Why men are more likely to develop cancer and have worse outcomes than women?

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Why men are more likely to develop cancer and have worse outcomes than women?

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Why men are more likely to develop cancer and have worse outcomes than women?

Whether it is in appearance, personality and thinking, there are significant differences between men and women. However, gender does not only affect these.

Scientific research shows that gender has a heterogeneous impact on the occurrence and development of many human diseases, including obesity, aging, COVID-19 infection, Alzheimer’s disease, etc., as well as more deadly cancer.

In fact, scientists have long known that gender can affect cancer incidence, clinical outcomes, and cancer biology. For example, male patients tend to have a worse prognosis than female patients in most cancer types.

The sex-specific mechanisms behind this difference are not well understood, but some studies suggest that the Y chromosome may play a key role in this.

On June 21, 2023, two research papers published in the top international academic journal Nature at the same time revealed the role of the Y chromosome in gender differences in cancer outcomes, making males usually more adversely affected than females .

One of the papers is titled: Histone demethylase KDM5D upregulation drives sex differences in colon cancer , completed by Ronald DePinho’s team at the University of Texas MD Anderson Cancer Center , and Jiexi Li is the first author of the paper.

The study identified an upregulated gene on the Y chromosome, KDM5D , that contributes to sex differences in colorectal cancer in male mice by driving tumor invasion and aiding immune escape.

Another paper titled: Y chromosome loss in cancer drives growth by evasion of adaptive immunity was completed by Dan Theodorescu’s team at Cedars-Sinai Medical Center and Zihai Li’s team at Ohio State University , Hany Abdel-Hafiz, Johanna M. Schafer and Chen Xingyu is the co-first author of the paper.

CONCLUSIONS: In bladder cancer, loss of the Y chromosome produces a more immunosuppressive tumor microenvironment, resulting in poorer clinical outcomes.

These findings will provide basic biological evidence for understanding sex differences in cancer, or will lead to the development of novel cancer immunotherapy approaches and potential cancer biomarkers to reduce sex-related cancer risk.

KDM5D upregulation contributes to sex differences in colon cancer

Sex has a profound impact on cancer incidence, lineage, and clinical outcome, but the molecular and genetic basis of this sex difference is poorly understood.

Previous studies have inferred the influence of X chromosome genes and sex hormones, but these studies ignored a more special human chromosome – the Y chromosome .

It is worth mentioning that the sex differences in cancer are particularly prominent in colorectal cancer (CRC) , in which males have significantly higher metastatic and mortality rates than females.

In the MD Anderson Cancer Center study, by constructing a mouse CRC model, the research team found that in CRC male mice carrying the oncogenic mutation KRAS (KRAS*) , the cancer metastasis was higher and the prognosis was worse.

KDM5D is associated with sex-specific KRAS* CRC metastasis

Comprehensive cross-species molecular and transcriptomic analyzes revealed that the histone demethylase KDM5D on the Y chromosome is a transcriptionally upregulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor .

Furthermore, KDM5D-dependent chromatin marks and transcriptome changes revealed repression of epithelial tight junctions and regulators of major histocompatibility complex class I (MHC I) .

KDM5D deletion in CRC cancer cells increases tight junction integrity, reduces cell invasiveness, and enhances CD8+ T cell killing of cancer cells.

In contrast, mice genetically engineered with KDM5D specifically overexpressed KDM5D in cancer cells and showed a propensity for more aggressive tumors.

KDM5D inhibits processing and presentation of MHC class I antigens

Thus, KRAS*-STAT4-mediated upregulation of Y-chromosomal KDM5D significantly contributes to sex differences in KRAS* CRC by disrupting cancer cell adhesion properties and tumor immunity, providing an actionable strategy for reducing the risk of metastasis in KRAS* CRC patients. treatment strategy.

Y chromosome loss facilitates immune escape in cancer

The Y chromosome is crucial for male sex determination and spermatogenesis. Recent studies have shown that loss of the Y chromosome (LOY) is present in several cancer types, including 10-40% of bladder cancers.

This is not surprising, as bladder cancer is often caused by environmental factors, such as exposure to tobacco or industrial chemicals, both of which can lead to DNA damage and LOY. However, the clinical and biological significance between LOY and cancer is still unclear.

In this study at Cedars-Sinai Medical Center, the research team used genomics and transcriptomics studies to report that LOY is associated with poor prognosis in bladder cancer patients.

The research team first conducted a statistical analysis of the clinical data of 300 male bladder cancer patients, thereby identifying an association between Y chromosome deletion and poorer prognosis.

Deletion of Y chromosome associated with poorer prognosis in men with bladder cancer

The researchers then studied bladder cancer cell lines, where they found that tumors lacking the Y chromosome (Y-) were more aggressive than those with the Y chromosome (Y+) .

High-dimensional outgrowth cell analysis revealed that Y-tumors promote marked dysfunction or exhaustion of CD8+ T cells in the tumor microenvironment. These deficiencies were validated by single-nucleus RNA-sequencing and spatial proteomic assessment of human bladder cancer.

Y-tumors promote exhaustion of CD8+ T cells in the tumor microenvironment

Even more interestingly, the research team also found that, whether in humans or mice, the loss of the Y chromosome makes tumors more sensitive to certain types of immunotherapy.

For example, Y- tumors showed an increased response to anti-PD1 immune checkpoint blockade therapy in mice and cancer patients compared with Y+ tumors, pointing to a potential therapeutic avenue for this subset of bladder cancers.

Taken together, these two studies show that the Y chromosome, which determines male sex, has an important impact on the development of cancer, and loss of Y chromosome ( LOY) or corresponding Y chromosome gene loss (such as KDM5D and UTY) will endow a variety of cancers with stronger The aggressive phenotype of the tumor promotes T cell exhaustion, which leads to sex differences in cancer.

Of course, from another point of view, this gender difference also shows that for cancer patients of different genders, the biomarkers and effective treatment methods are also different, which will promote the development of new cancer diagnosis and treatment methods .

Paper link :
1. https://www.nature.com/articles/s41586-023-06254-7
2. https://www.nature.com/articles/s41586-023-06234-x

Why men are more likely to develop cancer and have worse outcomes than women?

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