PO.PS01.03 · 人群科学

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

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

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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