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Sex disparities matter in cancer development and therapy

Nature Reviews Cancer volume 21, pages 393–407 (2021)Cite this article

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Abstract

Curing cancer through precision medicine is the paramount aim of the new wave of molecular and genomic therapies. Currently, whether patients with non-reproductive cancers are male or female according to their sex chromosomes is not adequately considered in patient standard of care. This is a matter of consequence because there is growing evidence that these cancer types generally initiate earlier and are associated with higher overall incidence and rates of death in males compared with females. Gender, in contrast to sex, refers to a chosen sexual identity. Hazardous lifestyle choices (notably tobacco smoking) differ in prevalence between genders, aligned with disproportionate cancer risk. These add to underlying genetic predisposition and influences of sex steroid hormones. Together, these factors affect metabolism, immunity and inflammation, and ultimately the fidelity of the genetic code. To accurately understand how human defences against cancer erode, it is crucial to establish the influence of sex. Our Perspective highlights evidence from basic and translational research indicating that including genetic sex considerations in treatments for patients with cancer will improve outcomes. It is now time to adopt the challenge of overhauling cancer medicine based on optimized treatment strategies for females and males.

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Fig. 1: Non-reproductive cancers per 100,000 males and females.
Fig. 2: Gene expression from the sex chromosomes differs between males and females.
Fig. 3: Gene pathways are enriched on the X chromosome.
Fig. 4: Sex disparity in cancer therapy benefits in humans.
Fig. 5: Sex differences in cancer metabolic pathways and immune response contribute to cancer sex disparity.

References

  1. National Cancer Institute. SEER*Explorer. An interactive website for SEER cancer statistics https://seer.cancer.gov/explorer/ (2020).

  2. Cook, M. B., McGlynn, K. A., Devesa, S. S., Freedman, N. D. & Anderson, W. F. Sex disparities in cancer mortality and survival. Cancer Epidemiol. Biomarkers Prev. 20, 1629–1637 (2011).

    PubMed  PubMed Central  Google Scholar 

  3. Clayton, J. A. & Collins, F. S. NIH to balance sex in cell and animal studies. Nature 509, 282–283 (2014).

    PubMed  PubMed Central  Google Scholar 

  4. Mauvais-Jarvis, F. et al. Sex and gender: modifiers of health, disease, and medicine. Lancet 396, 565–582 (2020).

    PubMed  PubMed Central  Google Scholar 

  5. Lopes-Ramos, C. M. et al. Sex differences in gene expression and regulatory networks across 29 human tissues. Cell Rep. 31, 107795 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Oliva, M. et al. The impact of sex on gene expression across human tissues. Science 369, eaba3066 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Clocchiatti, A., Cora, E., Zhang, Y. & Dotto, G. P. Sexual dimorphism in cancer. Nat. Rev. Cancer 16, 330–339 (2016).

    CAS  PubMed  Google Scholar 

  8. Sun, T. et al. Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males. J. Clin. Invest. 124, 4123–4133 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Fane, M. & Weeraratna, A. T. How the ageing microenvironment influences tumour progression. Nat. Rev. Cancer 20, 89–106 (2020).

    CAS  PubMed  Google Scholar 

  10. Levine, A. J., Jenkins, N. A. & Copeland, N. G. The roles of initiating truncal mutations in human cancers: the order of mutations and tumor cell type matters. Cancer Cell 35, 10–15 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Podolskiy, D. I., Lobanov, A. V., Kryukov, G. V. & Gladyshev, V. N. Analysis of cancer genomes reveals basic features of human aging and its role in cancer development. Nat. Commun. 7, 12157 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Kim, J., Gosnell, J. E. & Roman, S. A. Geographic influences in the global rise of thyroid cancer. Nat. Rev. Endocrinol. 16, 17–29 (2020).

    PubMed  Google Scholar 

  13. Levine, A. J. p53: 800 million years of evolution and 40 years of discovery. Nat. Rev. Cancer 20, 471–480 (2020).

    CAS  PubMed  Google Scholar 

  14. Dominguez-Valentin, M. et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet. Med. 22, 15–25 (2020).

    CAS  PubMed  Google Scholar 

  15. Lortet-Tieulent, J. et al. State-level cancer mortality attributable to cigarette smoking in the United States. JAMA Intern. Med. 176, 1792–1798 (2016).

    PubMed  Google Scholar 

  16. Stone, T. W., McPherson, M. & Gail Darlington, L. Obesity and cancer: existing and new hypotheses for a causal connection. EBioMedicine 30, 14–28 (2018).

    PubMed  PubMed Central  Google Scholar 

  17. Barberio, A. M. et al. Central body fatness is a stronger predictor of cancer risk than overall body size. Nat. Commun. 10, 383 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Furman, D. et al. Chronic inflammation in the etiology of disease across the life span. Nat. Med. 25, 1822–1832 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Qian, S., Golubnitschaja, O. & Zhan, X. Chronic inflammation: key player and biomarker-set to predict and prevent cancer development and progression based on individualized patient profiles. EPMA J. 10, 365–381 (2019).

    PubMed  PubMed Central  Google Scholar 

  20. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).

    CAS  PubMed  Google Scholar 

  21. Yuan, Y. et al. Comprehensive characterization of molecular differences in cancer between male and female patients. Cancer Cell 29, 711–722 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Aunan, J. R., Cho, W. C. & Soreide, K. The biology of aging and cancer: a brief overview of shared and divergent molecular hallmarks. Aging Dis. 8, 628–642 (2017).

