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.2008 Oct 21;105(42):16224-9.
doi: 10.1073/pnas.0808041105. Epub 2008 Oct 13.

Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers

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Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers

Rebecca J Leary et al. Proc Natl Acad Sci U S A..

Abstract

We have performed a genome-wide analysis of copy number changes in breast and colorectal tumors using approaches that can reliably detect homozygous deletions and amplifications. We found that the number of genes altered by major copy number changes, deletion of all copies or amplification to at least 12 copies per cell, averaged 17 per tumor. We have integrated these data with previous mutation analyses of the Reference Sequence genes in these same tumor types and have identified genes and cellular pathways affected by both copy number changes and point alterations. Pathways enriched for genetic alterations included those controlling cell adhesion, intracellular signaling, DNA topological change, and cell cycle control. These analyses provide an integrated view of copy number and sequencing alterations on a genome-wide scale and identify genes and pathways that could prove useful for cancer diagnosis and therapy.

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Conflict of interest statement

Conflict of interest statement: Under separate licensing agreements between Beckman Coulter and the Johns Hopkins University and Genzyme Corporation and the Johns Hopkins University, V.E.V., K.W.K., and B.V. are entitled to a share of royalties received by the University on sales of products described in this article. V.E.V., K.W.K., and B.V. and the University own Genzyme Corporation stock, which is subject to certain restrictions under University policy. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

Figures

Fig. 1.
Fig. 1.
Alterations in the combined FGF, EGFR, ERBB2, and PI3K pathways. Genes affected by copy number alterations are circled in red, whereas those altered by point mutations are circled in blue. The number of breast (B) and colorectal (C) tumors containing alterations are indicated in boxes adjacent to each gene.
Fig. 2.
Fig. 2.
Genomic landscape of copy number and nucleotide alterations in two typical cancer samples.A indicates breast cancer alterations, whereasB indicates colorectal cancer alterations. The telomere of the short arm of chromosome 1 is represented in the rear left corner of the green plane and ascending chromosomal positions continue in the direction of the arrow. Chromosomal positions that follow the front edge of the plane are continued at the back edge of the plane of the adjacent row and chromosomes are appended end to end. Peaks indicate the 60 highest-ranking candidate cancer genes for each tumor type, with peak heights reflecting the passenger probability scores. The yellow peaks correspond to genes that are altered by copy number changes, whereas those altered only by point mutations are purple. The dots represent genes that were altered by copy number changes (red squares) or point mutations (white circles) in the B9C breast or Mx27 colorectal tumor samples. Altered genes participating in significant gene groups or pathways (Table S6) are indicated as black circles or squares.
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