JT Lee. YY1 tethers Xist RNA to the inactive X nucleation center. Cell. 2011;146(1):119-133.
114	Y Liu, Y Wang, W Li, P Zheng, Y Liu. Activating transcription factor 2 and c-Jun-mediated induction of FoxP3 for experimental therapy of mammary tumor in the mouse. Cancer Res. 2009;69(14):5954-5960.
115	Y Marahrens, B Panning, J Dausman, W Strauss, R Jaenisch. Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes Dev. 1997;11(2):156-166.
116	L Carrel, HF Willard. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005;434(7031):400-404.
117	R Chaligne, T Popova, MA Mendoza-Parra, et al. The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer. Genome Res. 2015;25(4):488-503.
118	L Richart, ML Picod-Chedotel, M Wassef, et al. XIST loss impairs mammary stem cell differentiation and increases tumorigenicity through mediator hyperactivation. Cell. 2022;185(12):2164-2183. .e2125.
119	J Zawacka-Pankau, G Selivanova. Pharmacological reactivation of p53 as a strategy to treat cancer. J Intern Med. 2015;277(2):248-259.
120	Z Zhou, X Song, B Li, MI Greene. FOXP3 and its partners: structural and biochemical insights into the regulation of FOXP3 activity. Immunol Res. 2008;42(1-3):19-28.
121	H Katoh, P Zheng, Y Liu. Signalling through FOXP3 as an X-linked tumor suppressor. Int J Biochem Cell Biol. 2010;42(11):1784-1787.
122	J Zhao, J Meisel, Y Guo, et al. Evaluation of PD-L1, tumor-infiltrating lymphocytes, and CD8+ and FOXP3+ immune cells in HER2-positive breast cancer treated with neoadjuvant therapies. Breast Cancer Res Treat. 2020;183(3):599-606.
123	J Choi, DR Pease, S Chen, B Zhang, H Phee. P21-activated kinase 2 is essential in maintenance of peripheral Foxp3(+) regulatory T cells. Immunology. 2018;154(2):309-321.
124	Y Liang, Q Lu, W Li, et al. Reactivation of tumour suppressor in breast cancer by enhancer switching through NamiRNA network. Nucleic Acids Res. 2021;49(15):8556-8572.
125	A Kazanets, T Shorstova, K Hilmi, M Marques, M Witcher. Epigenetic silencing of tumor suppressor genes: Paradigms, puzzles, and potential. Biochim Biophys Acta. 2016;1865(2):275-288.
126	R Chaligné, E Heard. X-chromosome inactivation in development and cancer. FEBS Lett. 2014;588(15):2514-2522.
127	X Deng, JB Berletch, DK Nguyen, CM Disteche. X chromosome regulation: diverse patterns in development, tissues and disease. Nat Rev Genet. 2014;15(6):367-378.
128	DT Jones, N J?ger, M Kool, et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012;488(7409):100-105.
129	CS Grasso, Y-M Wu, DR Robinson, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487(7406):239-243.
130	V Faundes, S Goh, R Akilapa, et al. Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2. Genet Med. 2021;23(7):1202-1210.
131	A Gropman, CA Samango-Sprouse, Neurocognitive variance and neurological underpinnings of the X and Y chromosomal variations. In: American Journal of Medical Genetics Part C: Seminars in Medical Genetics: 2013: Wiley Online Library; 2013:35-43.
132	D Lederer, B Grisart, MC Digilio, et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet. 2012;90(1):119-124.
133	AM Lindgren, T Hoyos, ME Talkowski, et al. Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate. Hum Genet. 2013;132(5):537-552.
134	N Miyake, S Mizuno, N Okamoto, et al. KDM 6 A point mutations cause K abuki syndrome. Hum Mutat. 2013;34(1):108-110.
135	R Simensen, R Rogers, J Collins, F Abidi, C Schwartz, RE Stevenson. Short-term memory deficits in carrier females with KDM5C mutations. Genet Couns. 2012;23(1):31-40.
