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Distinct Cancer Drivers, Markers Detected in Tumor Samples from African Ancestry Patients

NEW YORK – A team from Memorial Sloan Kettering Cancer Center, Henry Ford Health System, Foundation Medicine, and other centers in the US and beyond has identified tumor alterations that are either overrepresented or found at lower-than-usual levels in individuals of African ancestry, offering clues to potential treatment strategies or biomarkers.

"[O]ur study uncovered ancestry-associated driver alterations and biomarkers across multiple cancer types and subtypes," senior and corresponding author Jian Carrot-Zhang, an epidemiology and biostatistics researcher at MSKCC, and her colleagues wrote in a study published in Cancer Cell on Thursday.

The investigators considered half a dozen cancer types, starting with clinical information and tumor-only sequence data for 333,908 individuals from differing continental ancestries treated in the US, including more than 255,500 patients of European ancestry, 32,865 patients of African ancestry, 29,691 American individuals, and 15,814 East or South Asian individuals.

Using these data, the team tracked down alterations that were enriched or muted in tumor samples from African-ancestry cancer patients relative to patients from other ancestry groups. They further validated findings from this discovery cohort in another 64,173 individuals who had matched tumor and normal sample testing done through the MSK-IMPACT platform.

"We showed that it is important to jointly investigate genetic ancestry, environmental exposure, and ancestry-environment interaction in understanding genomic differences between different ancestral groups," the authors wrote, arguing that the effort "demonstrated the power of using real-world sequencing data that opens the door to large-scale interrogation of disparities in cancer genomics."

Along with an uptick in MYC amplifications in lung, breast, and prostate cancer samples from individuals of African ancestry, for example, the researchers saw reduced representation of BRAF changes in tumors from African ancestry patients with colorectal or pancreatic cancer.

They also flagged African ancestry-related tumor alterations or alleles that were informative within a single cancer type, including a potentially targetable ROS1 fusion that was found at higher-than-usual rates in lung cancers in African ancestry patients. Further, informative KRAS or EGFR mutations turned up less frequently in lung cancers from African ancestry patients than their European ancestry counterparts.

In addition, the analyses highlighted tumor alterations in African ancestry individuals that appeared to interact with environmental or lifestyle factors. In particular, the team found that tumors tied to TP53 mutations were specifically enhanced in lung cancer patients with a history of smoking in the African ancestry group, contrasting with patterns found in lung cancer patients of European ancestry.

"Interestingly, in lung cancer, KRAS mutations are less common in both smokers and nonsmokers with [African] ancestry," the authors added, "whereas the association of TP53 mutations with [African] ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates."

Based on their results so far, they further called for "routine and expanded inclusion of patients with [African] ancestry in future genomic studies and clinical trials to improve diagnostics and precision medicine for all."