Matejcic Marco, Teer Jamie K, Hoehn Hannah J, Diaz Diana B, Shankar Kritika, Gong Jun, Nguyen Nathalie T, Loroña Nicole C, Coppola Domenico, Fulmer Clifton G, Saglam Ozlen, Jiang Kun, Cress W Douglas, Muñoz-Antonia Teresita, Flores Idhaliz, Gordián Edna R, Oliveras Torres José A, Felder Seth I, Sanchez Julian, Fleming Jason B, Siegel Erin M, Freedman Jennifer A, Dutil Julie, Stern Mariana C, Fridley Brooke L, Figueiredo Jane C, Schmit Stephanie L
Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.
Cancer Res. 2025 May 15;85(10):1928-1944. doi: 10.1158/0008-5472.CAN-24-0747.
Admixed populations, including the Hispanic/Latino/a community, are underrepresented in cancer genetic/genomic studies. Leveraging the Latino Colorectal Cancer Consortium (LC3) and other existing datasets, we analyzed whole-exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer to map somatic mutational features by ethnicity and genetic similarity. Global proportions of African, Asian, European, and Native American genetic ancestries were estimated using ADMIXTURE. Associations between these proportions and somatic mutational features were examined using logistic regression. APC, TP53, and KRAS were the top three mutated genes across all participants and in the subset of Latino individuals in LC3. In analyses examining recurrently mutated genes, tumors from patients of Latino ethnicity had fewer KRAS and PIK3CA mutations compared with tumors from non-Latino patients. Genetic ancestry overall was associated with CDC27 mutation status, and African genetic ancestry was associated with SMAD2 mutation status. In exome-wide analyses, African genetic ancestry was significantly associated with higher odds of mutation in KNCN and TMEM184B. Native American genetic ancestry was associated with a lower frequency of microsatellite instability-high tumors. The SBS11 mutational signature was associated with Native American genetic ancestry as well as Latino ethnicity. In an independent replication dataset, MSK-IMPACT, estimates of association were largely consistent in direction but nonsignificant. A meta-analysis of LC3 and MSK-IMPACT showed that African genetic ancestry was significantly associated with KRAS mutation status and MSI status. This work facilitates precision medicine initiatives by providing insights into the contribution of genetic ancestry to molecular features of colorectal tumors. Significance: Analysis of tumors from various populations can broadly characterize genomic landscapes and enhance precision medicine strategies.
包括西班牙裔/拉丁裔群体在内的混合人群在癌症遗传/基因组研究中的代表性不足。利用拉丁裔结直肠癌联盟（LC3）和其他现有数据集，我们分析了718例结直肠癌患者肿瘤/正常组织对的全外显子测序数据，以按种族和遗传相似性绘制体细胞突变特征图谱。使用ADMIXTURE估计非洲、亚洲、欧洲和美洲原住民遗传血统的全球比例。使用逻辑回归检验这些比例与体细胞突变特征之间的关联。APC、TP53和KRAS是所有参与者以及LC3中拉丁裔个体亚组中突变最多的三个基因。在检查复发性突变基因的分析中，与非拉丁裔患者的肿瘤相比，拉丁裔患者的肿瘤中KRAS和PIK3CA突变较少。总体遗传血统与CDC27突变状态相关，非洲遗传血统与SMAD2突变状态相关。在全外显子分析中，非洲遗传血统与KNCN和TMEM184B中较高的突变几率显著相关。美洲原住民遗传血统与微卫星不稳定性高的肿瘤频率较低相关。SBS11突变特征与美洲原住民遗传血统以及拉丁裔种族相关。在一个独立的复制数据集MSK-IMPACT中，关联估计在方向上基本一致，但不显著。LC3和MSK-IMPACT的荟萃分析表明非洲遗传血统与KRAS突变状态和微卫星高度不稳定状态显著相关。这项工作通过深入了解遗传血统对结直肠肿瘤分子特征的贡献，促进了精准医学计划。意义：对不同人群肿瘤的分析可以广泛地描绘基因组景观并加强精准医学策略。