136	LR Jensen, H Bartenschlager, S Rujirabanjerd, et al. A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C. Pathogenetics. 2010;3(1):2.
137	JI Grill, FT Kolligs. DRO1/CCDC80: a novel tumor suppressor of colorectal carcinogenesis. Curr Colorectal Cancer Rep. 2015;11:200-208.
138	D Umlauf, J Bonnet, F Waharte, et al. The human TREX-2 complex is stably associated with the nuclear pore basket. J Cell Sci. 2013;126(12):2656-2667. Pt.
139	V Bhatia, SI Barroso, ML García-Rubio, E Tumini, E Herrera-Moyano, AJN Aguilera. BRCA2 prevents R-loop accumulation and associates with TREX-2 mRNA export factor PCID2. Nature. 2014;511(7509):362-365.
140	M LLeonart, F Vidal, D Gallardo, et al. New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas. Oncol Rep. 2006;16(3):603-608.
141	A Grohmann, K Tanneberger, A Alzner, J Schneikert, J Behrens. AMER1 regulates the distribution of the tumor suppressor APC between microtubules and the plasma membrane. J Cell Sci. 2007;120(21):3738-3747.
142	K Chen, A Gorgen, A Ding, et al. Dual-specificity phosphatase 9 regulates cellular proliferation and predicts recurrence after surgery in hepatocellular carcinoma. Hepatol Commun. 2021;5(7):1310-1328.
143	S Middendorp, AE Zijlstra, R Kersseboom, GM Dingjan, H Jumaa, RWJB Hendriks. Tumor suppressor function of Bruton tyrosine kinase is independent of its catalytic activity. Blood. 2005;105(1):259-265.
144	K Zhu, Q Liu, Y Zhou, et al. Oncogenes and tumor suppressor genes: comparative genomics and network perspectives. Bmc Genomics [Electronic Resource]. 2015;16(7):1-11.
145	H Lodish, A Berk, SL Zipursky, P Matsudaira, D Baltimore, J Darnell, Molecular Cell Biology. 4th edition. 2000:9.
146	F Lo-Coco, M Breccia, N Noguera, WH Miller Jr. Diagnostic value of detecting fusion proteins derived from chromosome translocations in acute leukaemia. Best Pract Res Clin Haematol. 2003;16(4):653-670.
147	R Osborne, V Leech. Polymerase chain reaction allelotyping of human ovarian cancer. Br J Cancer. 1994;69(3):429-438.
148	M Kavianpour, A Ahmadzadeh, S Shahrabi, N Saki. Significance of oncogenes and tumor suppressor genes in AML prognosis. Tumour Biol. 2016;37:10041-10052.
149	TB Dansen, BMT Burgering. Unravelling the tumor-suppressive functions of FOXO proteins. Trends Cell Biol. 2008;18(9):421-429.
150	R Rattan, K Narita, J Chien, et al. TCEAL7, a putative tumor suppressor gene, negatively regulates NF-κB pathway. Oncogene. 2010;29(9):1362-1373.
151	K-K Wong, DI Izaguirre, S-Y Kwan, et al. Poor survival with wild-type TP53 ovarian cancer? Gynecol Oncol. 2013;130(3):565-569.
152	TC Voss, GL Hager. Dynamic regulation of transcriptional states by chromatin and transcription factors. Nat Rev Genet. 2014;15:69-81.
153	TI Lee, RA Young. Transcriptional regulation and its misregulation in disease. Cell. 2013;152(6):1237-1251.
154	P Carlsson, M Mahlapuu. Forkhead transcription factors: key players in development and metabolism. Dev Biol. 2002;250(1):1-23.
155	CM Hernandez-Garcia, JJ Finer. Identification and validation of promoters and cis-acting regulatory elements. Plant Sci. 2014;217-218:109-119.
