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Sex-Biased Molecular Signature for Overall Survival of Liver Cancer Patients

  • Kim, Sun Young (Department of Chemistry, College of Natural Sciences, Duksung Women's University) ;
  • Song, Hye Kyung (Department of Chemistry, College of Natural Sciences, Duksung Women's University) ;
  • Lee, Suk Kyeong (Department of Medical Life Sciences, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Kim, Sang Geon (College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University_Seoul) ;
  • Woo, Hyun Goo (Department of Physiology, Ajou University School of Medicine) ;
  • Yang, Jieun (Department of Physiology, Ajou University School of Medicine) ;
  • Noh, Hyun-Jin (Department of Biomedical Science, Graduate School, Ajou University) ;
  • Kim, You-Sun (Department of Biomedical Science, Graduate School, Ajou University) ;
  • Moon, Aree (Duksung Innovative Drug Center, College of Pharmacy, Duksung Women's University)
  • Received : 2020.09.09
  • Accepted : 2020.09.18
  • Published : 2020.11.01

Abstract

Sex/gender disparity has been shown in the incidence and prognosis of many types of diseases, probably due to differences in genes, physiological conditions such as hormones, and lifestyle between the sexes. The mortality and survival rates of many cancers, especially liver cancer, differ between men and women. Due to the pronounced sex/gender disparity, considering sex/gender may be necessary for the diagnosis and treatment of liver cancer. By analyzing research articles through a PubMed literature search, the present review identified 12 genes which showed practical relevance to cancer and sex disparities. Among the 12 sex-specific genes, 7 genes (BAP1, CTNNB1, FOXA1, GSTO1, GSTP1, IL6, and SRPK1) showed sex-biased function in liver cancer. Here we summarized previous findings of cancer molecular signature including our own analysis, and showed that sex-biased molecular signature CTNNB1High, IL6High, RHOAHigh and GLIPR1Low may serve as a female-specific index for prediction and evaluation of OS in liver cancer patients. This review suggests a potential implication of sex-biased molecular signature in liver cancer, providing a useful information on diagnosis and prediction of disease progression based on gender.

Keywords

References

  1. Addis, R., Campesi, I., Fois, M., Capobianco, G., Dessole, S., Fenu, G., Montella, A., Cattaneo, M. G., Vicentini, L. M. and Franconi, F. (2014) Human umbilical endothelial cells (HUVECs) have a sex: characterisation of the phenotype of male and female cells. Biol. Sex Differ. 5, 18. https://doi.org/10.1186/s13293-014-0018-2
  2. Allahyar, A. and de Ridder, J. (2015) FERAL: network-based classifier with application to breast cancer outcome prediction. Bioinformatics 31, i311-i319. https://doi.org/10.1093/bioinformatics/btv255
  3. Awasthi, A., Woolley, A. G., Lecomte, F. J., Hung, N., Baguley, B. C., Wilbanks, S. M., Jeffs, A. R. and Tyndall, J. D. (2013) Variable expression of GLIPR1 correlates with invasive potential in melanoma cells. Front. Oncol. 3, 225. https://doi.org/10.3389/fonc.2013.00225
  4. Babaei, S., Hulsman, M., Reinders, M. and de Ridder, J. (2013) Detecting recurrent gene mutation in interaction network context using multi-scale graph diffusion. BMC Bioinformatics 14, 29. https://doi.org/10.1186/1471-2105-14-29
  5. Barker, N. (2008) The canonical Wnt/beta-catenin signalling pathway. Methods Mol. Biol. 468, 5-15. https://doi.org/10.1007/978-1-59745-249-6_1
  6. Behari, J. (2010) The Wnt/$\beta$-catenin signaling pathway in liver biology and disease. Expert Rev. Gastroenterol. Hepatol. 4, 745-756. https://doi.org/10.1586/egh.10.74
  7. Bellizzi, A., Mangia, A., Chiriatti, A., Petroni, S., Quaranta, M., Schittulli, F., Malfettone, A., Cardone, R. A., Paradiso, A. and Reshkin, S. J. (2008) RhoA protein expression in primary breast cancers and matched lymphocytes is associated with progression of the disease. Int. J. Mol. Med. 22, 25-31.
