PO.PS01.03 · 人群科学

结直肠癌中遗传祖源与体细胞突变谱之间的关联

Association between genetic ancestry and somatic mutational profiles in colorectal cancer

编号 5066 展板 6 时间 4/21 09:00–12:00 区域 Section 36 主讲 Marco Matejcic

分会场 Etiology and Molecular Epidemiology Approaches to Decipher Cancer Disparities

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作者与单位 Authors & Affiliations

Marco Matejcic¹, Jamie Teer², Daniel Sobieski³, Eric M. Cockman³, Esther Jean-Baptiste⁴, Nathalie Nguyen⁵, Diana B. Diaz⁶, Ya-Yu Tsai¹, Hannah J. Hoehn⁴, Kritika Shankar³, Rusché Wilson³, Karina Brito³, Allyson Koepfler³, Seth Felder⁷, Julian Sanchez⁷, Nicole Catalina Lorona⁵, W. Douglas Cress⁸, Teresita Muñoz-Antonia⁹, Idhaliz Flores⁹, Edna Gordian⁸, Jose Oliveras Torres¹⁰, Ozlen Saglam¹¹, Kun Jiang¹², Clifton Fulmer¹³, Domenico Coppola¹², Erin M. Siegel¹⁴, Mariana C. Stern¹⁵, Jane C. Figueiredo⁵, Stephanie L. Schmit¹⁶

¹Genomic Sciences and System Biology, Cleveland Clinic Lerner College of Medicine, Cleveland, OH,²Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL,³Genomic Sciences and System Biology, Cleveland Clinic, Cleveland, OH,⁴Non-Therapeutic Research Office, Moffitt Cancer Center, Tampa, FL,⁵Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA,⁶Moffitt Cancer Center, Tampa, FL,⁷Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL,⁸Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL,⁹Puerto Rico Biobank, Ponce Health Sciences University, Ponce, Puerto Rico,¹⁰Department of Microbiology, Ponce Health Sciences University, Ponce, PR,¹¹California University Science and Medicine, Colton, CA,¹²Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL,¹³Diagnostics Institute, Robert J. Tomsich Department of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH,¹⁴Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL,¹⁵Department of Population and Public Health Sciences, USC Norris Comprehensive Cancer Center, Los Angeles, CA,¹⁶Genomic Sciences and System Biology, Cleveland Clinic, Cleveland Clinic, OH

摘要 Abstract

中文摘要

结直肠癌（CRC）的死亡率在不同人群中存在差异，这些差异不能完全由社会人口学因素和医疗可及性来解释。通过扩展癌症基因组数据集以纳入来自不同社区患者的肿瘤图谱，可以更好地理解健康差异的生物学决定因素。我们利用来自拉丁裔结直肠癌联盟（LC3）的全外显子组测序数据及其他数据集，按族裔和遗传推断的祖源来刻画体细胞突变谱。我们假设在不同人群间存在差异的祖源单倍型有助于形成不同的体细胞突变谱。使用包括Burrows-Wheeler MEM Aligner、基因组分析工具包（GATK）、MuTect、Strelka、MuSE、SomaticSniper、freebayes和Lancet在内的分析流程，从配对的肿瘤和种系/正常样本中检出体细胞突变。使用GATK识别遗传变异。基于千人基因组计划（1000 Genomes Project）和人类基因组多样性计划（Human Genome Diversity Project），使用ADMIXTURE估算非洲、东亚、欧洲、美洲原住民和南亚祖源的全局比例。在纳入的1,243例原发性CRC病例中，391例（31.5%）为拉丁裔，488例（39.3%）为非拉丁裔。使用逻辑回归检验全局祖源与体细胞突变特征之间的关联。在CRC常见突变基因中，与非拉丁裔患者相比，拉丁裔参与者的肿瘤在BRAF（OR=0.59，95%CI=0.34-0.99，p=0.048）、CTNBB1（OR=0.54，95%CI=0.30-0.96，p=0.037）、FBXW7（OR=0.61，95%CI=0.38-0.99，p=0.045）、KRAS（OR=0.71，95%CI=0.52-0.95，p=0.023）中的突变频率较低，但在CDC27（OR=11.74，95%CI=1.39-99.09，p=0.024）和SMAD2（OR=2.30，95%CI=1.08-4.89，p=0.03）中的突变频率较高。此外，非洲祖源与APC（OR=1.10，95%CI=1.02-1.18，p=0.013）和PIK3CA（OR=1.08，95%CI=1.00-1.15，p=0.037）突变的较高几率显著相关，而美洲原住民祖源与BRAF（OR=0.83，95%CI=0.70-0.97，p=0.02）和FBXW7（OR=0.85，95%CI=0.75-0.97，p=0.012）突变的较低几率相关。全基因组分析显示，全局遗传祖源与CFAP54、LMBRD2、MUC12和TTC6的突变状态相关（FDR校正的4自由度LRT p<0.05）。美洲原住民祖源与LMBRD2突变的较低几率相关（OR=0.47，95%CI=0.24-0.95，p=0.034），但与CFAP54（OR=1.32，95%CI=1.17-1.49，p=7.55×10⁻⁰⁶）、MUC12（OR=1.29，95%CI=1.08-1.55，p=0.0049）和TTC6（OR=1.31，95%CI=1.11-1.53，p=0.0011）突变的较高几率相关。与非拉丁裔患者相比，拉丁裔患者的肿瘤突变负荷显著降低（OR=0.78，95%CI=0.64-0.94，p=0.012）。这些发现通过增进我们对祖源相关分子异质性的理解，推动了精准医学的进展。

