Why do focal aberrations in cancer more intense than arm-length aberrations?

Question

[Avro]

Hi everyone,

I am using aCGH data. I have noticed that focal events are much more aberrated than arm-length (i.e higher log2 ratio). I am looking for a biological explanation. Does someone have an idea or could please refer me to some articles?

Thank you!

Answer 1

[fongchunchan]

A higher log2 ratio may be indicative of a more significant copy number alteration (e.g. homozygous deletion). Tumour cells may actually select against having entire chromosomal arm homozygous deletion as this may be deleterious to the cells. However, a focal homozygous deletion (e.g. CDKN2A) gives a selective advantage to the tumour cells with potentially no harmful effects.

This is just an hypothesis of course. But there is some evidence for this line of thinking. For instance Figure 2 of "Emerging landscape of oncogenic signatures across human cancers " shows cancers often harbour either lots copy number alterations or single point mutations, but often not both. This is likely attributed to synthetic lethality since acquisition of such alterations is typically associated with deficiencies in DNA damage repairs mechanisms. If tumour cells have both copy number AND single point DNA repair mechanisms, this is potentially lethal to them. This is why selection may operate to negatively select against these types of tumour cells and selects for tumour cell with either one of these DNA repair deficiency.

Hope that helps.