    PubMed  PubMed Central  Google Scholar 

  23. Falzone, L., Salomone, S. & Libra, M. Evolution of cancer pharmacological treatments at the turn of the third millennium. Front. Pharmacol. 9, 1300 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Barros de Andrade, E. S. L. et al. Kinetics of Xist-induced gene silencing can be predicted from combinations of epigenetic and genomic features. Genome Res. 29, 1087–1099 (2019).

    Google Scholar 

  25. Delbridge, A. R. D. et al. Loss of p53 causes stochastic aberrant X-chromosome inactivation and female-specific neural tube defects. Cell Rep. 27, 442–454.e5 (2019).

    CAS  PubMed  Google Scholar 

  26. Aken, B. L. et al. The Ensembl gene annotation system. Database https://doi.org/10.1093/database/baw093 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tukiainen, T. et al. Landscape of X chromosome inactivation across human tissues. Nature 550, 244–248 (2017).

    PubMed  PubMed Central  Google Scholar 

  28. Peeters, S. B., Cotton, A. M. & Brown, C. J. Variable escape from X-chromosome inactivation: identifying factors that tip the scales towards expression. Bioessays 36, 746–756 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Migeon, B. R. X-linked diseases: susceptible females. Genet. Med. 22, 1156–1174 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Di Palo, A. et al. What microRNAs could tell us about the human X chromosome. Cell Mol Life Sci. 77, 4069–4080 (2020).

    PubMed  PubMed Central  Google Scholar 

  31. Care, A. et al. Sex disparity in cancer: roles of microRNAs and related functional players. Cell Death Differ. 25, 477–485 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Chamekh, M. & Casimir, G. Editorial: sexual dimorphism of the immune inflammatory response in infectious and non-infectious diseases. Front. Immunol. 10, 107 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Spolarics, Z., Pena, G., Qin, Y., Donnelly, R. J. & Livingston, D. H. Inherent X-linked genetic variability and cellular mosaicism unique to females contribute to sex-related differences in the innate immune response. Front. Immunol. 8, 1455 (2017).

    PubMed  PubMed Central  Google Scholar 

  34. Chaligne, R. & Heard, E. X-chromosome inactivation in development and cancer. FEBS Lett. 588, 2514–2522 (2014).

    CAS  PubMed  Google Scholar 

  35. Wang, D. et al. Abnormal X chromosome inactivation and tumor development. Cell Mol. Life Sci. 77, 2949–2958 (2020).

    CAS  PubMed  Google Scholar 

  36. van Kempen, L. C. et al. The protein phosphatase 2A regulatory subunit PR70 is a gonosomal melanoma tumor suppressor gene. Sci. Transl Med. 8, 369ra177 (2016).

    PubMed  Google Scholar 

  37. Andricovich, J. et al. Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors. Cancer Cell 33, 512–526.e8 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Dunford, A. et al. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nat. Genet. 49, 10–16 (2017).

    CAS  PubMed  Google Scholar 

  39. Yildirim, E. et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell 152, 727–742 (2013).

    CAS  PubMed  Google Scholar 

  40. Yang, L., Yildirim, E., Kirby, J. E., Press, W. & Lee, J. T. Widespread organ tolerance to Xist loss and X reactivation except under chronic stress in the gut. Proc. Natl Acad. Sci. USA 117, 4262–4272 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Ren, W. et al. Disruption of ATRX–RNA interactions uncovers roles in ATRX localization and PRC2 function. Nat. Commun. 11, 2219 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Haupt, S. et al. Identification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network. Nat. Commun. 10, 5385 (2019).

    PubMed  PubMed Central  Google Scholar 

  43. Sun, T., Plutynski, A., Ward, S. & Rubin, J. B. An integrative view on sex differences in brain tumors. Cell Mol. Life Sci. 72, 3323–3342 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Emran, A. A. 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 12, 2082 (2020).

    PubMed Central  Google Scholar 

  45. George, S. L. et al. Therapeutic vulnerabilities in the DNA damage response for the treatment of ATRX mutant neuroblastoma. EBioMedicine 59, 102971 (2020).

    PubMed  PubMed Central  Google Scholar 

  46. Ler, L. D. et al. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Sci. Transl Med. 9, eaai8312 (2017).

    PubMed  Google Scholar 

  47. Meester, I. et al. SeXY chromosomes and the immune system: reflections after a comparative study. Biol. Sex. Differ. 11, 3 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Caceres, A., Jene, A., Esko, T., Perez-Jurado, L. A. & Gonzalez, J. R. Extreme down-regulation of chromosome Y and cancer risk in men. J. Natl Cancer Inst. 112, 913–920 (2020).

    PubMed  PubMed Central  Google Scholar 

  49. Hollows, R. et al. Association between loss of Y chromosome and poor prognosis in male head and neck squamous cell carcinoma. Head Neck 41, 993–1006 (2019).

    PubMed  Google Scholar 

  50. Loftfield, E. et al. Mosaic Y loss is moderately associated with solid tumor risk. Cancer Res. 79, 461–466 (2019).

    CAS  PubMed  Google Scholar 

  51. Brown, D. W., Machiela, M. J. & Why, Y. Down-regulation of chromosome Y genes potentially contributes to elevated cancer risk. J. Natl Cancer Inst. 112, 871–872 (2020).