  8. Bianchi, I., Lleo, A., Gershwin, M. E., and Invernizzi, P. (2012) The X chromosome and immune associated genes. J. Autoimmun. 38, J187-J192. https://doi.org/10.1016/j.jaut.2011.11.012
  9. Borras, C., Sastre, J., Garcia-Sala, D., Lloret, A., Pallardo, F. V. and Vina, J. (2003) Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic. Biol. Med. 34, 546-552. https://doi.org/10.1016/S0891-5849(02)01356-4
  10. Bottarelli, L., Azzoni, C., Necchi, F., Lagrasta, C., Tamburini, E., D'Adda, T., Pizzi, S., Sarli, L., Rindi, G. and Bordi, C. (2007) Sex chromosome alterations associate with tumor progression in sporadic colorectal carcinomas. Clin. Cancer Res. 13, 4365-4370. https://doi.org/10.1158/1078-0432.CCR-06-2736
  11. Bovelstad, H. M., Nygard, S., Storvold, H. L., Aldrin, M., Borgan, O., Frigessi, A. and Lingjaerde, O. C. (2007) Predicting survival from microarray data-a comparative study. Bioinformatics 23, 2080-2087. https://doi.org/10.1093/bioinformatics/btm305
  12. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A. and Jemal, A. (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394-424. https://doi.org/10.3322/caac.21492
  13. Budhu, A., Jia, H. L., Forgues, M., Liu, C., Goldstein, D., Lam, A., Zanetti, K. A., Ye, Q., Qin, L., Croce, C. M., Tang, Z. and Wang, X. W. (2008) Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 47, 897-907. https://doi.org/10.1002/hep.22160
  14. Cantuti-Castelvetri, I., Keller-McGandy, C., Bouzou, B., Asteris, G., Clark, T. W., Frosch, M. P. and Standaert, D. G. (2007) Effects of gender on nigral gene expression and parkinson disease. Neurobiol. Dis. 26, 606-614. https://doi.org/10.1016/j.nbd.2007.02.009
  15. Clayton, J. A. and Tannenbaum, C. (2016) Reporting sex, gender, or both in clinical research? JAMA 316, 1863-1864. https://doi.org/10.1001/jama.2016.16405
  16. Cohen, A. L., Soldi, R., Zhang, H., Gustafson, A. M., Wilcox, R., Welm, B. E., Chang, J. T., Johnson, E., Spira, A., Jeffrey, S. S. and Bild, A. H. (2011) A pharmacogenomic method for individualized prediction of drug sensitivity. Mol. Syst. Biol. 7, 513. https://doi.org/10.1038/msb.2011.47
  17. Cook, M. B., Dawsey, S. M., Freedman, N. D., Inskip, P. D., Wichner, S. M., Quraishi, S. M., Devesa, S. S. and McGlynn, K. A. (2009) Sex disparities in cancer incidence by period and age. Cancer Epidemiol. Biomarkers Prev. 18, 1174-1182. https://doi.org/10.1158/1055-9965.EPI-08-1118
  18. De Rienzo, A., Archer, M. A., Yeap, B. Y., Dao, N., Sciaranghella, D., Sideris, A. C., Zheng, Y., Holman, A. G., Wang, Y. E., Dal Cin, P. S. Fletcher, J. A., Rubio, R., Croft, L., Quackenbush, J., Sugarbaker, P. E., Munir, K. J., Battilana, J, R., Gustafson, C. E., Chirieac, L. R., Ching, S. M., Wong, J., Tay, L. C., Rudd, S., Hercus, R., Sugarbaker, D. J., Richards, W. J. and Bueno, R. (2016) Gender-specific molecular and clinical features underlie malignant pleural mesothelioma. Cancer Res. 76, 319-328. https://doi.org/10.1158/0008-5472.CAN-15-0751
  19. El-Maarri, O., Becker. T., Junen, J., Manzoor, S. S., Diaz-Lacava, A., Schwaab, R., Wienker, T. and Oldenburg, J. (2007) Gender specific differences in levels of DNA methylation at selected loci from human total blood: a tendency toward higher methylation levels in males. Hum. Genet. 122, 505-514. https://doi.org/10.1007/s00439-007-0430-3
  20. Erstad, D. J., Fuchs, B. C. and Tanabe, K. K. (2018) Molecular signatures in hepatocellular carcinoma: a step toward rationally designed cancer therapy. Cancer 124, 3084-3104. https://doi.org/10.1002/cncr.31257
  21. Evanson, J. R., Guyton, M. K., Oliver, D. L., Hire, J. M., Topolski, R. L., Zumbrun, S. D., McPherson, J. C. and Bojescul, J. A. (2014) Gender and age differences in growth factor concentrations from platelet-rich plasma in adults. Mil. Med. 179, 799-805. https://doi.org/10.7205/MILMED-D-13-00336
  22. Fish, E. N. (2008) The X-files in immunity: sex-based differences predispose immune responses. Nat. Rev. Immunol. 8, 737-744. https://doi.org/10.1038/nri2394
  23. Gabriele, L., Buoncervello, M., Ascione, B., Bellenghi, M., Matarrese, P. and Care, A. (2016) The gender perspective in cancer research and therapy: novel insights and on-going hypotheses. Ann. Ist. Super. Sanita 52, 213-222.
