Intra-tumor genetic heterogeneity in rectal cancer

被引:56
作者
Hardiman, Karin M. [1 ]
Ulintz, Peter J. [2 ]
Kuick, Rork D. [3 ]
Hovelson, Daniel H. [2 ]
Gates, Christopher M. [2 ]
Bhasi, Ashwini [2 ]
Grant, Ana Rodrigues [2 ]
Liu, Jianhua [1 ]
Cani, Andi K. [4 ]
Greenson, Joel K. [2 ]
Tomlins, Scott A. [4 ,5 ]
Fearon, Eric R. [4 ,6 ,7 ]
机构
[1] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA
[2] Univ Michigan, Dept Bioinformat, Ann Arbor, MI 48109 USA
[3] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA
[5] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA
[6] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA
[7] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA
关键词
EVOLUTION; MUTATIONS; IMPACT; ADENOCARCINOMAS; CHEMORADIATION; DISCOVERY; VARIANTS; FREQUENT; GENOMES;
D O I
10.1038/labinvest.2015.131
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Colorectal cancer arises in part from the cumulative effects of multiple gene lesions. Recent studies in selected cancer types have revealed significant intra-tumor genetic heterogeneity and highlighted its potential role in disease progression and resistance to therapy. We hypothesized the existence of significant intra-tumor genetic heterogeneity in rectal cancers involving variations in localized somatic mutations and copy number abnormalities. Two or three spatially disparate regions from each of six rectal tumors were dissected and subjected to the next-generation whole-exome DNA sequencing, Oncoscan SNP arrays, and targeted confirmatory sequencing and analysis. The resulting data were integrated to define subclones using SciClone. Mutant-allele tumor heterogeneity (MATH) scores, mutant allele frequency correlation, and mutation percent concordance were calculated, and copy number analysis including measurement of correlation between samples was performed. Somatic mutations profiles in individual cancers were similar to prior studies, with some variants found in previously reported significantly mutated genes and many patient-specific mutations in each tumor. Significant intra-tumor heterogeneity was identified in the spatially disparate regions of individual cancers. All tumors had some heterogeneity but the degree of heterogeneity was quite variable in the samples studied. We found that 67-97% of exonic somatic mutations were shared among all regions of an individual's tumor. The SciClone computational method identified 2-8 shared and unshared subclones in the spatially disparate areas in each tumor. MATH scores ranged from 7 to 41. Allele frequency correlation scores ranged from R-2 = 0.69-0.96. Measurements of correlation between samples for copy number changes varied from R-2 = 0.74-0.93. All tumors had some heterogeneity, but the degree was highly variable in the samples studied. The occurrence of significant intra-tumor heterogeneity may allow selected tumors to have a genetic reservoir to draw from in their evolutionary response to therapy and other challenges.
引用
收藏
页码:4 / 15
页数:12
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