    PubMed  PubMed Central  Google Scholar 

  52. Walport, L. J. et al. Human UTY(KDM6C) is a male-specific N-methyl lysyl demethylase. J. Biol. Chem. 289, 18302–18313 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Gozdecka, M. et al. UTX-mediated enhancer and chromatin remodeling suppresses myeloid leukemogenesis through noncatalytic inverse regulation of ETS and GATA programs. Nat. Genet. 50, 883–894 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Sarne, V. et al. Promoter methylation of selected genes in non-small-cell lung cancer patients and cell lines. Int. J. Mol. Sci. 21, 4595 (2020).

    CAS  PubMed Central  Google Scholar 

  55. Iranzo, J., Martincorena, I. & Koonin, E. V. Cancer-mutation network and the number and specificity of driver mutations. Proc. Natl Acad. Sci. USA 115, E6010–E6019 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Li, C. H., Haider, S., Shiah, Y. J., Thai, K. & Boutros, P. C. Sex differences in cancer driver genes and biomarkers. Cancer Res. 78, 5527–5537 (2018).

    CAS  PubMed  Google Scholar 

  57. Li, C. H. et al. Sex differences in oncogenic mutational processes. Nat. Commun. 11, 4330 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Lopes-Ramos, C. M. et al. Gene regulatory network analysis identifies sex-linked differences in colon cancer drug metabolism. Cancer Res. 78, 5538–5547 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Jung, Y. S. & Park, J. I. Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Exp. Mol. Med. 52, 183–191 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Kobrinski, D. A., Yang, H. & Kittaneh, M. BAP1: role in carcinogenesis and clinical implications. Transl Lung Cancer Res. 9, S60–S66 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gillette, M. A. et al. Proteogenomic characterization reveals therapeutic vulnerabilities in lung adenocarcinoma. Cell 182, 200–225.e35 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Tsuji, T. et al. YAP1 mediates survival of ALK-rearranged lung cancer cells treated with alectinib via pro-apoptotic protein regulation. Nat. Commun. 11, 74 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Pinto, J. A. et al. Gender and outcomes in non-small cell lung cancer: an old prognostic variable comes back for targeted therapy and immunotherapy? ESMO Open 3, e000344 (2018).

    PubMed  PubMed Central  Google Scholar 

  65. Soussi, T. & Wiman, K. G. TP53: an oncogene in disguise. Cell Death Differ. 22, 1239–1249 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Jia, P. & Zhao, Z. Characterization of tumor-suppressor gene inactivation events in 33 cancer types. Cell Rep. 26, 496–506.e3 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Levine, A. J. Targeting therapies for the p53 protein in cancer treatments. Annu. Rev. Cancer Biol. 3, 21–34 (2019).

    Google Scholar 

  68. Donehower, L. A. et al. Integrated analysis of TP53 gene and pathway alterations in The Cancer Genome Atlas. Cell Rep. 28, 1370–1384.e5 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Williams, A. B. & Schumacher, B. p53 in the DNA-damage–repair process. Cold Spring Harb. Perspect. Med. 6, a026070 (2016).

    PubMed  PubMed Central  Google Scholar 

  70. Cancer Genome Atlas Research Network. et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45, 1113–1120 (2013).

    PubMed Central  Google Scholar 

  71. Olive, K. P. et al. Mutant p53 gain of function in two mouse models of Li–Fraumeni syndrome. Cell 119, 847–860 (2004).

    CAS  PubMed  Google Scholar 

  72. Zore, T., Palafox, M. & Reue, K. Sex differences in obesity, lipid metabolism, and inflammation — a role for the sex chromosomes? Mol. Metab. 15, 35–44 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Clegg, D. J. & Mauvais-Jarvis, F. An integrated view of sex differences in metabolic physiology and disease. Mol. Metab. 15, 1–2 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Keramida, G. & Peters, A. M. Fasting hepatic glucose uptake is higher in men than women. Physiol. Rep. 5, e13174 (2017).

    PubMed  PubMed Central  Google Scholar 

  76. Han, H. et al. Blood glucose concentration and risk of liver cancer: systematic review and meta-analysis of prospective studies. Oncotarget 8, 50164–50173 (2017).

    PubMed  PubMed Central  Google Scholar 

  77. Vulcan, A., Manjer, J. & Ohlsson, B. High blood glucose levels are associated with higher risk of colon cancer in men: a cohort study. BMC Cancer 17, 842 (2017).

    PubMed  PubMed Central  Google Scholar 

  78. Wang, J. et al. Glucose transporter GLUT1 expression and clinical outcome in solid tumors: a systematic review and meta-analysis. Oncotarget 8, 16875–16886 (2017).

    PubMed  PubMed Central  Google Scholar 

  79. Schwartzenberg-Bar-Yoseph, F., Armoni, M. & Karnieli, E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res. 64, 2627–2633 (2004).

    CAS  PubMed  Google Scholar 

  80. Tan, Z., Yang, C., Zhang, X., Zheng, P. & Shen, W. Expression of glucose transporter 1 and prognosis in non-small cell lung cancer: a pooled analysis of 1665 patients. Oncotarget 8, 60954–60961 (2017).

    PubMed  PubMed Central  Google Scholar 

  81. Zhang, C. et al. Tumour-associated mutant p53 drives the Warburg effect. Nat. Commun. 4, 2935 (2013).

    PubMed  Google Scholar 

  82. Rodriguez, O. C. et al. Dietary downregulation of mutant p53 levels via glucose restriction: mechanisms and implications for tumor therapy. Cell Cycle 11, 4436–4446 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Labuschagne, C. F., Zani, F. & Vousden, K. H. Control of metabolism by p53—cancer and beyond. Biochim. Biophys. Acta Rev. Cancer 1870, 32–42 (2018).