  24. Garcia-Herreros, M., Aparicio, I. M., Rath, D., Fair, T. and Lonergan, P. (2012) Differential glycolytic and glycogenogenic transduction pathways in male and female bovine embryos produced in vitro. Reprod. Fertil. Dev. 24, 344-352. https://doi.org/10.1071/RD11080
  25. Ghuwalewala, S., Ghatak, D., Das, P., Dey, S., Sarkar, S., Alam, N., Panda, C. K. and Roychoudhury, S. (2016) CD44(high)CD24(low) molecular signature determines the Cancer Stem Cell and EMT phenotype in Oral Squamous Cell Carcinoma. Stem Cell Res. 16, 405-417. https://doi.org/10.1016/j.scr.2016.02.028
  26. Gleicher, N. and Barad, D. H. (2007) Gender as risk factor for autoimmune diseases. J. Autoimmun. 28, 1-6. https://doi.org/10.1016/j.jaut.2006.12.004
  27. Graveley, B. R. (2000) Sorting out the complexity of SR protein functions. RNA 6, 1197-1211. https://doi.org/10.1017/S1355838200000960
  28. Guy, J. and Peters, M. G. (2013) Liver disease in women: the influence of gender on epidemiology, natural history, and patient outcomes. Gastroenterol. Hepatol. 10, 633-639.
  29. Haley, W. E., Roth, D. L., Howard, G. and Safford, M. M. (2010) Caregiving strain and estimated risk for stroke and coronary heart disease among spouse caregivers: differential effects by race and sex. Stroke 41, 331-336. https://doi.org/10.1161/STROKEAHA.109.568279
  30. Hanahan, D. and Weinberg, R. A. (2011) Hallmarks of cancer: the next generation. Cell 144, 646-674. https://doi.org/10.1016/j.cell.2011.02.013
  31. Harish, G., Venkateshappa, C., Mahadevan, A., Pruthi, N., Bharath, M. M. and Shankar, S. K. (2013) Mitochondrial function in human brains is affected by pre- and post mortem factors. Neuropathol. Appl. Neurobiol. 39, 298-315. https://doi.org/10.1111/j.1365-2990.2012.01285.x
  32. Heasman, S. J. and Ridley, A. J. (2008) Mammalian Rho GTPases: new insights into their functions from in vivo studies. Nat. Rev. Mol. Cell Biol. 9, 690-701. https://doi.org/10.1038/nrm2476
  33. Heidari, S., Babor, T. F., De Castro, P., Tort, S. and Curno, M. (2016) Sex and gender equity in research: rationale for the SAGER guidelines and recommended use. Res. Integr. Peer Rev. 1, 2. https://doi.org/10.1186/s41073-016-0007-6
  34. Hines, A., Staff, F. J., Widdows, J., Compton, R. M., Falciani, F. and Viant, M. R. (2010) Discovery of metabolic signatures for predicting whole organism toxicology. Toxicol. Sci. 115, 369-378. https://doi.org/10.1093/toxsci/kfq004
  35. Hou, J., Xu, J., Jiang, R., Wang, Y., Chen, C., Deng, L., Huang, X., Wang, X., and Sun, B. (2013) Estrogen-sensitive PTPRO expression represses hepatocellular carcinoma progression by control of STAT3. Hepatology 57, 678-688. https://doi.org/10.1002/hep.25980
  36. Hur, J., Sullivan, K. A., Pande, M., Hong, Y., Sima, A. A. F., Jagadish, H. V., Kretzler, M. and Feldman, E. L. (2011) The identification of gene expression profiles associated with progression of human diabetic neuropathy. Brain 134, 3222-3235. https://doi.org/10.1093/brain/awr228
  37. Ippolito, J. E., Yim, A. K., Luo, J., Chinnaiyan, P. and Rubin, J. B. (2017) Sexual dimorphism in glioma glycolysis underlies sex differences in survival. JCI Insight 2, e92142. https://doi.org/10.1172/jci.insight.92142
  38. Jiao, Y., Li, Y., Jiang, P., Han, W. and Liu, Y. (2019) PGM5: a novel diagnostic and prognostic biomarker for liver cancer. PeerJ 7, e7070. https://doi.org/10.7717/peerj.7070
  39. Jung, K. W., Won, Y. J., Kong, H. J. and Lee, E. S. (2019) Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2016. Cancer Res. Treat. 51, 417-430. https://doi.org/10.4143/crt.2019.138
  40. Klein, S. L. and Flanagan, K. L. (2016) Sex differences in immune responses. Nat. Rev. Immunol. 16, 626-638. https://doi.org/10.1038/nri.2016.90
  41. Klinge, C. M. (2012) miRNAs and estrogen action. Trends Endocrinol. Metab. 23, 223-233. https://doi.org/10.1016/j.tem.2012.03.002
