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I am studying copy-number variation. I am reading

C. H. Mermel, S. E. Schumacher, B. Hill, M. L. Meyerson, R. Beroukhim, and G. Getz, “GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers,” Genome Biol., vol. 12, no. 4, p. R41, 2011.

Here, it is written that

Segmented copy number profiles represent the summed outcome of all the SCNAs [somatic copy number alterations] that occurred during cancer development. Accurate modeling of the background rate of copy-number alteration requires analysis of the individual SCNAs. However, because SCNAs may overlap, it is impossible to directly infer the underlying events from the final segmented copy-number profile alone.

It is not clear to me how a segmented copy number profile represents the summed outcome of all the SCNAs. Is it because different alterations can be present in the same sample, or can alter the copy-number in different moments, or both?

And, do they overlap spatially, temporally, or both?

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  • $\begingroup$ Yes, one sample can contain different alterations. For each patient there is typically one tumour specimen that is removed. That specimen may be divided up into several samples (e.g. one for DNA sequencing, one for RNA sequencing, one for methylation microarray, and one for copy-number variation microarray), however each sample contains thousands of individual cells and two adjacent cells may have different CNVs (depending on their clonal ancestry, etc.). In other words, a tumour is a heterogeneous collection of cells. For some tumour types there can even be healthy cells mixed in. $\endgroup$ – mdperry Jun 3 '15 at 16:15
  • $\begingroup$ Hi, can you please put it in an answer, if it's an answer.. and with references.. so I can accept it. $\endgroup$ – gc5 Jun 4 '15 at 9:20
  • $\begingroup$ There you go. Done! $\endgroup$ – mdperry Jun 5 '15 at 11:55
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Yes, one sample can contain different alterations. For each patient there is typically one tumour specimen that is removed. That specimen may be divided up into several samples (e.g. one for DNA sequencing, one for RNA sequencing, one for methylation microarray, and one for copy-number variation microarray), however each sample contains thousands of individual cells and two adjacent cells may have different CNVs (depending on their clonal ancestry, etc.). In other words, a tumour is a heterogeneous collection of cells. For some tumour types there can even be healthy cells mixed in.

The term in the literature is clonal evolution, there is a nice image in this article: Tumor Heterogeneity

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To directly respond to the quote presented,

Segmented copy number profiles represent the summed outcome of all the SCNAs [somatic copy number alterations] that occurred during cancer development.

As a tumor progresses, genomic instability can often increase. That is, more and more SCNAs occur. Because of this, one SCNA can overlap another.

Copy Number profile in evolving tumor

For example, look at the tumor progression of the chromosome above. Let's say you have a loss on this chromosome (Event 1 the MATERNAL chromosome). This loss can occur by many mechanisms which I won't go into. The tumor proliferates, splitting many times, and mutations are accumulating. These mutations can cause more events to occur, and perhaps on this same chromosome arm, the distal part of the remaining copy is duplicated (Event 2 the PATERNAL chromosome).

In the copy number profile, it will look as though you had a loss on just an interstitial part of the chromosome. But looking closely at the data, you can see that you've lost heterozygosity on the distal portion of the chromosome as well (we now have two copies of the PATERNAL chromosome, and 0 copies of the MATERNAL). This is a simplified example, and many events can occur along the same chromosome arm. If the paternal chromosome holds a mutation, this can mean a selective advantage for the tumor or resistance to drug therapies.

Therefore, the CN profile represents a snapshot in time of what the copy number state was at that moment, with no explicit information on how that copy number state was obtained.

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