156	K Gupta, D Sari-Ak, M Haffke, S Trowitzsch, I Berger. Zooming in on transcription preinitiation. J Mol Biol. 2016;428(12):2581-2591.
157	JT Kadonaga. Perspectives on the RNA polymerase II core promoter. Wiley Interdiscip Rev Dev Biol. 2012;1(1):40-51.
158	B Manzano-Winkler, CD Novina, AL Roy. TFII is required for transcription of the naturally TATA-less but initiator-containing Vβ promoter (?). J Biol Chem. 1996;271(20):12076-12081.
159	PJ Mitchell, R Tjian. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989;245(4916):371-378.
160	JA Hellyer, H Stehr, M Das, et al. Impact of KEAP1/NFE2L2/CUL3 mutations on duration of response to EGFR tyrosine kinase inhibitors in EGFR mutated non-small cell lung cancer. Lung Cancer. 2019;134:42-45.
161	R Frank, M Scheffler, S Merkelbach-Bruse, et al. Clinical and pathological characteristics of KEAP1-and NFE2L2-mutated non–small cell lung carcinoma (NSCLC). Clin Cancer Res. 2018;24(13):3087-3096.
162	LD Goldstein, J Lee, F Gnad, et al. Recurrent loss of NFE2L2 exon 2 is a mechanism for Nrf2 pathway activation in human cancers. Cell Rep. 2016;16(10):2605-2617.
163	B Wang, H Guo, H Yu, Y Chen, H Xu, G Zhao. The role of the transcription factor EGR1 in cancer. Front Oncol. 2021;11:642547.
164	T-T Li, M-R Liu, D-S Pei. Friend or foe, the role of EGR-1 in cancer. Med Oncol. 2020;37(1):7.
165	L Wang, A Shilatifard. UTX mutations in human cancer. Cancer Cell. 2019;35(2):168-176.
166	M Gozdecka, E Meduri, M Mazan, et al. UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nat Genet. 2018;50(6):883-894.
167	J Andricovich, S Perkail, Y Kai, N Casasanta, W Peng, A Tzatsos. Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors. Cancer Cell. 2018;33(3):512-526. .e518.
168	KB Shpargel, J Starmer, C Wang, K Ge, T Magnuson. UTX-guided neural crest function underlies craniofacial features of Kabuki syndrome. Proc Natl Acad Sci USA. 2017;114(43):E9046-E9055.
169	JH Kim, J Hwang, JH Jung, HJ Lee, DY Lee, SH Kim. Molecular networks of FOXP family: dual biologic functions, interplay with other molecules and clinical implications in cancer progression. Mol Cancer. 2019;18(1):180.
170	F Wang, N Zhao, G Gao, et al. Prognostic value of TP53 co-mutation status combined with EGFR mutation in patients with lung adenocarcinoma. J Cancer Res Clin Oncol. 2020;146(11):2851-2859.
171	A Kuzmichev, K Nishioka, H Erdjument-Bromage, P Tempst, D Reinberg. Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste protein. Genes Dev. 2002;16(22):2893-2905.
172	HJ Li, PN Yu, KY Huang, et al. NKX6.1 functions as a metastatic suppressor through epigenetic regulation of the epithelial-mesenchymal transition. Oncogene. 2016;35(17):2266-2278.
173	F Caramia, TP Speed, H Shen, Y Haupt, S Haupt. Establishing the Link between X-Chromosome Aberrations and TP53 Status, with Breast Cancer Patient Outcomes. Cells. 2023;12(18):2245.
174	O Shoshani, B Bakker, L de Haan, et al. Transient genomic instability drives tumorigenesis through accelerated clonal evolution. Genes Dev. 2021;35(15-16):1093-1108.
175	V Greger, E Passarge, W H?pping, E Messmer, B Horsthemke. Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma. Hum Genet. 1989;83:155-158.