  42. Kohi, M. P. (2016) Gender-related differences in hepatocellular carcinoma: does sex matter? J. Vasc. Interv. Radiol. 27, 1338-1341. https://doi.org/10.1016/j.jvir.2016.06.035
  43. Kouzmenko, A. P., Takeyama, K., Ito, S., Furutani, T., Sawatsubashi, S., Maki, A., Suzuki, E., Kawasaki, Y., Akiyama, T., Tabata, T. and Kato, T. (2004) Wnt/beta-catenin and estrogen signaling converge in vivo. J. Biol. Chem. 279, 40255-40258. https://doi.org/10.1074/jbc.C400331200
  44. Krumsiek, J., Mittelstrass, K., Do, K. T., Stuckler, F., Ried, J., Adamski, J., Peters, A., Illig, T., Kronenberg, F., Friedrich, N., Nauck, M., Pietzner, M., Mook-Kanamori, D. O., Suhre, K., Gieger, C., Grallert, H., Theis, F. J. and Kastenmuller, G. (2015) Gender-specific pathway differences in the human serum metabolome. Metabolomics 11, 1815-1833. https://doi.org/10.1007/s11306-015-0829-0
  45. Kumari, N., Dwarakanath, B. S., Das, A. and Bhatt, A. N. (2016) Role of interleukin-6 in cancer progression and therapeutic resistance. Tumour Biol. 37, 11553-11572. https://doi.org/10.1007/s13277-016-5098-7
  46. Laffont, S., Blanquart, E. and Guery, J. C. (2017) Sex differences in asthma: a key role of androgen-signaling in group 2 innate lymphoid cells. Front. Immunol. 8, 1069. https://doi.org/10.3389/fimmu.2017.01069
  47. Li, C. H., Haider, S., Shiah, Y. J., Thai, K. and Boutros, P. C. (2018) Sex differences in cancer driver genes and biomarkers. Cancer Res. 78, 5527-5537. https://doi.org/10.1158/0008-5472.CAN-18-0362
  48. Li, L., Ren, C., Yang, G., Fattah, E. A., Goltsov, A. A., Kim, S. M., Lee, J. S., Park, S., Demayo, F. J., Ittmann, M. M., Troncoso, P. and Thompson, T. C. (2011) GLIPR1 suppresses prostate cancer development through targeted oncoprotein destruction. Cancer Res. 71, 7694-7704. https://doi.org/10.1158/0008-5472.CAN-11-1714
  49. Li, Y., Kang, K., Krahn, J. M., Croutwater, N., Lee, K., Umbach, D. M. and Li, L. (2017) A comprehensive genomic pan-cancer classification using The Cancer Genome Atlas gene expression data. BMC Genomics 18, 508. https://doi.org/10.1186/s12864-017-3906-0
  50. Li, Z., Tuteja, G., Schug, J. and Kaestner, K. H. (2012) Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell 148, 72-83. https://doi.org/10.1016/j.cell.2011.11.026
  51. Libert, C., Dejager, L., and Pinheiro, I. (2010) The X chromosome in immune functions: when a chromosome makes the difference. Nat. Rev. Immunol. 10, 594-604 https://doi.org/10.1038/nri2815
  52. Lin, C. W., Lin, C. C., Mo, L. R., Chang, C. Y., Perng, D. S., Hsu, C. C., Lo, G. H., Chen, Y. S., Yen, Y. C., Hu, J. T., Yu, M. L., Lee, P. H., Lin, J. T. and Yang, S. S. (2013) Heavy alcohol consumption increases the incidence of hepatocellular carcinoma in hepatitis B virus-related cirrhosis. J. Hepatol. 58, 730-735. https://doi.org/10.1016/j.jhep.2012.11.045
  53. Liu, F., Yuan, J. H., Huang, J. F., Yang, F., Wang, T. T., Ma, J. Z., Zhang, L., Zhou, C. C., Wang, F., Yu, J., Zhou, W. P. and Sun, S. H. (2016) Long noncoding RNA FTX inhibits hepatocellular carcinoma proliferation and metastasis by binding MCM2 and miR-374a. Oncogene 35, 5422-5434. https://doi.org/10.1038/onc.2016.80
  54. Liu, W. C. and Liu, Q. Y. (2014) Molecular mechanisms of gender disparity in hepatitis B virus-associated hepatocellular carcinoma. World J. Gastroenterol. 20, 6252-6261. https://doi.org/10.3748/wjg.v20.i20.6252
  55. Masoomian, B., Shields, J. A. and Shields, C. L. (2018) Overview of BAP1 cancer predisposition syndrome and the relationship to uveal melanoma. J. Curr. Ophthalmol. 30, 102-109. https://doi.org/10.1016/j.joco.2018.02.005
  56. Mehrabian, M., Allayee, H., Stockton, J., Lum, P. Y. , Drake, T. A., Castellani, L. W., Suh, M., Armour, C., Edwards, S., Lamb, J., Lusis, A. J. and Schadt, E. E. (2007) Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits. Nat. Genet. 37, 1224-1233. https://doi.org/10.1038/ng1619
