Why study sex as a biological variable?
Men have higher incidence by 1.4 times compared to women across all cancers (1). Bladder cancer (BC), specifically, ranks 1st in this comparison—men being 3-5 times more susceptible to the disease than females.
Initially, many attributed these sex disparities to extrinsic factors such as environmental risks and behavioral patterns (e.g workplace chemical hazards, tobacco smoking, etc.). In 1990, however, Hartge et al found that sex differences remained even after correcting for these extrinsic factors, strongly suggesting that intrinsic biological factors play an important but previously underappreciated role (2). The implications of such an observation is this—if fundamental biological variables such as sex can alter disease risk, biological changes in an individual (e.g. aging, sex hormone therapy, etc.) could also change an individual's risk to diseases such as cancer.
Historically, sexual differentiation in mammals was thought to occur after the development of the sex gonads and ensuing sex hormones signaling. This understanding of sexual differentiation was incomplete and resulted in an inaccurate emphasis on sex gonads and hormones alone to explain sex biases in disease incidence, progression, and outcomes.
Within the last decade, this framework has been a gradually expanding to include other important sex-biasing factors such as the baseline chromosomal differences between males and females (XY vs. XX) (3). Advances in genomic databases and technology (e.g. The Cancer Genome Atalas and International Cancer Genome Consortium) and novel application of the four-core genotypes (FCG) mice have additionally revealed other missing pieces to the puzzle; these include X-inactivation escape genes, epigenetics, immunity, somatic mutations, single nucleotide polymorphisms, transcription regulation, metabolism, the microbiome, and more (4-12).
Despite progress, patients with bladder cancer and other non-reproductive cancers exhibiting sex differences are still clinical managed in highly similar ways (aside from anatomical differences). This is due to a lack of mechanistic studies; past studies have largely been correlative.
The Bladder Cancer Gender & Sex Program represents one of the first nationwide coordinated multi-investigator efforts to advance our knowledge of “sex as a biological variable” (SABV) in bladder cancer. We aim to identify key immunological, hormonal, chromosomal, genetic and epigenetic pathways responsible for sex-driven biological phenotypes in BC. Successful completion of our research goals will provide the necessary biological foundation to design novel line(s) of BC therapeutics based on a patient’s biological sex while improving efficacy of existing treatments such as immune checkpoint blockade therapy (ICB).
1) National Cancer Institute: https://www.cancer.gov/about-cancer/understanding/statistics
2) Hartge P, Harvey EB, Linehan WM, Silverman DT, Sullivan JW, Hoover RN, et al. Unexplained excess risk of bladder cancer in men. Journal of the National Cancer Institute. 1990;82(20):1636-40.
3) Arnold AP. Conceptual frameworks and mouse models for studying sex differences in physiology and disease: why compensation changes the game. Experimental neurology. 2014;259:2-9.
4) Dunford A, Weinstock DM, Savova V, Schumacher SE, Cleary JP, Yoda A, et al. Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nat Genet. 2017;49(1):10-6.
5) Kaneko S, Li X. X chromosome protects against bladder cancer in females via a KDM6A-dependent epigenetic mechanism. Sci Adv. 2018;4(6):eaar5598.
6) Yuan Y, Liu L, Chen H, Wang Y, Xu Y, Mao H, et al. Comprehensive Characterization of Molecular Differences in Cancer between Male and Female Patients. Cancer Cell. 2016;29(5):711-22.
7) Li CH, Haider S, Shiah YJ, Thai K, Boutros PC. Sex Differences in Cancer Driver Genes and Biomarkers. Cancer Res. 2018;78(19):5527-37.
8) Li CH, Prokopec SD, Sun RX, Yousif F, Schmitz N, Subtypes PT, et al. Sex differences in oncogenic mutational processes. Nat Commun. 2020;11(1):4330.
9) Ye Y, Jing Y, Li L, Mills GB, Diao L, Liu H, et al. Sex-associated molecular differences for cancer immunotherapy. Nat Commun. 2020;11(1):1779.
10) Lopes-Ramos CM, Chen CY, Kuijjer ML, Paulson JN, Sonawane AR, Fagny M, et al. Sex Differences in Gene Expression and Regulatory Networks across 29 Human Tissues. Cell reports. 2020;31(12):107795.
11) Oliva M, Munoz-Aguirre M, Kim-Hellmuth S, Wucher V, Gewirtz ADH, Cotter DJ, et al. The impact of sex on gene expression across human tissues. Science. 2020;369(6509).
12) Rubin JB, Lagas JS, Broestl L, Sponagel J, Rockwell N, Rhee G, et al. Sex differences in cancer mechanisms. Biology of sex differences. 2020;11(1):17.
To address the current gaps in knowledge, we are excited to syngergize the expertise of three different labs specializing in: (1) epigenetics, (2) cancer genomics, and (3) immunology. Together, we aim to tackle the remaining questions on how the complex interplay between major sex-biasing variables differentially modify disease risk and tumor progression based on a patient's sex.