Lung Cancer Driver Mutations in Middle Eastern Americans: Associations with Smoking and Comparative Analysis with Middle Eastern Populations.

[BACKGROUND] Middle Eastern Americans represent a growing and understudied population in cancer genomics. While lung cancer driver mutations are well characterized in many populations, data remain limited for individuals of Middle Eastern ancestry living in the United States. Smoking histories were observed, but available evidence in this population is sparse.

[METHODS] We conducted a retrospective, descriptive analysis of lung carcinoma specimens from 31 Middle Eastern American patients who underwent next-generation sequencing (NGS). Mutations in KRAS, EGFR, ALK, BRAF, and MET were identified using targeted NGS panels. Smoking exposure and duration of U.S. residence were summarized descriptively. Mutation frequencies were compared with published datasets from Middle Eastern populations, including My Cancer Genome and the American University of Beirut Medical Center. NGS using the formalin-fixed paraffin-embedded block was performed using the TruSight Oncology 500 Kit or the TruSight Tumor 15 Kit (Illumina, San Diego, California, United States). Data analysis was performed by aligning to human genome assembly GRCh37 (hg19). A custom variant filter was set up to include only nonsynonymous variants with coding consequences and read depth greater than 100X. Variants classified as IA or IB in ALK, BRAF, EGFR, KRAS, and MET were compared in this study. Benign variants, based on the ClinVar database, were excluded. Given the limited sample size, analyses were descriptive in nature. Continuous variables are presented as means, and categorical variables as counts and percentages. No inferential statistical testing was performed due to insufficient statistical power to reliably detect associations between smoking history and mutation status. The study is intended to be hypothesis-generating.

[RESULTS] KRAS mutations were the most frequently observed (38.7%), followed by EGFR (19.4%) and ALK (9.7%). EGFR mutations occurred predominantly in individuals with minimal smoking exposure, whereas KRAS mutations were more common among individuals with higher pack-year histories. BRAF and MET mutations were rare. Due to limited sample size, no inferential statistical testing was performed, and findings should be interpreted as exploratory.

[CONCLUSION] This descriptive study characterizes lung cancer driver mutations in Middle Eastern Americans and identifies patterns consistent with known smoking-associated and non-smoking-associated mutation profiles. While limited by sample size, the findings emphasize the importance of including Middle Eastern Americans in cancer genomic research and larger, statistically powered studies incorporating additional smoking history and ancestry data are needed to clarify these associations and their clinical implications. KRAS mutations were the most common mutations in our study, occurring in 38.71% of cases, with an average of 10.42 years of residence in the United States and 27.3 pack-years of smoking exposure. EGFR mutations are found in 19.35% of cases, with relatively low smoking exposure (1.25 pack-year). Both MET and BRAF mutations are rare, each accounting for 3.23% of the cases. BRAF mutations were detected in patients with the highest smoking exposure (70 pack-years); however, it should be noted that this value is elevated due to only having one positive case in this study. ALK mutations account for 9.68% of cases. On average, the study population spent 8.58 years of residency in the United States and 22.67 pack-years of smoking exposure, demonstrating a range of smoking histories and mutation frequencies. These findings were compared with data from My Cancer Genome, the American University of Beirut Medical Center, and specific EGFR mutation rates in the Middle Eastern population. Understanding these dynamics is essential for developing targeted public health strategies that address the unique challenges faced by this population, balancing their cultural heritage with the realities of modern American life. Further analysis and wider scope studies are necessary to explore the implications of these findings on health outcomes.