  57. Mervic, L. (2012) Time course and pattern of metastasis of cutaneous melanoma differ between men and women. PLoS ONE 7, e32955. https://doi.org/10.1371/journal.pone.0032955
  58. Mittelstrass, K., Ried, J. S., Yu, Z., Krumsiek, J., Gieger, C., Prehn, C., Roemisch-Margl, W., Polonikov, A., Peters, A., Theis, F. J., Meitinger, T., Kronenberg, F., Weidinger, S., Wichmann, H. E., Suhre, K., Wang-Sattler, R., Adamski, J. and Illig, T. (2011) Discovery of sexual dimorphisms in metabolic and genetic biomarkers. PLoS Genet. 7, e1002215. https://doi.org/10.1371/journal.pgen.1002215
  59. Mosley, M., Weathington, J., Cortes, L. R., Bruggeman, E., Castillo-Ruiz, A., Xue, B. and Forger, N. G. (2017) Neonatal inhibition of DNA methylation alters cell phenotype in sexually dimorphic regions of the mouse brain. Endocrinology 158, 1838-1848. https://doi.org/10.1210/en.2017-00205
  60. Mulligan, M. A., Wegner, K. A., Keil, K. P., Mehta, V., Taketo, M. M. and Vezina, C. M. (2017) Beta-catenin and estrogen signaling collaborate to drive cyclin D1 expression in developing mouse prostate. Differentiation 93, 66-71. https://doi.org/10.1016/j.diff.2016.11.002
  61. Murphy, E. V., Zhang, Y., Zhu, W. and Biggs, J. (1995) The human glioma pathogenesis-related protein is structurally related to plant pathogenesis-related proteins and its gene is expressed specifically in brain tumors. Gene 159, 131-135. https://doi.org/10.1016/0378-1119(95)00061-A
  62. Naugler, W. E., Sakurai, T., Kim, S., Maeda, S., Kim, K., Elsharkawy, A. M. and Karin, M. (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121-124. https://doi.org/10.1126/science.1140485
  63. Niu, D., Zhang, J., Ren, Y., Feng, H. and Chen, W. N. (2009) HBx genotype D represses GSTP1 expression and increases the oxidative level and apoptosis in HepG2 cells. Mol. Oncol. 3, 67-76. https://doi.org/10.1016/j.molonc.2008.10.002
  64. Nilsson, R., Bjorkegren, J. and Tegner, J. (2009) On reliable discovery of molecular signatures. BMC Bioinformatics 10, 38. https://doi.org/10.1186/1471-2105-10-38
  65. Nugent, B. M., Wright, C. L., Shetty, A. C., Hodes, G. E., Lenz, K. M., Mahurkar, A., Russo, S. J., Devine, S. E. and McCarthy, M. M. (2015) Brain feminization requires active repression of masculinization via DNA methylation. Nat. Neurosci. 18, 690-697. https://doi.org/10.1038/nn.3988
  66. Pal, S. K. and Hurria, A. (2010) Impact of age, sex, and comorbidity on cancer therapy and disease progression. J. Clin. Oncol. 28, 4086-4093. https://doi.org/10.1200/JCO.2009.27.0579
  67. Pelletier, R., Khan, N. A., Cox, J., Daskalopoulou, S. S., Eisenberg, M. J., Bacon, S. L., Lavoie, K. L., Daskupta, K., Rabi, D., Humphries, K. H., Norris, C. M., Thanassoulis, G., Behlouli, H. and Pilote, L.; GENESIS-PRAXY Investigators (2016) Sex versus gender-related characteristics: which predicts outcome after acute coronary syndrome in the young? J. Am. Coll. Cardiol. 67, 127-135.
  68. Pinheiro, I., Dejager, L. and Libert, C. (2011) X-chromosome-located microRNAs in immunity: might they explain male/female differences? The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females. Bioessays 33, 791-802. https://doi.org/10.1002/bies.201100047
  69. Pittman, J., Huang, E., Dressman, H., Horng, C. F., Cheng, S. H., Tsou, M., Chen, C., Bild, A., Iversen, E. S., Huang, A. T., Nevins, J. R. and West, M. (2004) Integrated modeling of clinical and gene expression information for personalized prediction of disease outcomes. Proc. Natl. Acad. Sci. U.S.A. 101, 8431-8436. https://doi.org/10.1073/pnas.0401736101