    CAS  PubMed  Google Scholar 

  84. Jiang, P. et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase. Nat. Cell Biol. 13, 310–316 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang, Y., Xiao, J., Zhao, Y., Du, S. & Du, J. Effect of metformin on the mortality of colorectal cancer patients with T2DM: meta-analysis of sex differences. Int. J. Colorectal Dis. 35, 827–835 (2020).

    PubMed  Google Scholar 

  86. Mele, L. et al. A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo. Cell Death Dis. 9, 572 (2018).

    PubMed  PubMed Central  Google Scholar 

  87. Li, W. et al. Effects of hyperglycemia on the progression of tumor diseases. J. Exp. Clin. Cancer Res. 38, 327 (2019).

    PubMed  PubMed Central  Google Scholar 

  88. Mueller, F. et al. Gender-specific elimination of continuous-infusional 5-fluorouracil in patients with gastrointestinal malignancies: results from a prospective population pharmacokinetic study. Cancer Chemother. Pharmacol. 71, 361–370 (2013).

    CAS  PubMed  Google Scholar 

  89. Hu, X., Chao, M. & Wu, H. Central role of lactate and proton in cancer cell resistance to glucose deprivation and its clinical translation. Signal. Transduct. Target. Ther. 2, 16047 (2017).

    PubMed  PubMed Central  Google Scholar 

  90. de la Cruz-Lopez, K. G., Castro-Munoz, L. J., Reyes-Hernandez, D. O., Garcia-Carranca, A. & Manzo-Merino, J. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front. Oncol. 9, 1143 (2019).

    PubMed  PubMed Central  Google Scholar 

  91. Ippolito, J. E., Yim, A. K., Luo, J., Chinnaiyan, P. & Rubin, J. B. Sexual dimorphism in glioma glycolysis underlies sex differences in survival. JCI Insight 2, e92142 (2017).

    PubMed Central  Google Scholar 

  92. Cao, J., Ng, M. & Felmlee, M. A. Sex hormones regulate rat hepatic monocarboxylate transporter expression and membrane trafficking. J. Pharm. Pharm Sci. 20, 435–444 (2017).

    CAS  PubMed  Google Scholar 

  93. Pinheiro, C. et al. The metabolic microenvironment of melanomas: prognostic value of MCT1 and MCT4. Cell Cycle 15, 1462–1470 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Renner, K. et al. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep. 29, 135–150.e9 (2019).

    CAS  PubMed  Google Scholar 

  95. Beloueche-Babari, M. et al. Monocarboxylate transporter 1 blockade with AZD3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration. Br. J. Cancer 122, 895–903 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Hendriks, S. H. et al. Association between body mass index and obesity-related cancer risk in men and women with type 2 diabetes in primary care in the Netherlands: a cohort study (ZODIAC-56). BMJ Open 8, e018859 (2018).

    PubMed  PubMed Central  Google Scholar 

  97. O’Flanagan, C. H., Smith, L. A., McDonell, S. B. & Hursting, S. D. When less may be more: calorie restriction and response to cancer therapy. BMC Med. 15, 106 (2017).

    PubMed  PubMed Central  Google Scholar 

  98. Karczewski, J. et al. Obesity and the risk of gastrointestinal cancers. Dig. Dis. Sci. 64, 2740–2749 (2019).

    PubMed  PubMed Central  Google Scholar 

  99. Mancuso, P. The role of adipokines in chronic inflammation. Immunotargets Ther. 5, 47–56 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Wlodarczyk, M. & Nowicka, G. Obesity, DNA damage, and development of obesity-related diseases. Int. J. Mol. Sci. 20, 1146 (2019).

    CAS  PubMed Central  Google Scholar 

  101. Kern, L. et al. Obesity-induced TNFα and IL-6 signaling: the missing link between obesity and inflammation-driven liver and colorectal cancers. Cancers 11, 24 (2018).

    PubMed Central  Google Scholar 

  102. Chia, V. M. et al. Leptin concentrations, leptin receptor polymorphisms, and colorectal adenoma risk. Cancer Epidemiol. Biomarkers Prev. 16, 2697–2703 (2007).

    CAS  PubMed  Google Scholar 

  103. Starling, S. New therapeutic promise for leptin. Nat. Rev. Endocrinol. 15, 625 (2019).

    CAS  PubMed  Google Scholar 

  104. Orthofer, M. et al. Identification of ALK in thinness. Cell 181, 1246–1262.e22 (2020).

    CAS  PubMed  Google Scholar 

  105. Roberts, D. L., Dive, C. & Renehan, A. G. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu. Rev. Med. 61, 301–316 (2010).

    CAS  PubMed  Google Scholar 

  106. Manieri, E. et al. Adiponectin accounts for gender differences in hepatocellular carcinoma incidence. J. Exp. Med. 216, 1108–1119 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Di Zazzo, E. et al. Adiponectin as link factor between adipose tissue and cancer. Int. J. Mol. Sci. 20, 839 (2019).

    CAS  PubMed Central  Google Scholar 

  108. He, L. & Wondisford, F. E. Metformin action: concentrations matter. Cell Metab. 21, 159–162 (2015).

    CAS  PubMed  Google Scholar 

  109. Qin, Y. et al. An obesity-associated gut microbiome reprograms the intestinal epigenome and leads to altered colonic gene expression. Genome Biol. 19, 7 (2018).

