Although overlooked and underappreciated, sexual dimorphism (distinction based on sexual phenotype) is a crucial aspect of understanding human cancer. It could contribute to a better understanding of cancer etiology and prevention, as well as sex-specific clinical diagnosis and treatment.

Current population-based reports on cancer tend to explore geographic locations and specific populations. The impact of sex on cancer treatment is worth your special attention.

 

Understanding sexual dimorphism

These include genetics, environmental exposure, and lifestyle choices.

Sex hormones (eg, male androgens and female estrogens) could drive differences in cancer initiation and development due to sex-hormone signaling via androgen and estrogen receptors.

Some research has shown that there are sex-dimorphic differences in energy balance and homeostasis that could lead to differences in gastrointestinal cancer, for example Sex-related differences in miRNA expression have also been noted in some cancers. Furthermore, mesothelioma is more prevalent in men who aren’t miners versus women, and HIV-related cancers such as Kaposi sarcoma are also more common in men.

In a study published in BMC Cancer, investigating sex differences in worldwide cancer incidence, researchers analyzed four sets of cancer incidence data: from SEER (USA, 1975–2015), from the Cancer Registry at Mayo Clinic (1970–2015), from Sweden (1970–2015), and from the World Cancer Report (2012).

Zheng D, Trynda J, Williams C, et al. Sexual dimorphism in the incidence of human cancers. BMC Cancer. 2019;19(1):684.

 

They found that all human cancers exhibited statistically significant sexual dimorphism with male predominance—with the exception of thyroid cancer, which is more prevalent in females.

 

The role of sex hormones

Based on the data, researchers hypothesize that sex hormone receptor–mediated signaling pathways contribute to the sexual dimorphism of cancer via initiation, progression, metastasis, and prognosis. Three types of estrogen receptors are involved—ERα, ERβ, and GPER1—along with the androgen receptor (AR), in mediating sexual dimorphic expression of human cancers.

According to the authors of a review published in Cancer Letters, “...sex hormone signaling or sex hormone receptor-mediated signaling does not always regulate the progression of human cancers in the same direction or plays opposite roles in two types of cancers or even in the same type of cancer."

Zheng D. Regulation of sex hormone receptors in sexual dimorphism of human cancers. Cancer Lett. 2018;438:24–31.

 

Here are some findings presented by the authors:

• ERα-mediated estrogen signaling facilitates the growth of breast, cervical, uterine, and ovarian cancers, while it hinders the growth of liver cancer.

• Estrogen signaling via ERα and ERβ plays exhibit opposite roles in stomach and ovarian cancers.

• Estrogen receptor-mediated estrogen signaling exhibits substantial tissue or cancer specificity, such as ERα in liver cancer, ERβ in mesothelioma cancer, and GPER1 in kidney cancer.

• ERα, ERβ, and GPER1, and also AR, moderate the tumorigenesis of urinary bladder cancer, oral cancer, and thyroid cancer.

The review’s authors also highlighted that while cancer was more frequent in men, women usually manifested more severe disease with decreased survival.

 

What needs to be done

Such data could help improve cancer prevention and inform precision-medicine strategies for treatment. Currently, many strategies used in genomics research exclude sex chromosomes due to associated technical challenges, according to the authors of a review published in Frontiers in Oncology.

Lopes-Ramos CM, Quackenbush J, DeMeo DL. Genome-wide sex and gender differences in cancer. Front Oncol. 2020;10:597788.

 

“A framework to address sex differences in genomics analysis needs to (1) ensure adequate male and female ratio and sample size for powered analyses of each sex; (2) include the sex chromosomes in downstream analyses; (3) account for sequencing data mapping biases due to sequence similarity between the sex chromosomes; (4) statistically test for sex interaction effects,” the authors recommended.