  70. Qiu, J., Peng, B., Tang, Y., Qian, Y., Guo, P., Li, M., Luo, J., Chen, B., Tang, H., Lu, C., Cai, M., Ke, Z., He, W., Zheng, Y., Xie, D., Li, B. and Yuan, Y. (2017) CpG methylation signature predicts recurrence in early-stage hepatocellular carcinoma: results from a multicenter study. J. Clin. Oncol. 35, 734-742. https://doi.org/10.1200/JCO.2016.68.2153
  71. Qu, K., Liu, S. S., Wang, Z. X., Huang, Z. C., Liu, S. N., Chang, H. L., Xu, X. S., Lin, T., Dong, Y. F. and Liu, C. (2015) Polymorphisms of glutathione S-transferase genes and survival of resected hepatocellular carcinoma patients. World J. Gastroenterol. 21, 4310-4322. https://doi.org/10.3748/wjg.v21.i14.4310
  72. Rahbari, R., Zhang L. and Kebebew, E. (2010) Thyroid cancer gender disparity. Future Oncol. 6, 1771-1779. https://doi.org/10.2217/fon.10.127
  73. Rebouissou, S., Franconi, A., Calderaro, J., Letouze, E., Imbeaud, S., Pilati, C., Nault, J. C., Couchy, G., Laurent, A., Balabaud, C., Bioulac-Sage, P. and Zucman-Rossi, J. (2016) Genotype-phenotype correlation of CTNNB1 mutations reveals different ${\beta}$-catenin activity associated with liver tumor progression. Hepatology 64, 2047-2061. https://doi.org/10.1002/hep.28638
  74. Reizel, Y., Spiro, A., Sabag, O., Skversky, Y., Hecht, M., Keshet, I., Berman, B. P. and Cedar, H. (2015) Gender-specific postnatal demethylation and establishment of epigenetic memory. Genes Dev. 29, 923-933. https://doi.org/10.1101/gad.259309.115
  75. Ren, C., Li, L., Yang, G., Timme, T. L., Goltsov, A., Ren, C., Ji, X., Addai, J., Luo, H., Ittmann, M. M. and Thompson, T. C. (2004) RTVP-1, a tumor suppressor inactivated by methylation in prostate cancer. Cancer Res. 64, 969-976. https://doi.org/10.1158/0008-5472.CAN-03-2592
  76. Rich, N. E., Murphy, C. C., Yopp, A. C., Tiro, J., Marrero, J. A. and Singal, A. G. (2020) Sex disparities in presentation and prognosis of 1110 patients with hepatocellular carcinoma. Aliment. Pharmacol. Ther. 52, 701-709. https://doi.org/10.1111/apt.15917
  77. Rubin, J. B., Lagas, J. S., Broestl, L., Sponagel, J., Rockwell, N., Rhee, G., Rosen, S. F., Chen, S., Klein, R. S., Imoukhuede, P. and Luo, J. (2020) Sex differences in cancer mechanisms. Biol. Sex Differ. 11, 17. https://doi.org/10.1186/s13293-020-00291-x
  78. Sailland, J., Tribollet, V., Forcet, C., Billon, C., Barenton, B., Carnesecchi, J., Bachmann, A., Gauthier, K. C., Yu, S., Giguere, V., Chan, F. L. and Vanacker, J. (2014) Estrogen-related receptor $\alpha$ decreases RHOA stability to induce orientated cell migration. Proc. Natl. Acad. Sci. U.S.A. 111, 15108-15113. https://doi.org/10.1073/pnas.1402094111
  79. Salehi, S., Jafarian, A. H., Montazer, M., Moghbeli, M. and Forghanifard, M. M. (2017) BRUCE protein, new marker for targeted therapy of gastric carcinoma. J. Gastrointest. Cancer 48, 151-155. https://doi.org/10.1007/s12029-016-9874-9
  80. Scosyrev, E., Noyes, K., Feng, C. and Messing, E. (2009) Sex and racial differences in bladder cancer presentation and mortality in the US. Cancer 115, 68-74, https://doi.org/10.1002/cncr.23986
  81. Scotland, R. S., Stables, M. J., Madalli, S., Watson, P. and Gilroy, D. W. (2011) Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice. Blood 118, 5918-5927. https://doi.org/10.1182/blood-2011-03-340281
  82. Setiawan, V. W., Lim, U., Lipworth, L., Lu, S. C., Shepherd, J., Ernst, T., Wilkens, L. R., Henderson, B. E. and Le Marchand, L. (2016) Sex and ethnic differences in the association of obesity with risk of hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 14, 309-316. https://doi.org/10.1016/j.cgh.2015.09.015
  83. Shin, J. Y., Jung, H. J. and Moon, A. (2019) Molecular markers in sex differences in cancer. Toxicol. Res. 35, 331-341. https://doi.org/10.5487/TR.2019.35.4.331
  84. Shirasaki, F., Takata, M., Hatta, N. and Takehara, K. (2001) Loss of expression of the metastasis suppressor gene KiSS1 during melanoma progression and its association with LOH of chromosome 6q16.3-q23. Cancer Res. 61, 7422-7425.
