Ancestry Outpaces Race in Predicting HNSCC Biology, Survival

New genomic analyses reveal a link between ancestry and head and neck cancer biology, with direct implications for risk stratification and targeted therapy. The study, led by researchers at the University of Maryland School of Medicine (UMSOM), underscores that genetic ancestry is a key determinant of tumor biology in head and neck squamous cell carcinoma (HNSCC), a factor that may help explain stark survival disparities and inform future precision medicine strategies. Further, the data spotlight ancestry-specific biomarkers and vulnerabilities, including upregulated genes such as POLB, that could reshape diagnostic and prognostic approaches.

The study, published in Cancer and Metastasis Reviews, analyzes data from 523 patients in The Cancer Genome Atlas determined that genetic ancestry, rather than self-identified race, was a stronger predictor of fundamental genetic differences between tumors. These differences are associated with gene mutations that drive how quickly tumor cells divide and whether they will respond to chemotherapy or metastasize.

The review notes that African American patients survive on average 2.5 years after a diagnosis of HNSCC, whereas European American patients survive an average of 4.8 years, nearly twice as long. Although survival differences have been associated with lifestyle risk factors like tobacco use or disparities in access to care, the new study suggests tumors arising in patients with different genetic ancestries can exhibit distinct biological features. These include changes in key genes that affect cancer cell growth or treatment response.

This work points to the potential for developing more precise and effective treatment approaches for HNSCC patients by accounting for these fundamental biological differences rooted in genetic ancestry. Ancestry-linked genomic alterations can also point to targeted treatments. For example, CCNE1 amplifications, which accelerate tumors by activating CDK2, are tied to aggressive disease and treatment resistance. Finding these amplifications in specific ancestry groups suggests a strategic opportunity: targeting these tumors with CDK2 inhibitors.

"Genetic ancestry reflects biologically encoded variation in DNA," senior author Daria Gaykalova, PhD, a scientist at the Institute for Genome Sciences and Associate Professor at UMSOM, said. "This review reinforces that social factors matter, but it also shows that biological drivers linked to ancestry must be considered if we want truly effective precision medicine."

The researchers, including first author student researcher Madeleine Ndahayo, found that genetic ancestry influences patterns of tumor mutations, DNA copy gains or losses, and gene activity. This suggests ancestry associated biology may shape tumor development and progression, with some alterations being protective and others contributing to more aggressive disease.

“This interesting manuscript suggests that incidence and clinical course of response to treatment may be influenced by genomic ancestry and germline predispositions,” Robert L. Ferris, MD, PhD, co-editor-in-chief, Targeted Therapies in Oncology, and executive director, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, said in an interview. “These polymorphisms reflect the rich inherited genomic status and reinforce the need to enroll broad groups in cancer clinical trials and cohorts.”

REFERENCE

Ndahayo M, Saxena A, Thomas H, Barry KH, Gaykalova DA. The impact of genomic ancestry on tumor genomics in head and neck squamous cell carcinoma. Cancer Metastasis Rev. 2026;45(6). doi:10.1007/s10555-026-10312-7