176	A Merlo, JG Herman, L Mao, et al. 5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med. 1995;1(7):686-692.
177	JG Herman, A Merlo, L Mao, et al. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995;55(20):4525-4530.
178	M Gonzalez-Zulueta, CM Bender, AS Yang, et al. Methylation of the 5′ CpG island of the p16/CDKN2 tumor suppressor gene in normal and transformed human tissues correlates with gene silencing. Cancer Res. 1995;55(20):4531-4535.
179	M Esteller, PG Corn, SB Baylin, JG Herman. A gene hypermethylation profile of human cancer. Cancer Res. 2001;61(8):3225-3229.
180	M Esteller. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21(35):5427-5440.
181	SJ Clark, PL Molloy. Early insights into cancer epigenetics: Gene promoter hypermethylation emerges as a potential biomarker for cancer detection. Cancer Res. 2022;82(8):1461-1463.
182	MJ Pajares, E Alemany-Cosme, S Go?i, E Bandres, C Palanca-Ballester, J Sandoval. Epigenetic regulation of microRNAs in cancer: shortening the distance from bench to bedside. Int J Mol Sci. 2021;22(14):7350.
183	NE Kushlinskii, DO Utkin, VI Loginov, et al. Clinical significance of methylation of a group of miRNA genes in patients with ovarian cancer. Klin Lab Diagn. 2020;65(5):321-327.
184	E Filippova, V Loginov, A Burdennyi, et al. Hypermethylated genes of MicroRNA in ovarian carcinoma: metastasis prediction marker systems. Bull Exp Biol Med. 2019;167(1):79-83.
185	A Lujambio. CpG island hypermethylation of tumor suppressor microRNAs in human cancer. Cell Cycle. 2007;6(12):1454-1458.
186	OA Sukocheva, E Lukina, M Friedemann, M Menschikowski, A Hagelgans, G Aliev. The crucial role of epigenetic regulation in breast cancer anti-estrogen resistance: Current findings and future perspectives. Semin Cancer Biol. Elsevier; 2022:35-59.
187	L Lopez-Serra, E Ballestar, MF Fraga, M Alaminos, F Setien, M Esteller. A profile of methyl-CpG binding domain protein occupancy of hypermethylated promoter CpG islands of tumor suppressor genes in human cancer. Cancer Res. 2006;66(17):8342-8346.
188	J Chien, J Staub, R Avula, et al. Epigenetic silencing of TCEAL7 (Bex4) in ovarian cancer. Oncogene. 2005;24(32):5089-5100.
189	MF Berger, ER Mardis. The emerging clinical relevance of genomics in cancer medicine. Nat Rev Clin Oncol. 2018;15(6):353-365.
190	DD Shi, JA Guo, HI Hoffman, et al. Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities. Lancet Oncol. 2022;23(2):e62-e74.
191	I Martinez-Reyes, NS Chandel. Cancer metabolism: looking forward. Nat Rev Cancer. 2021;21(10):669-680.
192	F Supek, B Minana, J Valcarcel, T Gabaldon, B Lehner. Synonymous mutations frequently act as driver mutations in human cancers. Cell. 2014;156(6):1324-1335.
193	JE Rubnitz, B Gibson, FO Smith. Acute myeloid leukemia. Pediatr Clin N Am. 2008;55(1):21-51.
194	T Sjoblom, S Jones, LD Wood, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314(5797):268-274.
195	LD Wood, DW Parsons, S Jones, et al. The genomic landscapes of human breast and colorectal cancers. Science. 2007;318(5853):1108-1113.
196	SP Shah, RD Morin, J Khattra, et al. Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009;461(7265):809-813.
197	Q-W Zhang, L Liu, C-Y Gong, et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One. 2012;7(12):e50946.
198	DA Landau, E Tausch, AN Taylor-Weiner, et al. Mutations driving CLL and their evolution in progression and relapse. Nature. 2015;526(7574):525-530.
199	J Liu, C He, C Xing, Y Yuan. Nucleotide excision repair related gene polymorphisms and genetic susceptibility, chemotherapeutic sensitivity and prognosis of gastric cancer. Mutat Res. 2014;765:11-21.