  85. Skavdahl, M., Steenbergen, C., Clark, J., Myers, P., Demianenko, T., Mao, L., Rockman, H. A., Korach, K. S. and Murphy, E. (2005) Estrogen receptor-beta mediates male-female differences in the development of pressure overload hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 288, 469-476. https://doi.org/10.1152/ajpheart.00723.2004
  86. Smalley, K. S. (2018) Why do women with melanoma do better than men? Elife 7, e33511. https://doi.org/10.7554/eLife.33511
  87. Smyth, E. C., Fassan, M., Cunningham, D., Allum, W. H., Okines, A. F. C., Lampis, A., Hahne, J. C., Rugge, M., Peckitt, C., Nankivell, M., Langley, R., Ghidini, M., Braconi, C., Wotherspoon, A., Grabsch, H. I. and Valeri, N. (2016) Effect of pathologic tumor response and nodal status on survival in the medical research council adjuvant gastric infusional chemotherapy trial. J. Clin. Oncol. 34, 2721-2727. https://doi.org/10.1200/JCO.2015.65.7692
  88. Smyth, E. C., Nyamundanda, G., Cunningham, D., Fontana, E., Ragulan, C., Tan, I. B., Lin, S. J., Wotherspoon, A., Nankivell, M., Fassan, M., Lampis, A., Hahne, J. C., Davies, A. R., Lagergren, J., Gossage, J. A., Maisey, N., Green, M., Zylstra, J. L., Allum, W. H., Langley, R. E., Tan, P., Valeri, N. and Sadanandam, A. (2018) A seven-Gene Signature assay improves prognostic risk stratification of perioperative chemotherapy treated gastroesophageal cancer patients from the MAGIC trial. Ann. Oncol. 29, 2356-2362. https://doi.org/10.1093/annonc/mdy407
  89. Snell, D. M. and Turner, J. M. A. (2018) Sex chromosome effects on male-female differences in mammals. Curr. Biol. 28, R1313-R1324. https://doi.org/10.1016/j.cub.2018.09.018
  90. So, A. R., Si, J. M., Lopez, D. and Pellegrini, M. (2020) Molecular signatures for inflammation vary across cancer types and correlate significantly with tumor stage, sex and vital status of patients. PLoS ONE 15, e0221545. https://doi.org/10.1371/journal.pone.0221545
  91. Spatz, A., Borg, C. and Feunteun, J. (2004) X-chromosome genetics and human cancer. Nat. Rev. Cancer 4, 617-629. https://doi.org/10.1038/nrc1413
  92. Stein, B. and Yang, M. X. (1995) Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol. Cell. Biol. 15, 4971-4979. https://doi.org/10.1128/MCB.15.9.4971
  93. Sung, J., Wang, Y., Chandrasekaran, S., Witten, D. M. and Price, N. D. (2012) Molecular signatures from omics data: from chaos to consensus. Biotechnol. J. 7, 946-957. https://doi.org/10.1002/biot.201100305
  94. Tang, H., Wang, S., Xiao, G., Schiller, J., Papadimitrakopoulou, V., Minna, J., Wistuba, I. and Xie, Y. (2017) Comprehensive evaluation of published gene expression prognostic signatures for biomarker-based lung cancer clinical studies. Ann. Oncol. 28, 733-740. https://doi.org/10.1093/annonc/mdw683
  95. Tobi, E. W., Lumey, L. H., Talens, R. P., Kremer, D., Putter, H., Stein, A. D., Slagboom, P. E. and Heijmans, B. T. (2009) DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum. Mol. Genet. 18, 4046-4053. https://doi.org/10.1093/hmg/ddp353
  96. van de Vijver, M. J., He, Y. D., van't Veer, L. J., Dai, H., Hart, A. A., Voskuil, D. W., Schreiber, G. J., Peterse, J. L., Roberts, C., Marton, M. J., Parrish, M., Atsma, D., Witteveen, A., Glas, A., Delahaye, L., van der Velde, T., Bartelink, H., Rodenhuis, S., Rutgers, E. T., Friend, S. H. and Bernards, R. (2002) A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999-2009. https://doi.org/10.1056/NEJMoa021967
  97. Villa, E., Critelli, R., Lei, B., Marzocchi, G., Camma, C., Giannelli, G., Pontisso, P., Cabibbo, G., Enea, M., Colopi, S., Caporali, C., Pollicino, T., Milosa, F., Karampatou, A., Todesca, P., Bertolini, E., Maccio, L., Martinez-Chantar, M. L., Turola, E., Del Buono, M., De Maria, N., Ballestri, S., Schepis, F., Loria, P., Gerunda, G. E., Losi, L. and Cillo, U. (2016) Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study. Gut 65, 861-869. https://doi.org/10.1136/gutjnl-2014-308483
  98. Wang, R., Ye, X. H., Zhao, X. L., Liu, J. L. and Zhang, C. Y. (2019) Development of a five-gene signature as a novel prognostic marker in ovarian cancer. Neoplasma 66, 343-349. https://doi.org/10.4149/neo_2018_180705N447
  99. Wang, Y., Xing, T., Huang, L., Song, G., Sun, X., Zhong, L., Fan, J., Yan, D., Zhou, C., Cui, F., Yu, F., Chen, J., Yu, Y., Li, C., Tang, H., Peng, Z. and Wang, X. (2015) Period 1 and estrogen receptor-beta are downregulated in Chinese colon cancers. Int. J. Clin. Exp. Pathol. 8, 8178-8188.
