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Sex disparities matter in cancer development and therapy

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.

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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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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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Correspondence to Sue Haupt or Ygal Haupt.

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Nature Reviews Cancer thanks G. P. Dotto, J. Feunteun and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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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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