200	C He, H Tu, L Sun, et al. SNP interactions of Helicobacter pylori-related host genes PGC, PTPN11, IL1B, and TLR4 in susceptibility to gastric carcinogenesis. Oncotarget. 2015;6(22):19017-19026.
201	MA Schirmer, CM Lüske, S Roppel, et al. Relevance of Sp binding site polymorphism in WWOX for treatment outcome in pancreatic cancer. J Natl Cancer Inst. 2016;108(5):djv387.
202	C He, Q Xu, H Tu, et al. Polymorphic rs9471643 and rs6458238 upregulate PGC transcription and protein expression in overdominant or dominant models. Mol Carcinog. 2016;55(5):586-599.
203	H Wu, K Zhang, P Gong, et al. A novel functional TagSNP Rs7560488 in the DNMT3A1 promoter is associated with susceptibility to gastric cancer by modulating promoter activity. PLoS One. 2014;9(3):e92911.
204	M Xu, Y Gao, T Yu, et al. Functional promoter rs2295080 T>G variant in MTOR gene is associated with risk of colorectal cancer in a Chinese population. Biomed Pharmacother. 2015;70:28-32.
205	H Fan, D Liu, X Qiu, et al. A functional polymorphism in the DNA methyltransferase-3A promoter modifies the susceptibility in gastric cancer but not in esophageal carcinoma. BMC Med. 2010;8:12.
206	L Yang, X Yang, W Ji, et al. Effects of a functional variant c. 353T>C in snai1 on risk of two contextual diseases. Chronic obstructive pulmonary disease and lung cancer. Am J Respir Crit Care Med. 2014;189(2):139-148.
207	W Fang, F Qiu, L Zhang, et al. The functional polymorphism of NBS1 p. Glu185Gln is associated with an increased risk of lung cancer in Chinese populations: Case–control and a meta-analysis. Mutat Res. 2014;770:61-68.
208	P Griseri, C Bourcier, C Hieblot, et al. A synonymous polymorphism of the Tristetraprolin (TTP) gene, an AU-rich mRNA-binding protein, affects translation efficiency and response to Herceptin treatment in breast cancer patients. Hum Mol Genet. 2011;20(23):4556-4568.
209	HY Xiong, B Alipanahi, LJ Lee, et al. The human splicing code reveals new insights into the genetic determinants of disease. Science. 2015;347(6218):1254806.
210	H Li, W Gan, L Lu, et al. A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. Diabetes. 2013;62(1):291-298.
211	C Pagenstecher, M Wehner, W Friedl, et al. Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. Hum Genet. 2006;119:9-22.
212	Q Xu, Q Dong, C He, et al. A new polymorphism biomarker rs629367 associated with increased risk and poor survival of gastric cancer in Chinese by up-regulated miRNA-let-7a expression. PLoS One. 2014;9(4):e95249.
213	Q Xu, M-Y Chen, C-Y He, L-P Sun, Y Yuan. Promoter polymorphisms in trefoil factor 2 and trefoil factor 3 genes and susceptibility to gastric cancer and atrophic gastritis among Chinese population. Gene. 2013;529(1):104-112.
214	NR Dunna, SM Naushad, S Vuree, et al. Association of thymidylate synthase 5'-UTR 28 bp tandem repeat and serine hydroxymethyltransfarase C1420T polymorphisms with susceptibility to acute leukemia. Asian Pac J Cancer Prev. 2014;15(4):1719-1723.
215	X-F Chen, D-L Zhu, M Yang, et al. An osteoporosis risk SNP at 1p36. 12 acts as an allele-specific enhancer to modulate LINC00339 expression via long-range loop formation. Am J Hum Genet. 2018;102(5):776-793.
216	N Cheng, C Bi, Y Shi, et al. Effect predictor of driver synonymous mutations based on multi-feature fusion and iterative feature representation learning. IEEE J Biomed Health Inform. 2024;28(2):1144-1151.
