Therapeutic implications of cancer gene amplifications without mRNA overexpression: silence may not be golden.

Amplifications of oncogenic genes are often considered actionable. However, not all patients respond. Questions have therefore arisen regarding the degree to which amplifications, especially non-focal ones, mediate overexpression. We found that a subset of high-level gene amplifications (≥ 6 copies) (from The Cancer Genome Atlas database) was not over-expressed at the RNA level. Unexpectedly, focal amplifications were more frequently silenced than non-focal amplifications. Most non-focal amplifications were not silenced; therefore, non-focal amplifications, if over-expressed, may be therapeutically tractable. Furthermore, specific silencing of high-level focal or non-focal gene amplifications may explain resistance to drugs that target the relevant gene product.