title: Intra-tumor genetic heterogeneity in rectal cancer.
abstract: 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.
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Hardiman
authors.affiliation: Department of Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ulintz
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Rork D
authors.initials: RD
authors.lastname: Kuick
authors.affiliation: Department of Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.affiliation: Department of Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Gates
authors.affiliation: Department of Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Bhasi
authors.affiliation: Department of Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodrigues Grant
authors.affiliation: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Andi K
authors.initials: AK
authors.lastname: Cani
authors.affiliation: Department of Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Joel K
authors.initials: JK
authors.lastname: Greenson
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Urology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.|Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.|Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fearon
mesh_terms: D000368:Aged; D019295:Computational Biology; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics*; D018740:Genetic Heterogeneity; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012004:Rectal Neoplasms / Q000737:chemistry / Q000235:genetics*; D012007:Rectum / Q000737:chemistry