217	Z Zeng, Y Bromberg. Inferring potential cancer driving synonymous variants. Genes (Basel). 2022;13(5):778.
218	N Cheng, M Li, L Zhao, et al. Comparison and integration of computational methods for deleterious synonymous mutation prediction. Brief Bioinform. 2020;21(3):970-981.
219	I Bianchi, A Lleo, ME Gershwin, P Invernizzi. The X chromosome and immune associated genes. J Autoimmun. 2012;38(2-3):J187-J192.
220	B Lv, Y Wang, D Ma, et al. Immunotherapy: reshape the tumor immune microenvironment. Front Immunol. 2022;13:844142.
221	X Zhao, R Zhao, J Wen, et al. Bioinformatics-based screening and analysis of the key genes involved in the influence of antiangiogenesis on myeloid-derived suppressor cells and their effects on the immune microenvironment. Med Oncol. 2024;41(5):96.
222	J Wang, Y Wang, L Wan, et al. Identification of lactate regulation pattern on tumor immune infiltration, therapy response, and DNA methylation in diffuse large B-cell lymphoma. Front Immunol. 2023;14:1230017.
223	H Schurz, M Salie, G Tromp, EG Hoal, CJ Kinnear, M Moller. The X chromosome and sex-specific effects in infectious disease susceptibility. Hum Genomics. 2019;13(1):2.
224	MT Dorak, E Karpuzoglu. Gender differences in cancer susceptibility: an inadequately addressed issue. Front Genet. 2012;3:268.
225	RL Siegel, KD Miller, SA Fedewa, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177-193.
226	EA Khramtsova, LK Davis, BE Stranger. The role of sex in the genomics of human complex traits. Nat Rev Genet. 2019;20(3):173-190.
227	I Ben-Batalla, ME Vargas-Delgado, G von Amsberg, M Janning, S Loges. Influence of androgens on immunity to self and foreign: effects on immunity and cancer. Front Immunol. 2020;11:1184.
228	A Irelli, MM Sirufo, C D'Ugo, L Ginaldi, M De Martinis. Sex and gender influences on cancer immunotherapy response. Biomedicines. 2020;8(7):232.
229	S Hutter, S Bolin, H Weishaupt, FJ Swartling. Modeling and targeting MYC genes in childhood brain tumors. Genes. 2017;8(4):107.
230	MA Collins, F Bednar, Y Zhang, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122(2):639-653.
231	H Ying, AC Kimmelman, CA Lyssiotis, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012;149(3):656-670.
232	MA Collins, J-C Brisset, Y Zhang, et al. Metastatic pancreatic cancer is dependent on oncogenic Kras in mice. PLoS One. 2012;7(12):e49707.
233	P Nenclares, K Harrington. The biology of cancer. Medicine (Baltimore). 2020;48(2):67-72.
234	K Koera, K Nakamura, K Nakao, et al. K-ras is essential for the development of the mouse embryo. Oncogene. 1997;15(10):1151-1159.
235	SG O'Brien, F Guilhot, RA Larson, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004.
236	JM Llovet, S Ricci, V Mazzaferro, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390.
237	X Yu, A Vazquez, AJ Levine, DR Carpizo. Allele-specific p53 mutant reactivation. Cancer Cell. 2012;21(5):614-625.
238	FM Boeckler, AC Joerger, G Jaggi, TJ Rutherford, DB Veprintsev, AR Fersht. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci USA. 2008;105(30):10360-10365.
239	V Raghavan, M Agrahari, DK Gowda. Virtual screening of p53 mutants reveals Y220S as an additional rescue drug target for PhiKan083 with higher binding characteristics. Comput Biol Chem. 2019;80:398-408.
240	Q Zhang, VJN Bykov, KG Wiman, J Zawacka-Pankau. APR-246 reactivates mutant p53 by targeting cysteines 124 and 277. Cell Death Dis. 2018;9(5):439.
