Matejcic Marco, Teer Jamie K, Hoehn Hannah J, Diaz Diana B, Shankar Kritika, Gong Jun, Nguyen Nathalie T, Lorona Nicole, Coppola Domenico, Fulmer Clifton, Saglam Ozlen, Jiang Kun, Cress Douglas, Muñoz-Antonia Teresita, Flores Idhaliz, Gordian Edna, Oliveras Torres José A, Felder Seth I, Sanchez Julian A, Fleming Jason, Siegel Erin M, Freedman Jennifer A, Dutil Julie, Stern Mariana C, Fridley Brooke L, Figueiredo Jane C, Schmit Stephanie L
medRxiv. 2024 Mar 15:2024.03.11.24303880. doi: 10.1101/2024.03.11.24303880.
Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry. Global proportions of African, East Asian, European, and Native American ancestries were estimated using ADMIXTURE. Associations between global genetic ancestry and somatic mutational features across genes were examined using logistic regression. , , and were the most recurrently mutated genes. Compared to non-Latino individuals, tumors from Latino individuals had fewer (OR=0.64, 95%CI=0.41-0.97, p=0.037) and mutations (OR=0.55, 95%CI=0.31-0.98, p=0.043). Genetic ancestry was associated with presence of somatic mutations in 39 genes (FDR-adjusted LRT p<0.05). Among these genes, a 10% increase in African ancestry was associated with significantly higher odds of mutation in (OR=1.34, 95%CI=1.09-1.66, p=5.74×10 ) and (OR=1.53, 95%CI=1.10-2.12, p=0.011). Among RMGs, we found evidence of association between genetic ancestry and mutation status in (LRT p=0.0084) and between mutation status and AFR ancestry (OR=1.14, 95%CI=1.00-1.30, p=0.046). Ancestry was not associated with tumor mutational burden. Individuals with above-average Native American ancestry had a lower frequency of microsatellite instable (MSI-H) vs microsatellite stable tumors (OR=0.45, 95%CI=0.21-0.99, p=0.048). Our findings provide new knowledge about the relationship between ancestral haplotypes and somatic mutational profiles that may be useful in developing precision medicine approaches and provide additional insight into genomic contributions to cancer disparities.
Our data in ancestrally diverse populations adds essential information to characterize mutational features in the colorectal cancer genome. These results will help enhance equity in the development of precision medicine strategies.
包括西班牙裔/拉丁裔社区在内的祖先多样化和混合人群在癌症遗传和基因组研究中的代表性不足。利用拉丁裔结直肠癌联盟，我们分析了718例结直肠癌患者（128例拉丁裔，469例非拉丁裔）肿瘤/正常组织对的全外显子测序数据，以按种族和遗传血统绘制体细胞突变特征图谱。使用ADMIXTURE估计非洲、东亚、欧洲和美洲原住民血统的全球比例。使用逻辑回归检验全球遗传血统与各基因体细胞突变特征之间的关联。 、 和 是最常发生突变的基因。与非拉丁裔个体相比，拉丁裔个体的肿瘤中 （比值比=0.64，95%置信区间=0.41-0.97，p=0.037）和 突变较少（比值比=0.55，95%置信区间=0.31-0.98，p=0.043）。遗传血统与39个基因中体细胞突变的存在相关（FDR校正的似然比检验p<0.05）。在这些基因中，非洲血统增加10%与 （比值比=1.34，95%置信区间=1.09-1.66，p=5.74×10 ）和
（比值比=1.53，95%置信区间=1.10-2.12，p=0.011）突变的显著更高几率相关。在RMG中，我们发现遗传血统与 中的突变状态之间存在关联的证据（似然比检验p=0.0084），以及 突变状态与非洲血统之间存在关联（比值比=1.14，95%置信区间=1.00-1.30，p=0.046）。血统与肿瘤突变负担无关。美洲原住民血统高于平均水平的个体中，微卫星不稳定（MSI-H）肿瘤与微卫星稳定肿瘤的频率较低（比值比=0.45，95%置信区间=0.21-0.99，p=0.048）。我们的发现提供了关于祖先单倍型与体细胞突变谱之间关系的新知识，这可能有助于开发精准医学方法，并为癌症差异的基因组贡献提供更多见解。
我们在祖先多样化人群中的数据为表征结直肠癌基因组中的突变特征增添了重要信息。这些结果将有助于提高精准医学策略开发中的公平性。
