Comparison of Breast Cancer Molecular Features and Survival by African and European Ancestry in The Cancer Genome Atlas.
Autor: | Huo D; Department of Public Health Sciences, The University of Chicago, Chicago, Illinois; Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois, Hu H; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, Pennsylvania, Rhie SK; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles; Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, Gamazon ER; Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, Tennessee, Cherniack AD; The Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, Liu J; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, Pennsylvania, Yoshimatsu TF; Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois, Pitt JJ; Committee of Genetics, Genomics, and Systems Biology, The University of Chicago, Chicago, Illinois, Hoadley KA; Department of Genetics and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Troester M; Department of Epidemiology, The University of North Carolina at Chapel Hill, Ru Y; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, Pennsylvania, Lichtenberg T; The Research Institute, Nationwide Children’s Hospital, Columbus, Ohio, Sturtz LA; Chan Soon-Shiong Institute of Molecular Medicine at Windber, Windber, Pennsylvania, Shelley CS; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Benz CC; Buck Institute for Research on Aging, Novato, California, Mills GB; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Laird PW; Center for Epigenetics, Van Andel Research Institute, Grand Rapids, Michigan, Shriver CD; Clinical Breast Care Project, Murtha Cancer Center, Walter Reed National Military Medical Center/Uniformed Services University of the Health Sciences, Bethesda, Maryland, Perou CM; Department of Genetics and Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Olopade OI; Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois; Committee of Genetics, Genomics, and Systems Biology, The University of Chicago, Chicago, Illinois |
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Jazyk: | angličtina |
Zdroj: | JAMA oncology [JAMA Oncol] 2017 Dec 01; Vol. 3 (12), pp. 1654-1662. |
DOI: | 10.1001/jamaoncol.2017.0595 |
Abstrakt: | Importance: African Americans have the highest breast cancer mortality rate. Although racial difference in the distribution of intrinsic subtypes of breast cancer is known, it is unclear if there are other inherent genomic differences that contribute to the survival disparities. Objectives: To investigate racial differences in breast cancer molecular features and survival and to estimate the heritability of breast cancer subtypes. Design, Setting, and Participants: Among a convenience cohort of patients with invasive breast cancer, breast tumor and matched normal tissue sample data (as of September 18, 2015) were obtained from The Cancer Genome Atlas. Main Outcomes and Measures: Breast cancer–free interval, tumor molecular features, and genetic variants. Results: Participants were 930 patients with breast cancer, including 154 black patients of African ancestry (mean [SD] age at diagnosis, 55.66 [13.01] years; 98.1% [n = 151] female) and 776 white patients of European ancestry (mean [SD] age at diagnosis, 59.51 [13.11] years; 99.0% [n = 768] female). Compared with white patients, black patients had a worse breast cancer-free interval (hazard ratio, HR=1.67; 95% CI, 1.02-2.74; P = .043). They had a higher likelihood of basal-like (odds ratio, 3.80; 95% CI, 2.46-5.87; P < .001) and human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])–enriched (odds ratio, 2.22; 95% CI, 1.10-4.47; P = .027) breast cancer subtypes, with the Luminal A subtype as the reference. Blacks had more TP53 mutations and fewer PIK3CA mutations than whites. While most molecular differences were eliminated after adjusting for intrinsic subtype, the study found 16 DNA methylation probes, 4 DNA copy number segments, 1 protein, and 142 genes that were differentially expressed, with the gene-based signature having an excellent capacity for distinguishing breast tumors from black vs white patients (cross-validation C index, 0.878). Using germline genotypes, the heritability of breast cancer subtypes (basal vs nonbasal) was estimated to be 0.436 (P = 1.5 × 10−14). The estrogen receptor–positive polygenic risk score built from 89 known susceptibility variants was higher in blacks than in whites (difference, 0.24; P = 2.3 × 10−5), while the estrogen receptor–negative polygenic risk score was much higher in blacks than in whites (difference, 0.48; P = 2.8 × 10−11). Conclusions and Relevance: On the molecular level, after adjusting for intrinsic subtype frequency differences, this study found a modest number of genomic differences but a significant clinical survival outcome difference between blacks and whites in The Cancer Genome Atlas data set. Moreover, more than 40% of breast cancer subtype frequency differences could be explained by genetic variants. These data could form the basis for the development of molecular targeted therapies to improve clinical outcomes for the specific subtypes of breast cancers that disproportionately affect black women. Findings also indicate that personalized risk assessment and optimal treatment could reduce deaths from aggressive breast cancers for black women. |
Databáze: | MEDLINE |
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