Allele-specific copy number analysis of tumors.
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.
Van Loo
Peter
P
Department of Genetics, Institute for Cancer Research, Clinic for Cancer and Surgery, Oslo University Hospital, Montebello, N-0310 Oslo, Norway.
Nordgard
Silje H
SH
Lingjærde
Ole Christian
OC
Russnes
Hege G
HG
Rye
Inga H
IH
Sun
Wei
W
Weigman
Victor J
VJ
Marynen
Peter
P
Zetterberg
Anders
A
Naume
Bjørn
B
Perou
Charles M
CM
Børresen-Dale
Anne-Lise
AL
Kristensen
Vessela N
VN
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