We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab- and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.

中文翻译：

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癌症机制的性别差异。


我们现在知道癌症是许多不同的疾病，即使在单一组织学亚型内也存在很大差异。当前重点是开发个性化的癌症治疗方法，令人惊讶的是我们尚未系统地将性别差异生物学纳入我们的实验室和临床癌症研究范式中。虽然癌症中的一些性别差异是由循环性激素的作用引起的，但其他性别差异与雌激素、睾酮或黄体酮水平无关。相反，这些差异是性别分化的结果，这一过程除了急性性激素作用外，还涉及遗传和表观遗传机制。性别分化从受精开始，并持续到更年期之后。它几乎影响每个身体系统，导致生长、寿命、新陈代谢和免疫等领域存在显着的性别差异，所有这些都会影响癌症进展、治疗反应和生存。这些有机体水平的差异在细胞水平上相关，因此，男性和女性在对癌症的保护和脆弱性方面存在根本差异，从细胞转化到进展、扩散和对治疗的反应的所有阶段。我们在本次综述中的目标是涵盖核心癌症途径中存在的一些明显的性别差异，并证明将性别作为所有实验室和临床癌症研究中的生物学变量。最后，我们讨论了在测试性别是否重要时应使用的基于实验室和临床的实验设计，以及应用于数据分析以严格评估潜在性别影响的适当统计模型。 我们的目标是促进癌症性别差异的评估，以改善所有患者的治疗结果。