    PubMed  PubMed Central  Google Scholar 

  110. Holloway, M. G., Miles, G. D., Dombkowski, A. A. & Waxman, D. J. Liver-specific hepatocyte nuclear factor-4α deficiency: greater impact on gene expression in male than in female mouse liver. Mol. Endocrinol. 22, 1274–1286 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Baars, A. et al. Sex differences in lipid metabolism are affected by presence of the gut microbiota. Sci. Rep. 8, 13426 (2018).

    PubMed  PubMed Central  Google Scholar 

  112. Almeida, A. et al. A new genomic blueprint of the human gut microbiota. Nature 568, 499–504 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Bana, B. & Cabreiro, F. The microbiome and aging. Annu. Rev. Genet. 53, 239–261 (2019).

    CAS  PubMed  Google Scholar 

  114. Vemuri, R. et al. The microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility. Semin. Immunopathol. 41, 265–275 (2019).

    PubMed  Google Scholar 

  115. Ma, Z. S. & Li, W. How and why men and women differ in their microbiomes: medical ecology and network analyses of the microgenderome. Adv. Sci. 6, 1902054 (2019).

    CAS  Google Scholar 

  116. Kim, Y. S., Unno, T., Kim, B. Y. & Park, M. S. Sex differences in gut microbiota. World J. Mens Health 38, 48–60 (2020).

    PubMed  Google Scholar 

  117. Santos-Marcos, J. A. et al. Sex differences in the gut microbiota as potential determinants of gender predisposition to disease. Mol. Nutr. Food Res. 63, e1800870 (2019).

    PubMed  Google Scholar 

  118. de la Cuesta-Zuluaga, J. et al. Age- and sex-dependent patterns of gut microbial diversity in human adults. mSystems 4, e00261-19 (2019).

    PubMed  PubMed Central  Google Scholar 

  119. Weger, B. D. et al. The mouse microbiome is required for sex-specific diurnal rhythms of gene expression and metabolism. Cell Metab. 29, 362–382.e8 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Panda, S. The arrival of circadian medicine. Nat. Rev. Endocrinol. 15, 67–69 (2019).

    PubMed  Google Scholar 

  121. Ma, W. et al. Gut microbiota shapes the efficiency of cancer therapy. Front. Microbiol. 10, 1050 (2019).

    PubMed  PubMed Central  Google Scholar 

  122. Cai, Y. et al. Sex differences in colon cancer metabolism reveal a novel subphenotype. Sci. Rep. 10, 4905 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Krall, A. S., Xu, S., Graeber, T. G., Braas, D. & Christofk, H. R. Asparagine promotes cancer cell proliferation through use as an amino acid exchange factor. Nat. Commun. 7, 11457 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Schmuck, R. et al. Gender comparison of clinical, histopathological, therapeutic and outcome factors in 185,967 colon cancer patients. Langenbecks Arch. Surg. 405, 71–80 (2020).

    PubMed  PubMed Central  Google Scholar 

  125. Yang, Y. et al. Gender differences in colorectal cancer survival: a meta-analysis. Int. J. Cancer 141, 1942–1949 (2017).

    CAS  PubMed  Google Scholar 

  126. Gubbels Bupp, M. R., Potluri, T., Fink, A. L. & Klein, S. L. The confluence of sex hormones and aging on immunity. Front. Immunol. 9, 1269 (2018).

    PubMed  PubMed Central  Google Scholar 

  127. Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).

    CAS  PubMed  Google Scholar 

  128. Scully, E. P., Haverfield, J., Ursin, R. L., Tannenbaum, C. & Klein, S. L. Considering how biological sex impacts immune responses and COVID-19 outcomes. Nat. Rev. Immunol. 20, 442–447 (2020).

    CAS  PubMed  Google Scholar 

  129. Schurz, H. et al. The X chromosome and sex-specific effects in infectious disease susceptibility. Hum. Genomics 13, 2 (2019).

    PubMed  PubMed Central  Google Scholar 

  130. Taniguchi, K. & Karin, M. NF-κB, inflammation, immunity and cancer: coming of age. Nat. Rev. Immunol. 18, 309–324 (2018).

    CAS  PubMed  Google Scholar 

  131. Marquez, E. J. et al. Sexual-dimorphism in human immune system aging. Nat. Commun. 11, 751 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Ley, K. M1 means kill; M2 means heal. J. Immunol. 199, 2191–2193 (2017).

    CAS  PubMed  Google Scholar 

  133. Lin, Y., Xu, J. & Lan, H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J. Hematol. Oncol. 12, 76 (2019).

    PubMed  PubMed Central  Google Scholar 

  134. Brown, J. M., Recht, L. & Strober, S. The promise of targeting macrophages in cancer therapy. Clin. Cancer Res. 23, 3241–3250 (2017).

    PubMed  PubMed Central  Google Scholar 

  135. Li, L. et al. TLR8-mediated metabolic control of human Treg function: a mechanistic target for cancer immunotherapy. Cell Metab. 29, 103–123.e5 (2019).

    CAS  PubMed  Google Scholar 

  136. Ono, M. Control of regulatory T-cell differentiation and function by T-cell receptor signalling and Foxp3 transcription factor complexes. Immunology 160, 24–37 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Vasanthakumar, A. et al. Sex-specific adipose tissue imprinting of regulatory T cells. Nature 579, 581–585 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Huang, L., Xu, H. & Peng, G. TLR-mediated metabolic reprogramming in the tumor microenvironment: potential novel strategies for cancer immunotherapy. Cell Mol. Immunol. 15, 428–437 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. de Martel, C., Georges, D., Bray, F., Ferlay, J. & Clifford, G. M. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob. Health 8, e180–e190 (2020).

