Molecular pathology selected abstracts

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Editors: Donna E. Hansel, MD, PhD, division head of pathology and laboratory medicine, MD Anderson Cancer Center, Houston; James Solomon, MD, PhD, assistant professor, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York; Erica Reinig, MD, assistant professor and medical director of molecular diagnostics, University of Wisconsin-Madison; Marcela Riveros Angel, MD, molecular genetic pathology fellow, Department of Pathology, OHSU; Maedeh Mohebnasab, MD, assistant professor of pathology, University of Pittsburgh; Alicia Dillard, MD, clinical pathology chief resident, New York-Presbyterian/Weill Cornell Medical Center; and Richard Wong, MD, PhD, assistant professor of pathology, University of California San Diego.

African heritage tumor sequencing: variation in mutational changes among prevalent cancer types

February 2024—Precision cancer medicine relies heavily on understanding the genomic landscape of tumors. Prior comparisons between African and European ancestry, though based on limited data, have indicated distinct differences in the landscape of cancer driver alterations between these populations. Whether these discrepancies are mediated by genetic variants or environmental influences is still unclear. Accurately characterizing ancestry-associated genomic alterations is essential to not only improving genomic diagnostic testing but also to developing targeted therapies, biomarkers, and personalized cancer care for diverse populations. The authors conducted a study that leveraged two large genomic cohorts to investigate the relationship between genomic alterations and African ancestry in six common cancers: prostate, pancreas, ovary, nonsmall cell lung cancer (NSCLC), colorectal, and breast. The study used 333,908 tumor-only samples as the discovery cohort and 64,173 paired tumor-normal samples as the validation cohort. The authors found that continental and subcontinental ancestry can be inferred from targeted gene panel sequencing of tumor-only DNA. African ancestry was identified in 9.8 percent of all samples in the discovery cohort. The sequenced cohort had a distribution across cancer types that closely mirrored patterns observed in the general population. The authors associated the percentage of African ancestry per individual with 253 cancer genes, using a logistic regression model adjusted for the presence or absence of an oncogenic alteration in the gene, while accounting for age, gender, tumor mutational burden, subtype, and panel version. Some associations were replicated in multiple tumor types. For example, MYC amplifications were associated with African ancestry in NSCLC, prostate cancer, and breast cancer. They were also associated with worse overall survival for each cancer type. In examining the prevalence of oncogenic drivers in NSCLC, the authors found that patients of African ancestry who did not exhibit the mutational signature associated with smoking had a greater occurrence of ROS1 fusions. African heritage was also found to be linked to a reduced occurrence of KRAS mutations, irrespective of smoking habits. Furthermore, driver mutations in TP53 were only associated with smoking. This implies that the effects of smoking on the body may differ in people of African descent. Another aspect of the study assessed biomarkers used to guide therapeutic decisions in patients of African ancestry, such as tumor mutational burden (TMB) and microsatellite instability (MSI) status for immune checkpoint inhibitors and homologous recombination repair (HRR) deficiency for poly-ADP ribose polymerase inhibitors. The results showed that TMB-high status was more common in patients of African ancestry who had NSCLC and prostate cancer and that colorectal cancer patients had a lower frequency of mutations in HRR genes and mismatch repair genes and of MSI-high status. The study findings underscore the importance of ensuring equal access to diagnostic testing and precision oncology to address disparities in cancer care. The authors stressed the need to incorporate a wide range of patient populations in future studies to gain a deeper understanding of how ancestry and environmental factors interact with tumor biology.

Jiagge E, Jin DX, Newberg JY, et al. Tumor sequencing of African ancestry reveals differences in clinically relevant alterations across common cancers. Cancer Cell. 2023;41:1963–1971.

Correspondence: Dr. Evelyn Jiagge at ejiagge1@hfhs.org