Send to

Choose Destination
Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):E11276-E11284. doi: 10.1073/pnas.1714877115. Epub 2017 Dec 11.

Identification of cancer genes that are independent of dominant proliferation and lineage programs.

Author information

Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115;


Large, multidimensional cancer datasets provide a resource that can be mined to identify candidate therapeutic targets for specific subgroups of tumors. Here, we analyzed human breast cancer data to identify transcriptional programs associated with tumors bearing specific genetic driver alterations. Using an unbiased approach, we identified thousands of genes whose expression was enriched in tumors with specific genetic alterations. However, expression of the vast majority of these genes was not enriched if associations were analyzed within individual breast tumor molecular subtypes, across multiple tumor types, or after gene expression was normalized to account for differences in proliferation or tumor lineage. Together with linear modeling results, these findings suggest that most transcriptional programs associated with specific genetic alterations in oncogenes and tumor suppressors are highly context-dependent and are predominantly linked to differences in proliferation programs between distinct breast cancer subtypes. We demonstrate that such proliferation-dependent gene expression dominates tumor transcriptional programs relative to matched normal tissues. However, we also identified a relatively small group of cancer-associated genes that are both proliferation- and lineage-independent. A subset of these genes are attractive candidate targets for combination therapy because they are essential in breast cancer cell lines, druggable, enriched in stem-like breast cancer cells, and resistant to chemotherapy-induced down-regulation.


bioinformatics; breast cancer; gene expression; oncogene; tumor biology

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center