241	S Lehmann, VJ Bykov, D Ali, et al. Targeting p53 in vivo: a first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J Clin Oncol. 2012;30(29):3633-3639.
242	S Deneberg, H Cherif, V Lazarevic, et al. An open-label phase I dose-finding study of APR-246 in hematological malignancies. Blood Cancer J. 2016;6(7):e447.
243	DA Sallman, AE DeZern, G Garcia-Manero, et al. Eprenetapopt (APR-246) and azacitidine in TP53-mutant myelodysplastic syndromes. J Clin Oncol. 2021;39(14):1584-1594.
244	JM Lambert, P Gorzov, DB Veprintsev, et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 2009;15(5):376-388.
245	H Yan, L Zhang, R Li. Identification of m6A suppressor EIF4A3 as a novel cancer prognostic and immunotherapy biomarker through bladder cancer clinical data validation and pan-cancer analysis. Sci Rep. 2023;13(1):16457.
246	S Zhang, J Gu, LL Shi, et al. A pan-cancer analysis of anti-proliferative protein family genes for therapeutic targets in cancer. Sci Rep. 2023;13(1):21607.
247	DC Yang, JF Head, RL Elliott. Gene targets of antisense therapies in breast cancer. Expert Opin Ther Targets. 2002;6(3):375-385.
248	GN Hortobagyi, NT Ueno, W Xia, et al. Cationic liposome-mediated E1A gene transfer to human breast and ovarian cancer cells and its biologic effects: a phase I clinical trial. J Clin Oncol. 2001;19(14):3422-3433.
249	GM Nitulescu, D Margina, P Juzenas, et al. Akt inhibitors in cancer treatment: The long journey from drug discovery to clinical use (Review). Int J Oncol. 2016;48(3):869-885.
250	AA Emran, J Nsengimana, G Punnia-Moorthy, et al. Study of the female sex survival advantage in melanoma—a focus on X-linked epigenetic regulators and immune responses in two cohorts. Cancers (Basel). 2020;12(8):2082.
251	L Sun, R Zhai, L Zhang, S Zhao. MicroRNA-149 suppresses the proliferation and increases the sensitivity of ovarian cancer cells to cisplatin by targeting X-linked inhibitor of apoptosis. Oncol Lett. 2018;15(5):7328-7334.
252	M Vacca, F Della Ragione, F Scalabrì, M D'Esposito. X inactivation and reactivation in X-linked diseases. Semin Cell Dev Biol. 2016;56:78-87.
253	A Dunford, DM Weinstock, V Savova, et al. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nat Genet. 2017;49(1):10-16.
254	PC Cheng, JA Gosewehr, TM Kim, et al. Potential role of the inactivated X chromosome in ovarian epithelial tumor development. J Natl Cancer Inst. 1996;88(8):510-518.
255	M Redpath. Unraveling the Role of the X Chromosome in Cancer: Characterization of FOXP3 Isoforms and PR70 in Cutaneous Melanoma. McGill University (Canada); 2019.
256	BP Balaton, O Fornes, WW Wasserman, CJ Brown. Cross-species examination of X-chromosome inactivation highlights domains of escape from silencing. Epigenet Chromatin. 2021;14(1):12.
257	MF Fernández, I Reina-Pérez, JM Astorga, A Rodríguez-Carrillo, J Plaza-Díaz, L Fontana. Breast cancer and its relationship with the microbiota. Int J Environ Res Public Health. 2018;15(8):1747.
258	P Buiga, A Elson, L Tabernero, J-M Schwartz. Regulation of dual specificity phosphatases in breast cancer during initial treatment with Herceptin: A Boolean model analysis. BMC Syst Biol. 2018;12(1):11.
259	F Arabpour, A Shafizad, M Rahimzadeh, M Norouzan, N Naderi. FoxP3 gene polymorphism is associated with breast cancer in Iranian patients. Exp Oncol. 2018;40(4):309-314.
