Tempus AI, 600 West Chicago Avenue, Suite 510, Chicago, IL, 60654, USA.
Department of Radiation Oncology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.
Genome Med. 2024 Aug 13;16(1):99. doi: 10.1186/s13073-024-01373-w.
There are known disparities in incidence and outcomes of colorectal cancer (CRC) by race and ethnicity. Some of these disparities may be mediated by molecular changes in tumors that occur at different rates across populations. Genetic ancestry is a measure complementary to race and ethnicity that can overcome missing data issues and better capture genetic similarity in admixed populations. We aimed to identify somatic mutations and tumor gene expression differences associated with both genetic ancestry and imputed race and ethnicity.
Sequencing was performed with the Tempus xT NGS 648-gene panel and whole exome capture RNA-Seq for 8454 primarily late-stage CRC patients. Genetic ancestry proportions for five continental groups-Africa (AFR), American indigenous (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS)-were estimated using ancestry informative markers. To address data gaps, race and ethnicity categories were imputed, resulting in assignments for 952 Hispanic/Latino, 420 non-Hispanic (NH) Asian, 1061 NH Black, and 5763 NH White individuals. We assessed association of genetic ancestry proportions and imputed race and ethnicity categories with somatic mutations in relevant CRC genes and in 2608 expression profiles, as well as 1957 consensus molecular subtypes (CMS).
Increased AFR ancestry was associated with higher odds of somatic mutations in APC, KRAS, and PIK3CA and lower odds of BRAF mutations. Additionally, increased EAS ancestry was associated with lower odds of mutations in KRAS, EUR with higher odds in BRAF, and the Hispanic/Latino category with lower odds in BRAF. Greater AFR ancestry and the NH Black category were associated with higher rates of CMS3, while a higher proportion of Hispanic/Latino patients exhibited indeterminate CMS classifications.
Molecular differences in CRC tumor mutation frequencies and gene expression that may underlie observed differences by race and ethnicity were identified. The association of AFR ancestry with increased KRAS mutations aligns with higher CMS3 subtype rates in NH Black patients. The increase of indeterminate CMS in Hispanic/Latino patients suggests that subtype classification methods could benefit from enhanced patient diversity.
结直肠癌（CRC）的发病率和结局存在种族和民族差异。这些差异中的一些可能是由肿瘤中的分子变化介导的，这些变化在不同人群中的发生速度不同。遗传祖先与种族和民族是互补的衡量标准，可以克服数据缺失问题，并更好地捕捉混合人群中的遗传相似性。我们旨在确定与遗传祖先和推断的种族和民族都相关的体细胞突变和肿瘤基因表达差异。
对 8454 名主要晚期 CRC 患者进行了 Tempus xT NGS 648 基因panel 和全外显子捕获 RNA-Seq 测序。使用遗传标记物估计了五个大陆群体的遗传祖先比例 - 非洲（AFR）、美洲原住民（AMR）、东亚（EAS）、欧洲（EUR）和南亚（SAS）。为了解决数据空白问题，推断了种族和民族类别，从而为 952 名西班牙裔/拉丁裔、420 名非西班牙裔（NH）亚裔、1061 名 NH 黑人、5763 名 NH 白人进行了分类。我们评估了遗传祖先比例和推断的种族和民族类别与相关 CRC 基因的体细胞突变以及 2608 个表达谱的关联，以及 1957 个共识分子亚型（CMS）。
AFR 祖先比例增加与 APC、KRAS 和 PIK3CA 的体细胞突变几率增加和 BRAF 突变几率降低相关。此外，EAS 祖先比例增加与 KRAS 突变几率降低相关，EUR 与 BRAF 突变几率增加相关，而西班牙裔/拉丁裔类别与 BRAF 突变几率降低相关。AFR 祖先比例增加和 NH 黑人类别与 CMS3 发生率增加相关，而更多的西班牙裔/拉丁裔患者表现出不确定的 CMS 分类。
确定了 CRC 肿瘤突变频率和基因表达的分子差异，这些差异可能是种族和民族差异的基础。AFR 祖先与 KRAS 突变增加相关，这与 NH 黑人患者 CMS3 亚型发生率增加一致。西班牙裔/拉丁裔患者不确定 CMS 的增加表明亚型分类方法可能受益于增强患者多样性。
