How Does Biological Sex Influence the Cancer Proteome?
Proteomic analysis uncovers how male and female tumors can differ at the protein level.
Biological sex is associated with cancer incidence, progression, and drug response. Sex-based biological differences can alter the genomic and transcriptomic profiles of a tumor, but how they affect the cancer proteome is poorly understood.
A new study from the Sanford Burnham Prebys Medical Discovery Institute has characterized sex differences across 1590 proteomes from 8 cancer types, demonstrating the impact of sex on the tumor proteome.
Sex-based differences in cancer
For most non-reproductive cancers, incidence and prevalence are slightly higher in males than females, and cancer-associated mortality is also generally higher in males.
Sex-based differences are also seen in cancer types; males are at a greater risk of developing esophageal, liver, stomach, kidney, and bladder cancer, but females have a higher risk of gallbladder and thyroid cancers.
Even within a cancer type, different forms can affect the sexes differently. For example, in lung cancer, squamous cell carcinoma disproportionately affects males, while adenocarcinoma occurs more frequently in females.
Differences in sex chromosomes, the immune response, circulating sex hormones, and genetic and epigenetic factors may contribute to these sex-based disparities.
The effect of sex on cancer genomes has been well characterized; genetic copy number variations and somatic mutation burdens differ by sex and are associated with clinical presentations. However, how these genetic sex differences translate into variations in the proteome remains understudied.
The importance of the cancer proteome
Proteins play a central role in cancer: they shape cellular activity, provide drug targets, and function as diagnostic, prognostic, and predictive biomarkers. Unlike the cancer genome, which paints a static picture of mutations, the proteome is dynamic and reflects how the expression of genes with cancer-linked mutations, as well as environmental factors, affect the cell.
In the new study, researchers analyzed 1590 proteomes from 934 cancer patients across 8 cancer types and quantified sex differences in protein abundance in each type.
The team began by comparing proteomic sex differences in normal tissues that neighbor cancer cells.
“We know that tumors are derived from normal cells,” said Dr. Paul Boutros, a professor at Sanford Burnham Prebys and the senior author of the paper. “That means we need to define the proteins in what is called tumor-adjacent normal tissue to serve as controls for comparing to the proteins in tumor cells.”
Most cancer types had two or fewer proteins that exhibited sex-differential abundance in their neighboring tissues. Lung adenocarcinoma and liver hepatocellular carcinoma were the exceptions, with over 300 proteins that showed significant sex differences.
By excluding the proteins that exhibited sex differences in the normal adjacent tissues from further analysis, the researchers could capture cancer-specific proteomic sex disparities.
The cancer proteome can be influenced by biological sex
After adjusting for confounding factors that impact gene expression, including age, race, smoking status, body mass index, and tumor stage and grade, the researchers determined the sex-biased proteins across each cancer type.
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Lung adenocarcinoma had the most sex-based differences in protein abundance, with 901 proteins differing between male and female patients.
“Lung adenocarcinoma stood out for its strong sex-based differences in protein levels,” said Dr. Chenghao (Trevor) Zhu, a research assistant professor at Sanford Burnham Prebys and the lead author of the study. “The other lung cancer type we studied—squamous cell carcinoma—had more modest changes.”
Several of the genes that encode for the sex-differential proteins in lung adenocarcinoma have established roles in tumor biology, the researchers noted. CNNA2 and MKI67, which regulate cell cycle progression and cell proliferation and are associated with poor prognosis, were more highly expressed in male samples. Genes including PRC1, TPX2, and SERPINB2, which are linked to favorable clinical outcomes, were also found to have a strong male bias.
Several of the female-biased protein-coding genes, including EPDR1, QPRT, and ABCC3, have been linked to cell proliferation, metabolism, and drug resistance in lung cancer and other cancer types.
Kidney renal clear cell carcinoma, pancreatic ductal adenocarcinoma, liver hepatocellular carcinoma, and glioblastoma also had moderate sex-based differences in protein abundance. No significant differences between male and female samples were observed for colon adenocarcinoma or head and neck squamous cell carcinoma.
Comparing cancer proteomes with genomes
Using data from the Pan-Cancer Analysis of Whole Genomes project, the team compared genes with sex-differential copy number variations within each cancer type to those linked to proteins with sex-based differences.
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Across pancreatic ductal adenocarcinoma, kidney renal clear cell carcinoma, liver hepatocellular carcinoma, and lung adenocarcinoma, the researchers found that 42 genes with sex-differential copy number variants showed significant sex-based differences in protein abundance.
However, in lung adenocarcinoma, which had the greatest number of genes with sex-differential protein abundance, only 35 of the 901 genes had sex-differential copy number variations, indicating the majority of sex-based proteomic differences in this cancer type are a result of additional regulatory mechanisms.
By comparing copy number variations and protein abundance, the team highlighted sex-specific differences in metabolism, protein synthesis, and immune modulation in lung adenocarcinoma.
A focus on lung adenocarcinoma
As lung adenocarcinoma exhibited the highest number of genes with sex-based differences in protein abundance, the researchers investigated whether these differences were also mirrored at the RNA level, using transcriptome data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC).
CPTAC was created following the launch of the Cancer Genome Atlas Program to connect genetic sequences, gene expression patterns, and tumor proteins.
“This was very important for the field,” said Zhu. “While we had earlier access to clinical genomics information, there weren’t any public resources allowing us to answer the questions we had about the cancer proteome until CPTAC began releasing data.”
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The researchers observed concordance between sex-differential RNA and protein abundance changes across all the quantified genes, with 73 genes showing significant sex differences in both RNA and protein abundance. Among these were genes related to cell cycle regulation, metabolism, and immune modulation.
The question remained: are genes with sex-differential protein expression functionally important in cancer cells? The researchers set out to answer this by cross-referencing the genes identified in their study with CRISPR gene dependency data from 52 lung adenocarcinoma-derived cell lines.
“When the genes we had identified were knocked out with CRISPR gene editing, it led to worse survival in the cell lines,” said Zhu.
This suggests that genes with sex-differential protein abundance are likely to contribute to cancer cell fitness and could represent a molecular vulnerability.
The findings highlight biological sex as a key factor in cancer biology and treatment response, paving the way for sex-specific proteomics profiles to be used for personalized oncology approaches.
“Proteins play a central role in cancer biology, and they are the most common drug targets and biomarkers,” said Boutros. “Better understanding of the cancer proteome and what shapes it is key to treating patients more precisely based on their unique characteristics and those of their cancers.”
Reference: Zhu C, Zeltser N, Oh J, Li CH, Boutros PC. Sex differences in the cancer proteome. BMJ Onc. 2026;5(2). doi: 10.1136/bmjonc-2026-001130
This article is a rework of a press release issued by the Sanford Burnham Prebys Medical Discovery Institute. Material has been edited for length and content.
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