Meta-analysis reveals differences in somatic alterations by genetic ancestry across common cancers

Area of Science:

• Genomics
• Oncology
• Population Genetics

Background:

• Genetic similarity and ancestry are linked to somatic alterations in various cancers.
• Previous studies suggest population-specific differences in cancer-related genetic mutations.

Purpose of the Study:

• To meta-analyze targeted panel sequencing data from large cohorts to identify ancestry-associated differences in cancer somatic alterations.
• To investigate the frequency of specific mutations (e.g., TERT promoter, ERBB2, MET) across different ancestral populations.
• To assess potential biases in current cancer genomic testing due to underrepresentation of diverse ancestries.

Main Methods:

• Meta-analysis of two targeted panel sequencing cohorts comprising 275,605 cancer samples.
• Analysis of 14 different cancer types to identify somatic alterations.
• Comparison of mutation frequencies across diverse ancestral groups, including European, African, and East Asian ancestries.

Main Results:

• A recurrent depletion of TERT promoter mutations was observed in patients of African and East Asian ancestry across multiple cancer types.
• Clinically actionable alterations like ERBB2 mutations (lung adenocarcinoma) and MET mutations (papillary renal cell carcinoma) were more frequent in non-European ancestries.
• Depletions in total driver alterations were found in non-European ancestries across multiple cancers, suggesting potential biases in current genomic panels.

Conclusions:

• Cancer somatic alterations exhibit significant variation based on genetic ancestry.
• Current targeted sequencing panels may be biased towards findings in European ancestry populations, potentially missing crucial alterations in other groups.
• Increased population diversity in genomic studies is essential for discovering novel cancer drivers and advancing precision oncology for all individuals.