    PubMed  Google Scholar 

  140. Guven-Maiorov, E., Tsai, C. J. & Nussinov, R. Oncoviruses can drive cancer by rewiring signaling pathways through interface mimicry. Front. Oncol. 9, 1236 (2019).

    PubMed  PubMed Central  Google Scholar 

  141. Te Marvelde, L. et al. Epidemiology of sepsis in cancer patients in Victoria, Australia: a population-based study using linked data. Aust. N. Z. J. Public Health 44, 53–58 (2020).

    Google Scholar 

  142. Wisnivesky, J. P. & Halm, E. A. Sex differences in lung cancer survival: do tumors behave differently in elderly women? J. Clin. Oncol. 25, 1705–1712 (2007).

    PubMed  Google Scholar 

  143. Morgese, F. et al. Gender differences and outcomes in melanoma patients. Oncol. Ther. 8, 103–114 (2020).

    PubMed  PubMed Central  Google Scholar 

  144. Roers, A., Hiller, B. & Hornung, V. Recognition of endogenous nucleic acids by the innate immune system. Immunity 44, 739–754 (2016).

    CAS  PubMed  Google Scholar 

  145. Souyris, M. et al. TLR7 escapes X chromosome inactivation in immune cells. Sci. Immunol. 3, eaap8855 (2018).

    PubMed  Google Scholar 

  146. Roach, J. C. et al. The evolution of vertebrate Toll-like receptors. Proc. Natl Acad. Sci. USA 102, 9577–9582 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat. Immunol. 11, 373–384 (2010).

    CAS  PubMed  Google Scholar 

  148. Vierbuchen, T., Stein, K. & Heine, H. RNA is taking its toll: impact of RNA-specific Toll-like receptors on health and disease. Allergy 74, 223–235 (2019).

    PubMed  Google Scholar 

  149. Zhang, Z. et al. Structural analyses of Toll-like receptor 7 reveal detailed RNA sequence specificity and recognition mechanism of agonistic ligands. Cell Rep. 25, 3371–3381.e5 (2018).

    CAS  PubMed  Google Scholar 

  150. Mui, U. N., Haley, C. T. & Tyring, S. K. Viral oncology: molecular biology and pathogenesis. J. Clin. Med. 6, 111 (2017).

    PubMed Central  Google Scholar 

  151. Ivashkiv, L. B. & Donlin, L. T. Regulation of type I interferon responses. Nat. Rev. Immunol. 14, 36–49 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Berghofer, B. et al. TLR7 ligands induce higher IFN-α production in females. J. Immunol. 177, 2088–2096 (2006).

    PubMed  Google Scholar 

  153. Oshiumi, H., Sakai, K., Matsumoto, M. & Seya, T. DEAD/H BOX 3 (DDX3) helicase binds the RIG-I adaptor IPS-1 to up-regulate IFN-β-inducing potential. Eur. J. Immunol. 40, 940–948 (2010).

    CAS  PubMed  Google Scholar 

  154. Phung, B. et al. The X-linked DDX3X RNA helicase dictates translation reprogramming and metastasis in melanoma. Cell Rep. 27, 3573–3586.e7 (2019).

    CAS  PubMed  Google Scholar 

  155. Libert, C., Dejager, L. & Pinheiro, I. The X chromosome in immune functions: when a chromosome makes the difference. Nat. Rev. Immunol. 10, 594–604 (2010).

    CAS  PubMed  Google Scholar 

  156. Klein, S. L. & Morgan, R. The impact of sex and gender on immunotherapy outcomes. Biol. Sex. Differ. 11, 24 (2020).

    PubMed  PubMed Central  Google Scholar 

  157. Golden, L. C. et al. Parent-of-origin differences in DNA methylation of X chromosome genes in T lymphocytes. Proc Natl Acad Sci USA 116, 26779–26787 (2019).

    CAS  PubMed Central  Google Scholar 

  158. Menendez, D. et al. p53-responsive TLR8 SNP enhances human innate immune response to respiratory syncytial virus. J. Clin. Invest. 129, 4875–4884 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Wang, P. F., Song, H. F., Zhang, Q. & Yan, C. X. Pan-cancer immunogenomic analyses reveal sex disparity in the efficacy of cancer immunotherapy. Eur. J. Cancer 126, 136–138 (2020).

    PubMed  Google Scholar 

  160. Freudenstein, D. et al. TP53 status, patient sex, and the immune response as determinants of lung cancer patient survival. Cancers 12, 1535 (2020).

    CAS  PubMed Central  Google Scholar 

  161. Kruger, S. et al. Advances in cancer immunotherapy 2019 — latest trends. J. Exp. Clin. Cancer Res. 38, 268 (2019).

    PubMed  PubMed Central  Google Scholar 

  162. Castro, A. et al. Strength of immune selection in tumors varies with sex and age. Nat. Commun. 11, 4128 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Ye, Y. et al. Sex-associated molecular differences for cancer immunotherapy. Nat. Commun. 11, 1779 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Badami, S. et al. Clinical and molecular characteristics associated with survival in advanced melanoma treated with checkpoint inhibitors. J. Oncol. 2018, 6279871 (2018).

    PubMed  PubMed Central  Google Scholar 

  165. Conforti, F. et al. Sex-based heterogeneity in response to lung cancer immunotherapy: a systematic review and meta-analysis. J. Natl Cancer Inst. 111, 772–781 (2019).