  100. Welzel, T. M., Graubard, B. I., Quraishi, S., Zeuzem, S., Davila, J. A., El-Serag, H. B. and McGlynn, K. A. (2013) Population-attributable fractions of risk factors for hepatocellular carcinoma in the United States. Am. J. Gastroenterol. 108, 1314-1321. https://doi.org/10.1038/ajg.2013.160
  101. Wijchers, P. J. and Festenstein, R. J. (2011) Epigenetic regulation of autosomal gene expression by sex chromosomes. Trends Genet. 27, 132-140. https://doi.org/10.1016/j.tig.2011.01.004
  102. Wu, E. M., Wong, L. L., Hernandez, B. Y., Ji, J. F., Jia, W., Kwee, S. A. and Kalathil, S. (2018) Gender differences in hepatocellular cancer: disparities in nonalcoholic fatty liver disease/steatohepatitis and liver transplantation. Hepatoma Res. 4, 66. https://doi.org/10.20517/2394-5079.2018.87
  103. Wu, Y., Yao, N., Feng, Y., Tian, Z., Yang, Y. and Zhao, Y. (2019) Identification and characterization of sexual dimorphism-linked gene expression profile in hepatocellular carcinoma. Oncol. Rep. 42, 937-952.
  104. Xia, J., Urabe, K., Moroi, Y., Koga, T., Duan, H., Li, Y. and Furue, M. (2006) beta-Catenin mutation and its nuclear localization are confirmed to be frequent causes of Wnt signaling pathway activation in pilomatricomas. J. Dermatol. Sci. 41, 67-75. https://doi.org/10.1016/j.jdermsci.2005.09.005
  105. Xie, L., Xie, L., Kinnings, S. L. and Bourne, P. E. (2012) Novel computational approaches to polypharmacology as a means to define responses to individual drugs. Annu. Rev. Pharmacol. Toxicol. 52, 361-379. https://doi.org/10.1146/annurev-pharmtox-010611-134630
  106. Xiong, G., Lingampalli, N., Koltsov, J. C. B., Leung, L. L., Bhutani, N., Robinson, W. H. and Chu, C. R. (2018) Men and women differ in the biochemical composition of platelet-rich plasma. Am. J. Sports Med. 46, 409-419. https://doi.org/10.1177/0363546517740845
  107. Xu, G., Zhang, M., Zhu, H. and Xu, J. (2017) A 15-gene signature for prediction of colon cancer recurrence and prognosis based on SVM. Gene 604, 33-40. https://doi.org/10.1016/j.gene.2016.12.016
  108. Xu, J., Deng, X., Watkins, R. and Disteche, C. M. (2008) Sex-specific differences in expression of histone demethylases Utx and Uty in mouse brain and neurons. J. Neurosci. 28, 4521-4527. https://doi.org/10.1523/JNEUROSCI.5382-07.2008
  109. Yaron, M., Renner, U., Gilad, S., Stalla, G. K., Stern, N. and Greenman, Y. (2015) KISS1 receptor is preferentially expressed in clinically non-functioning pituitary tumors. Pituitary 18, 306-311. https://doi.org/10.1007/s11102-014-0572-y
  110. Yu, L., Liu, X., Wang, X., Dang, Z., Jiang, Y., Wang, X. and Yang, Z. (2019) Impact of gender as a prognostic factor in HBV-related hepatocellular carcinoma: the survival strength of female patients in BCLC stage 0-B. J. Cancer 10, 4237-4244. https://doi.org/10.7150/jca.33430
  111. Yuasa, Y. (2010) Epigenetics in molecular epidemiology of cancer a new scope. Adv. Genet. 71, 211-235. https://doi.org/10.1016/B978-0-12-380864-6.00007-9
  112. Zhang, J., Jiang, H., Xia, W., Jiang, Y., Tan, X., Liu, P., Jia, H., Yang, X. and Shen, G. (2016) Serine-arginine protein kinase 1 is associated with hepatocellular carcinoma progression and poor patient survival. Tumour Biol. 37, 283-290. https://doi.org/10.1007/s13277-015-3771-x
  113. Zhang, L. J., Xiong, Y., Nilubol, N., He, M., Bommareddi, S., Zhu, X., Jia, L., Xiao, Z., Park, J. W., Xu, X., Patel, D., Willingham, M. C., Cheng, S. Y. and Kebebew, E. (2015) Testosterone regulates thyroid cancer progression by modifying tumor suppressor genes and tumor immunity. Carcinogenesis 36, 420-428. https://doi.org/10.1093/carcin/bgv001
  114. Zhao, L., Jiang, L., He, L., Wei, Q., Bi, J., Wang Y., Yu, L., He, M., Zhao, L. and Wei, M. (2019) Identification of a novel cell cycle-related gene signature predicting survival in patients with gastric cancer. J. Cell. Physiol. 234, 6350-6360. https://doi.org/10.1002/jcp.27365