查看英文原文 English abstract

Colorectal cancer (CRC) mortality rates differ across populations and differences are not fully accounted for by sociodemographic factors and access to care. Opportunities exist to better understand biological determinants of disparities by expanding cancer genomic datasets to include profiles of tumors from patients from varied communities. Using whole-exome sequencing data from the Latino Colorectal Cancer Consortium (LC3) and additional datasets, we characterized somatic mutational profiles by ethnicity and genetically-inferred ancestry. We hypothesized that ancestral haplotypes that vary across populations contribute to differential somatic mutational profiles. Somatic mutations were called from paired tumor and germline/normal samples using an analysis pipeline including Burrows-Wheeler MEM Aligner, the Genome Analysis Toolkit (GATK), MuTect, Strelka, MuSE, SomaticSniper, freebayes, and Lancet. Inherited variants were identified using GATK. Global proportions of African, East Asian, European, Native American, and South Asian ancestries were estimated using ADMIXTURE based on the 1000 Genomes Project and the Human Genome Diversity Project. Among the 1,243 primary CRC cases included, 391 (31.5%) were Latino, 488 (39.3%) were non-Latino. Associations between global ancestry and somatic mutational features were examined using logistic regression. Among commonly mutated genes in CRC, tumors from Latino participants exhibited lower frequencies of mutations in BRAF (OR=0.59, 95%CI=0.34-0.99, p=0.048), CTNBB1 (OR=0.54, 95%CI=0.30-0.96, p=0.037), FBXW7 (OR=0.61, 95%CI=0.38-0.99, p=0.045), KRAS (OR=0.71, 95%CI=0.52-0.95, p=0.023), but higher frequency of mutations in CDC27 (OR=11.74, 95%CI=1.39-99.09, p=0.024) and SMAD2 (OR=2.30, 95%CI=1.08-4.89, p=0.03) compared to non-Latino patients. In addition, African ancestry was significantly associated with higher odds of mutations in APC (OR=1.10, 95%CI=1.02-1.18, p=0.013) and PIK3CA (OR=1.08, 95%CI=1.00-1.15, p=0.037), while Native American ancestry was associated with lower odds of mutations in BRAF (OR=0.83, 95%CI=0.70-0.97, p=0.02) and FBXW7 (OR=0.85, 95%CI=0.75-0.97, p=0.012). Genome-wide analyses revealed that global genetic ancestry was associated with mutation status in CFAP54 , LMBRD2 , MUC12 , and TTC6 (FDR-adjusted 4-df LRT p<0.05). Native American ancestry was associated with reduced odds of mutations in LMBRD2 (OR= 0.47, 95%CI=0.24-0.95, p=0.034), but with higher odds of mutations in CFAP54 (OR=1.32, 95%CI=1.17-1.49, p=7.55x10 -06 ), MUC12 (OR=1.29, 95%CI=1.08-1.55, p=0.0049), and TTC6 (OR=1.31, 95%CI=1.11-1.53, p=0.0011). Tumor mutation burden was significantly reduced in Latino patients compared to non-Latino patients (OR= 0.78, 95%CI=0.64-0.94, p=0.012). These findings advance precision medicine efforts by improving our understanding of ancestry-associated molecular heterogeneity.

利益披露 Disclosure

M. Matejcic, None.. J. Teer, None.. D. Sobieski, None.. E. M. Cockman, None.. E. Jean-Baptiste, None.. N. Nguyen, None.. Y. Tsai, None.. H. J. Hoehn, None.. K. Shankar, None.. R. Wilson, None.. K. Brito, None.. A. Koepfler, None.. S. Felder, None.. J. Sanchez, None.. N. C. Lorona, None.. W. Cress, None.. T. Muñoz-Antonia, None.. I. Flores, None.. E. Gordian, None.. J. Oliveras Torres, None.. O. Saglam, None.. K. Jiang, None.. C. Fulmer, None.. D. Coppola, None.. E. M. Siegel, None.. M. C. Stern, None.. J. C. Figueiredo, None.. S. L. Schmit, None.

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