    PubMed  PubMed Central  Google Scholar 

  166. Wallis, C. J. D. et al. Association of patient sex with efficacy of immune checkpoint inhibitors and overall survival in advanced cancers: a systematic review and meta-analysis. JAMA Oncol. 5, 529–536 (2019).

    PubMed  PubMed Central  Google Scholar 

  167. Murthy, V. H., Krumholz, H. M. & Gross, C. P. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA 291, 2720–2726 (2004).

    CAS  PubMed  Google Scholar 

  168. Okyar, A. et al. Sex-, feeding-, and circadian time-dependency of P-glycoprotein expression and activity — implications for mechanistic pharmacokinetics modeling. Sci. Rep. 9, 10505 (2019).

    PubMed  PubMed Central  Google Scholar 

  169. Gopalakrishnan, V., Helmink, B. A., Spencer, C. N., Reuben, A. & Wargo, J. A. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 33, 570–580 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Gong, J. et al. The gut microbiome and response to immune checkpoint inhibitors: preclinical and clinical strategies. Clin. Transl Med. 8, 9 (2019).

    PubMed  PubMed Central  Google Scholar 

  171. Schroder, W. et al. Gender differences in antibiotic prescribing in the community: a systematic review and meta-analysis. J. Antimicrob. Chemother. 71, 1800–1806 (2016).

    PubMed  Google Scholar 

  172. Pinato, D. J. et al. Antibiotic therapy and outcome from immune-checkpoint inhibitors. J. Immunother. Cancer 7, 287 (2019).

    PubMed  PubMed Central  Google Scholar 

  173. Tibbs, T. N., Lopez, L. R. & Arthur, J. C. The influence of the microbiota on immune development, chronic inflammation, and cancer in the context of aging. Microb. Cell 6, 324–334 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. De Courcy, L., Bezak, E. & Marcu, L. G. Gender-dependent radiotherapy: the next step in personalised medicine? Crit. Rev. Oncol. Hematol. 147, 102881 (2020).

    PubMed  Google Scholar 

  175. Wagner, A. D. et al. Gender medicine and oncology: report and consensus of an ESMO workshop. Ann. Oncol. 30, 1914–1924 (2019).

    CAS  PubMed  Google Scholar 

  176. Davidson, M. et al. Influence of sex on chemotherapy efficacy and toxicity in oesophagogastric cancer: a pooled analysis of four randomised trials. Eur. J. Cancer 121, 40–47 (2019).

    CAS  PubMed  Google Scholar 

  177. Wheatley-Price, P. et al. The influence of sex on efficacy, adverse events, quality of life, and delivery of treatment in National Cancer Institute of Canada Clinical Trials Group non-small cell lung cancer chemotherapy trials. J. Thorac. Oncol. 5, 640–648 (2010).

    PubMed  Google Scholar 

  178. Yang, W. et al. Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data. Sci. Transl Med. 11, eaao5253 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Ozdemir, B. C., Csajka, C., Dotto, G. P. & Wagner, A. D. Sex differences in efficacy and toxicity of systemic treatments: an undervalued issue in the era of precision oncology. J. Clin. Oncol. 36, 2680–2683 (2018).

    CAS  PubMed  Google Scholar 

  180. Kim, H. I., Lim, H. & Moon, A. Sex differences in cancer: epidemiology, genetics and therapy. Biomol. Ther. 26, 335–342 (2018).

    CAS  Google Scholar 

  181. Yang, L. et al. Sex differences in the expression of drug-metabolizing and transporter genes in human liver. J. Drug. Metab. Toxicol. 3, 1000119 (2012).

    PubMed  PubMed Central  Google Scholar 

  182. Joseph, S. et al. Expression of drug transporters in human kidney: impact of sex, age, and ethnicity. Biol. Sex. Differ. 6, 4 (2015).

    PubMed  PubMed Central  Google Scholar 

  183. Bayik, D. et al. Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner. Cancer Discov. 10, 1210–1225 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Wagner, A. D. Sex differences in cancer chemotherapy effects, and why we need to reconsider BSA-based dosing of chemotherapy. ESMO Open 5, e000770 (2020).

    PubMed  PubMed Central  Google Scholar 

  185. Greenberg, M. V. C. & Bourc’his, D. The diverse roles of DNA methylation in mammalian development and disease. Nat. Rev. Mol. Cell Biol. 20, 590–607 (2019).

    CAS  PubMed  Google Scholar 

  186. Kolberg, L., Raudvere, U., Kuzmin, I., Vilo, J. & Peterson, H. gprofiler2 — an R package for gene list functional enrichment analysis and namespace conversion toolset g:profiler. F1000Res https://doi.org/10.12688/f1000research.24956.2 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Goodwin, M. L. et al. Lactate and cancer: a “lactatic” perspective on spinal tumor metabolism (part 1). Ann. Transl Med. 7, 220 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Sikora, M. J., Johnson, M. D., Lee, A. V. & Oesterreich, S. Endocrine response phenotypes are altered by charcoal-stripped serum variability. Endocrinology 157, 3760–3766 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. De Souza Santos, R., Frank, A. P., Palmer, B. F. & Clegg, D. J. Sex and media: considerations for cell culture studies. ALTEX 35, 435–440 (2018).

    PubMed  Google Scholar 

  190. Bittner, G. D., Yang, C. Z. & Stoner, M. A. Estrogenic chemicals often leach from BPA-free plastic products that are replacements for BPA-containing polycarbonate products. Environ. Health 13, 41 (2014).