260	V Kajabova, B Smolkova, I Zmetakova, et al. RASSF1A promoter methylation levels positively correlate with estrogen receptor expression in breast cancer patients. Transl Oncol. 2013;6(3):297-304.
261	R Guerrero-Preston, C Michailidi, L Marchionni, et al. Key tumor suppressor genes inactivated by “greater promoter” methylation and somatic mutations in head and neck cancer. Epigenetics. 2014;9(7):1031-1046.
262	L Han, PDW Witmer, E Casey, D Valle, S Sukumar. DNA methylation regulates MicroRNA expression. Cancer Biol Ther. 2007;6(8):1290-1294.
263	TC Bestor, PG Steinhoff, VL Bestor. Doing Fieldwork in Japan. University of Hawaii Press; 2003.
264	CF Mugal, PF Arndt, L Holm, H Ellegren. Genetics: Evolutionary consequences of DNA methylation on the GC content in vertebrate genomes. G3. 2015;5(3):441-447.
265	K Jabbari, S Cacciò, JPP De Barros, J Desgrès, GJ Bernardi. Evolutionary changes in CpG and methylation levels in the genome of vertebrates. Gene. 1997;205(1-2):109-118.
266	J Karlow. Cancer Epigenome Reprogramming. Washington University; 2021.
267	MC Maiuri, E Tasdemir, A Criollo, et al. Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ. 2009;16(1):87-93.
268	H Lu, L Tran, Y Park, et al. Reciprocal regulation of DUSP9 and DUSP16 expression by HIF1 controls ERK and p38 MAP kinase activity and mediates chemotherapy-induced breast cancer stem cell enrichment. Cancer Res. 2018;78(15):4191-4202.
269	M Zhao, P Kim, R Mitra, J Zhao, Z Zhao. TSGene 2.0: an updated literature-based knowledgebase for tumor suppressor genes. Nucleic Acids Res. 2016;44(D1):D1023-D1031.
270	T Davoli, AW Xu, KE Mengwasser, et al. Cumulative haploinsufficiency and triplosensitivity drive aneuploidy patterns and shape the cancer genome. Cell. 2013;155(4):948-962.
271	KO Wrzeszczynski, V Varadan, J Byrnes, et al. Identification of tumor suppressors and oncogenes from genomic and epigenetic features in ovarian cancer. PLoS One. 2011;6(12):e28503.
272	W Sun, L Qiao, Q Liu, et al. Anticancer activity of the PR domain of tumor suppressor RIZ1. Int J Med Sci. 2011;8(2):161.
273	D Pinkel, R Segraves, D Sudar, et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet. 1998;20(2):207-211.
274	C Collins, JM Rommens, D Kowbel, et al. Positional cloning of ZNF 217 and NABC 1: genes amplified at 20q13. 2 and overexpressed in breast carcinoma. Proc Natl Acad Sci USA. 1998;95(15):8703-8708.
275	DG Albertson, B Ylstra, R Segraves, et al. Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene. Nat Genet. 2000;25(2):144-146.
276	DL Tait, PS Obermiller, AR Hatmaker, S Redlin-Frazier, JT Holt. Ovarian cancer BRCA1 gene therapy: Phase I and II trial differences in immune response and vector stability. Clin Cancer Res. 1999;5(7):1708-1714.
277	A Hazafa, M Mumtaz, MF Farooq, et al. CRISPR/Cas9: A powerful genome editing technique for the treatment of cancer cells with present challenges and future directions. Life Sci. 2020;263:118525.
278	S Chen, NE Sanjana, K Zheng, et al. Genome-wide CRISPR screen in a mouse model of tumor growth and metastasis. Cell. 2015;160(6):1246-1260.
279	FJ Sánchez-Rivera, T Papagiannakopoulos, R Romero, et al. Rapid modelling of cooperating genetic events in cancer through somatic genome editing. Nature. 2014;516(7531):428-431.