Integrated Analyses of Breast and Colorectal Cancers

a technology of integrated analysis and breast cancer, which is applied in the field of breast and colorectal cancer, can solve the problems of difficult detection of primary tumors, infrequent detection of high copy amplification or homozygous deletion (hds), and difficult identification of focal hds

Inactive Publication Date: 2010-06-03
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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Problems solved by technology

However, identification of focal, high copy amplifications or homozygous deletions (HDs) have infrequently been reported because many prior copy number analyses on arrays have used genomic DNA purified from primary tumors.
Furthermore, HDs can be difficult to discern in primary tumors due to confounding hybridization signals from non-neoplastic cells (17).

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  • Integrated Analyses of Breast and Colorectal Cancers
  • Integrated Analyses of Breast and Colorectal Cancers
  • Integrated Analyses of Breast and Colorectal Cancers

Examples

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example 1

Optimization of Copy Number Analysis with Digital Karyotyping

[0042]Digital Karyotyping (DK) was used as a standard to develop criteria for assessing amplifications and HDs with Illumina high density SNP arrays. Analysis of DK libraries from 18 colorectal tumor samples identified a total of 21 amplification events, each containing relatively small chromosomal regions (41 kb to 2.3 Mb) with 12 to 186 copies per nucleus (SI Table 2). We also found 4 regions within the autosomal chromosomes where the tag density reached zero, representing HDs. As expected, we identified low-amplitude gains and losses of entire chromosomes, chromosomal arms, or other large genomic regions. We did not pursue these low-amplitude copy number changes as it is difficult to reliably identify candidate cancer genes from such large regions. To ensure that the copy number changes identified by DK were bona fide amplifications or HDs, we independently examined 12 alterations by quantitative PCR and confirmed the p...

example 2

Detection of Amplifications and Homozygous Deletions

[0045]A total of 45 breast and 36 colorectal tumors were analyzed by Illumina arrays containing either ˜317,000 or ˜550,000 SNPs (SI FIG. 1). To determine the fraction of alterations that were likely to be somatic (i.e., tumor derived), we analyzed these regions in 23 matched normal samples. In the normal samples, no amplifications and only four distinct HDs were detected. We removed these alterations from further analysis, as well as those corresponding to known copy number variation in normal human cells (27, 28). Finally, we removed any copy number changes where the boundaries were identical in two or more samples, as these were likely to represent germline variants. Based on this conservative strategy, we estimated that >95% of the 614 amplifications and 463 HDs (SI Table 3) represented true somatic alterations.

[0046]Breast cancers contributed to a majority of the alterations identified, comprising 68% and 81% of the total HDs ...

example 3

Genes Altered in More than One Tumor

[0048]One of the main challenges in the analysis of somatic alterations in cancers involves the distinction between those changes which are selected for during tumorigenesis (driver alterations) from those that provide no selective advantage (passenger alterations). Even in regions that have multiple copy number alterations, this distinction can be particularly difficult because regions of amplification and HD can contain multiple genes, only a subset of which are presumably the underlying targets. We reasoned that the integration of copy number analyses with sequence data would help reveal the driver genes that were more likely to contain genetic alterations. To accomplish this integration, we developed a new statistical approach for determining whether the observed genetic alterations of any type in any gene were likely to reflect an underlying mutation frequency that was significantly higher than the passenger rate. To analyze the probability t...

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Abstract

Genome-wide analysis of copy number changes in breast and colorectal tumors used approaches that can reliably detect homozygous deletions and amplifications. The number of genes altered by major copy number changes—deletion of all copies or amplification of at least twelve copies per cell—averaged thirteen per tumor. These data were integrated with previous mutation analyses of the Reference Sequence genes in these same tumor types to identify genes and cellular pathways affected by both copy number changes and point alterations. Pathways enriched for genetic alterations include 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 are useful for cancer diagnosis and therapy.

Description

[0001]The disclosed invention was made using funds from the U.S. government, particularly National Institutes of Health grants CA 043460, CA 057345, CA 062924, and CA 121113. The U.S. government therefore retains certain rights in the invention.TECHNICAL FIELD OF THE INVENTION[0002]This invention is related to the area of classifying, characterizing, detecting and diagnosing cancers. In particular, it relates to breast and colorectal cancers.BACKGROUND OF THE INVENTION[0003]It is well accepted that cancer is the result of the sequential mutations of oncogenes and tumor suppressor genes (1). Historically, the discovery of these genes has been accomplished through analyses of individual candidate genes chosen on the basis of functional or biologic data implicating them in the tumorigenic process. Recent advances in genomic technologies and bioinformatics have permitted simultaneous evaluation of many genes, thereby offering more comprehensive and unbiased information (2, 3). For examp...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12Q1/68
CPCC12Q2600/156C12Q1/6886A61P35/00
Inventor VOGELSTEIN, BERTKINZLER, KENNETH W.LEARY, REBECCA J.VELCULESCU, VICTOR E.
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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