SEX DIFFERENCES in the cancer proteome patterns have been identified across eight cancer types, with lung adenocarcinoma showing the largest number of proteins with differential abundance between male and female patients.
The study analysed publicly available proteogenomic datasets to explore how sex influenced protein profiles in tumours. Although sex differences in cancer incidence, progression and treatment response are well established, the impact of sex on the cancer proteome has remained poorly understood.
Researchers retrospectively analysed 1,590 proteomes from eight cancer types included in the Clinical Proteomic Tumor Analysis Consortium cohorts. They assessed sex-differential protein abundance and examined links with copy number aberrations, biological pathways and gene dependency.
The analysis identified 901 genes with sex-differential protein abundance in lung adenocarcinoma. Across five other tumour types, including lung squamous cell carcinoma, liver cancer, kidney clear cell cancer, pancreatic adenocarcinoma and glioblastoma, 20 genes showed sex-related differences in protein abundance.
In lung adenocarcinoma, proteins more abundant in males were enriched in MYC and E2F target pathways, while proteins more abundant in females were linked to metabolic and stress-response pathways. Some protein differences could be explained by sex-related copy number aberrations.
The researchers found that sex differences in cancer proteome profiles varied between tumour types. Lung adenocarcinoma showed pronounced differences, whereas other cancers demonstrated more modest variation.
Potential contributors include interactions between sex hormones, environmental exposures and the tumour microenvironment. However, the study could not fully assess the effects of unmeasured factors, including alcohol consumption, diet, exercise and environmental exposures.
The analysis was also limited by available proteogenomic datasets, which included fewer female patients in most cancer types. This imbalance reduced the ability to produce precise estimates and may limit how broadly the findings can be applied.
The findings support considering sex as a biological variable in cancer proteomics research and highlight the importance of sex-disaggregated data. Separating and analysing data by sex may help researchers better understand differences in tumour biology and their potential relevance to treatment response.
Future studies will require larger, sex-balanced cohorts that better represent cancer populations. Combining proteomic data with clinical, hormonal, environmental and lifestyle information may help clarify the factors driving sex differences in cancer and support the development of more personalised therapeutic strategies.
Zhu C et al. Sex differences in the cancer proteome. BMJ Oncol. 2026;DOI: 10.1136/bmjonc-2026-001130.
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