Lung cancer can co-opt genes that normally help a fetus develop and evade the mother's immune system. And while these pregnancy-specific glycoproteins (PSGs) can get activated in the cancers of both men and women, female patients had poorer outcomes, a Memorial Sloan Kettering Cancer Center (MSK) research team has found.
The analysis suggests targeting these genes might improve survival in female patients with lung cancer, according to findings presented at this year's American Associate for Cancer Research Annual Meeting .
Genes That Protect Fetuses… and Cancer?
During pregnancy, the placenta produces a group of proteins — PSGs — that support a pregnancy, including by regulating the mother's immune system to prevent it from treating the fetus as a threat, says study first author Jung Hun Oh, PhD , an associate attending computer scientist in MSK's Department of Medical Physics.
Previous MSK research found PSG genes are activated in about 20% of patients with lung, breast, uterus, and colon cancer, and that these patients generally had worse outcomes.
The new study builds on these findings, identifying significant differences in outcomes between male and female lung cancer patients in whose cancer these PSG genes are activated.
Using AI To Understand Sex Differences in Lung Cancer Outcomes
Using a type of artificial intelligence called machine learning, the team — overseen by senior author Joseph Deasy, PhD, Chair of the Department of Medical Physics — showed that female patients whose cancers expressed PSG genes fared significantly worse than their male counterparts. Furthermore, the analysis found that when several specific PSG genes were activated, the prognosis was particularly poor.
The researchers also found a clue that may help account for these differences: female lung cancer patients with PSG expression also often had changes in their KRAS signaling pathway. Mutations to the KRAS gene, which is important for cell growth and division, are frequently found in lung cancer. PSG expression in male lung cancer patients, however, did not worsen their outcomes.
The analysis was conducted using two different RNA-Seq expression datasets. The data included 235 male and 271 female patients in The Cancer Genome Atlas (TCGA) , and was validated in 70 male and 36 female patients from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) , where the impact on overall survival was even stronger.
Next Steps
The research team plans to use the findings to pursue additional grant funding to unravel the relationship between PSG expression and KRAS pathway activation, as well as to investigate the role played by pregnancy history and hormone-related genes.
"Targeting PSG-related pathways presents a new strategy for potentially improving outcomes for female patients with lung cancer — and perhaps other cancers where PSGs are activated," Dr. Deasy says. "Since PSGs are not typically expressed outside of pregnancy, they could be a promising drug target."
Additional Authors, Funding, and Disclosures
Additional authors include Gabrielle Rizzuto, MD, PhD, Rena Elkin, PhD, Corey Weistuch, PhD, and Larry Norton, MD, of MSK; and Gabriela Dveksler, PhD, of Uniformed Services University of Health Sciences.
The study was supported in part by the National Cancer Institute (R01CA285801, P30CA008748) and Breast Cancer Research Foundation (BCRF-17-193).
Dr. Norton reports several outside consulting roles and honoraria. Dr. Deasy is a co-founder of PAIGE.AI. Please refer to the conference abstract for details.
Citation: Pregnancy-specific glycoproteins in tumors are strong predictors of outcome in female lung adenocarcinoma patients, AACR Annual Meeting 2025