    PubMed  PubMed Central  Google Scholar 

  191. Austad, S. N. & Fischer, K. E. Sex differences in lifespan. Cell Metab. 23, 1022–1033 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Menendez, D. et al. The Toll-like receptor gene family is integrated into human DNA damage and p53 networks. PLoS Genet. 7, e1001360 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Norheim, F. et al. Gene-by-sex interactions in mitochondrial functions and cardio-metabolic traits. Cell Metab. 29, 932–949.e4 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. [No authors listed] Accounting for sex in the genome. Nat. Med. 23, 1243 (2017).

  195. Anderson, K., Canadas-Garre, M., Chambers, R., Maxwell, A. P. & McKnight, A. J. The challenges of chromosome Y analysis and the implications for chronic kidney disease. Front. Genet. 10, 781 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Duncan, C. G. et al. Dosage compensation and DNA methylation landscape of the X chromosome in mouse liver. Sci. Rep. 8, 10138 (2018).

    PubMed  PubMed Central  Google Scholar 

  197. Garieri, M. et al. Extensive cellular heterogeneity of X inactivation revealed by single-cell allele-specific expression in human fibroblasts. Proc. Natl Acad. Sci. USA 115, 13015–13020 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Cotton, A. M. et al. Landscape of DNA methylation on the X chromosome reflects CpG density, functional chromatin state and X-chromosome inactivation. Hum. Mol. Genet. 24, 1528–1539 (2015).

    CAS  PubMed  Google Scholar 

  199. Olney, K. C., Brotman, S. M., Andrews, J. P., Valverde-Vesling, V. A. & Wilson, M. A. Reference genome and transcriptome informed by the sex chromosome complement of the sample increase ability to detect sex differences in gene expression from RNA-seq data. Biol. Sex. Differ. 11, 42 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Rubin, J. B. et al. Sex differences in cancer mechanisms. Biol. Sex. Differ. 11, 17 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank C. Litchfield for undertaking the analyses for Figs 1 and 3 and also for Supplementary Tables 1 and 2. The Haupt laboratory acknowledges funding from the Sister Institution Network Fund (SINF), MD Anderson–Peter MacCallum Cancer Centre and Peter MacCallum Foundation. S.L.K. was supported in part by the National Institutes of Health (NIH) Specialized Center of Research Excellence (U54AG062333) and NIH Center of Excellence in Influenza Research and Surveillance (HHSN272201400007C). Work in the Rubin laboratory is supported by the NIH (R01 CA174737 to J.B.R.), The Children’s Discovery Institute of Washington University, Prayers for Maria Foundation, St Louis Children’s Hospital Foundation, Barnes-Jewish Hospital Foundation, Barnard Research Funds, Joshua’s Great Things Foundation and The American Brain Tumor Association.

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Authors and Affiliations

  1. Tumor Suppression and Cancer Sex Disparity Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

    Sue Haupt, Franco Caramia & Ygal Haupt

  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia

    Sue Haupt, Franco Caramia & Ygal Haupt

  3. W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Sabra L. Klein

  4. Department of Pediatrics and Neuroscience, Washington University School of Medicine, St Louis, MO, USA

    Joshua B. Rubin

  5. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Victoria, Australia

    Ygal Haupt

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All authors wrote the article. S.H. and F.C. researched data for the article. S.H. and Y.H. contributed substantially to discussion of content. S.H., F.C., S.L.K., J.B.R. and Y.H. reviewed and/or edited the manuscript before submission.

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Supplementary information

Glossary

Bi-allelic gene expression

Expression from the two chromosomal copies (alleles) of a gene, as opposed to expression from one chromosomal copy (mono-allelic expression).

COMPASS-like complex

(Complex of proteins associated with Set1). A conserved complex of core proteins that function with specific methyltransferases to catalyse methylation of histone H3 at K4 or demethylation, for example in the context of KDM6A, controlling transcriptional regulation.

Immune checkpoint

A receptor–ligand molecule whose normal function is to regulate the magnitude and duration of immune responses that can be exploited by cancers to prevent anticancer T cell responses. Checkpoint inhibitors block these interactions, thereby restoring the ability of T cells to attack cancer cells.

Mosaic expression

Expression, in females, of different copies of the X chromosome in different cells. This results in a mosaic pattern of expression of different X-linked genes or forms of X-linked genes within a tissue of an individual.

M1 and M2

Two classes of macrophages with different functions. M1 macrophages kill cancer cells and infectious agents, whereas M2 macrophages heal wounds. In many cancer types, M1 gene expression signatures correspond to a favourable outcome, whereas M2 signatures align with poor outcomes.

Pattern recognition receptor

A protein that engages signatures of pathogens or damages and primes the innate immune response. In the instance of Toll-like receptor 7 (TLR7) and TLR8 these proteins function as receptors for single-stranded RNA molecules, as relevant to triggering innate immunity against viral infections.

Skewing

An extreme form of mosaicism in which either the maternal or paternal X chromosome is preferentially active.

Sporadic cancers

Cancers that arise spontaneously from genomic damage that is acquired, in contrast to familial cancers associated with inherited genetic alterations that are predisposing.

Truncal mutations

Mutations that occur in the cell lineage that gave rise to the clonal tumour. These are also called clonal mutations.

X pseudoautosomal regions

The short regions at the end of the X and Y chromosomes that share homology. These regions are important for the pairing and segregation of the X and Y chromosomes during meiosis in males. The behaviour of these regions is similar to that of autosomes.

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Haupt, S., Caramia, F., Klein, S.L. et al. Sex disparities matter in cancer development and therapy. Nat Rev Cancer 21, 393–407 (2021). https://doi.org/10.1038/s41568-021-00348-y

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