Biological sex factors into cancer in ways you might not expect. In lung cancer, a form called squamous cell carcinoma disproportionately affects males while adenocarcinoma occurs more frequently in females.
Researchers want to know what is happening in our cells to cause these divergent outcomes in lung and other cancers, and how this knowledge can benefit physicians and patients.
Scientists at Sanford Burnham Prebys Medical Discovery Institute published findings July 15, 2026, in BMJ Oncology demonstrating differences in protein levels in tumor samples from male and female patients. The study shows that lung cancer featured more sex-based protein differences than other cancer types with available data. The authors also highlighted the need for more protein sequencing of clinical tumor samples to enable additional research.
Not long after the Human Genome Project, the National Institutes of Health launched The Cancer Genome Atlas program in 2006 to sequence the genomes and gene expression of tens of thousands of cancer samples spanning 33 cancer types. Five years later, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) was created to connect the dots among the genetic sequences, gene expression patterns and proteins found in tumors.
"This was very important for the field," said Chenghao (Trevor) Zhu, PhD, a research assistant professor at the NCI-designated Cancer Center at Sanford Burnham Prebys. "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."
When the research team conducted this study, they were able to look for sex-based differences in protein sequencing data from 934 cancer patients representing eight cancer types. Their first step was to turn to cancer cells' normal neighbors.
"We know that tumors are derived from normal cells," said Paul Boutros, PhD, MBA , director in and professor of the NCI-designated Cancer Center at Sanford Burnham Prebys and senior vice president for Data Sciences.
"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."
These comparisons revealed that lung adenocarcinoma featured the most sex-based differences with 901 proteins found in varying abundance between male and female patient samples.
"Lung adenocarcinoma stood out for its strong sex-based differences in protein levels," said Zhu, the lead and co-corresponding author of the study. "The other lung cancer type we studied—squamous cell carcinoma—had more modest changes."
Along with lung squamous cell carcinoma, the research team observed that kidney renal clear cell carcinoma, pancreatic ductal adenocarcinoma, liver hepatocellular carcinoma and glioblastoma had moderate sex-based differences in the types and amounts of proteins in tumor cells. No significant differences were uncovered in colon adenocarcinoma or head and neck squamous cell carcinoma.
To see if the proteomic variance they had unearthed was likely related to critical cancer cell functions, the scientists turned to the Dependency Map Consortium's efforts to accelerate precision cancer medicine by finding genes required for cell growth in many types of cancer. The researchers cross-referenced genes found to have sex-differential protein abundance in lung adenocarcinoma with the consortium's findings from studying potential genetic vulnerabilities in 52 lung adenocarcinoma 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.
The research team pursued this proteomics study to follow up on groundbreaking work on sex-based differences in cancer genomics. Fromer Boutros lab member and coauthor Constance H. Li, PhD , assistant professor at the University of Calgary, was the first author of early studies in the field that uncovered differences in mutation density and the frequency of mutation of specific genes, including well-known drivers of cancer. One such study found sex-biased differences across 1983 tumor samples and 28 tumor subtypes.
To continue expanding their proteomics research into other cancer types, the authors plan to analyze more recent data released by CPTAC as well as in-progress treatment response studies that will capture proteomic changes related to treatment resistance and cancer recurrence.
"Proteins play a central role in cancer biology, and they are the most common drug targets and biomarkers," said Boutros, the senior and co-corresponding author of the manuscript.
"Better understanding the cancer proteome and what shapes it is key to treating patients more precisely based on their unique characteristics and those of their cancers."
Nicole Zeltser, PhD, a former member of the Boutros lab, and Jieun Oh, a doctoral student studying bioinformatics at the University of California Los Angeles, share first authorship of the publication with Zhu.
The study was supported by the National Institutes of Health, National Cancer Institute, National Human Genome Research Institute and UCLA Jonsson Comprehensive Cancer Center.
The study's DOI is 10.1136/bmjonc-2026-001130 .
