title: Allele-specific copy number analysis of tumors.
abstract: We present an allele-specific copy number analysis of the in vivo breast cancer genome. We describe a unique bioinformatics approach, ASCAT (allele-specific copy number analysis of tumors), to accurately dissect the allele-specific copy number of solid tumors, simultaneously estimating and adjusting for both tumor ploidy and nonaberrant cell admixture. This allows calculation of "ASCAT profiles" (genome-wide allele-specific copy-number profiles) from which gains, losses, copy number-neutral events, and loss of heterozygosity (LOH) can accurately be determined. In an early-stage breast carcinoma series, we observe aneuploidy (>2.7n) in 45% of the cases and an average nonaberrant cell admixture of 49%. By aggregation of ASCAT profiles across our series, we obtain genomic frequency distributions of gains and losses, as well as genome-wide views of LOH and copy number-neutral events in breast cancer. In addition, the ASCAT profiles reveal differences in aberrant tumor cell fraction, ploidy, gains, losses, LOH, and copy number-neutral events between the five previously identified molecular breast cancer subtypes. Basal-like breast carcinomas have a significantly higher frequency of LOH compared with other subtypes, and their ASCAT profiles show large-scale loss of genomic material during tumor development, followed by a whole-genome duplication, resulting in near-triploid genomes. Finally, from the ASCAT profiles, we construct a genome-wide map of allelic skewness in breast cancer, indicating loci where one allele is preferentially lost, whereas the other allele is preferentially gained. We hypothesize that these alternative alleles have a different influence on breast carcinoma development.
authors.affiliation: Department of Genetics, Institute for Cancer Research, Clinic for Cancer and Surgery, Oslo University Hospital, Montebello, N-0310 Oslo, Norway.
authors.forename: Peter
authors.initials: P
authors.lastname: Van Loo
authors.forename: Silje H
authors.initials: SH
authors.lastname: Nordgard
authors.forename: Ole Christian
authors.initials: OC
authors.lastname: Lingjærde
authors.forename: Hege G
authors.initials: HG
authors.lastname: Russnes
authors.forename: Inga H
authors.initials: IH
authors.lastname: Rye
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Weigman
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Anders
authors.initials: A
authors.lastname: Zetterberg
authors.forename: Bjørn
authors.initials: B
authors.lastname: Naume
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
mesh_terms: D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D052138:Genes, Neoplasm; D015894:Genome, Human; D006801:Humans; D011003:Ploidies