high dna methylation pattern intratumoral diversity implies weak selection in many human colorectal cancers瘤内高dna甲基化模式的多样性意味着软弱选择在许多人类结肠直肠癌.pdfVIP

High DNA Methylation Pattern Intratumoral Diversity Implies Weak Selection in Many Human Colorectal Cancers 1 1 ´ 2,3 4 Kimberly D. Siegmund , Paul Marjoram , Simon Tavare , Darryl Shibata * 1 Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America, 2 Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America, 3 Department of Oncology, University of Cambridge, Cambridge, United Kingdom, 4 Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, California, United States of America Abstract Background: It is possible to infer the past of populations by comparing genomes between individuals. In general, older populations have more genomic diversity than younger populations. The force of selection can also be inferred from population diversity. If selection is strong and frequently eliminates less fit variants, diversity will be limited because new, initially homogeneous populations constantly emerge. Methodology and Results: Here we translate a population genetics approach to human somatic cancer cell populations by measuring genomic diversity within and between small colorectal cancer (CRC) glands. Control tissue culture and xenograft experiments demonstrate that the population diversity of certain passenger DNA methylation patterns is reduced after cloning but subsequently increases with time. When measured in CRC gland populations, passenger methylation diversity from different parts of nine CRCs was relatively high and uniform, consistent with older, stable lineages rather than mixtures of younger homogeneous p