Today we celebrated my official Group Leader appointment and paper publications with bubbles and prinsesstårta, the Swedish way! 🍰🥂🍾 Skål!

10/ RBM14 amplification (which occurs in the CCND1 locus) is clinically actionable! We find that RBM14 amplification status is correlated with survival in a recently published cohort of >1000 colorectal cancer patients treated with irradiation as standard of care.

9/ We additionally find that RBM14 overexpression can induce an innate immune response, activating the STING-STAT3 axis (we interpret changes in STING perinuclear localization as a marker of pathway activation) and rendering cells more sensitive to STAT3 inhibition.

8/ Given its role in c-NHEJ-mediated DNA repair, we evaluated the effects of RBM14 overexpression in DNA damage response. We found that gene overexpression increases reliance on DNA repair by c-NHEJ (an error-prone process) over HR, increasing the rate of aberrant cell divisions.

7/ We observe a similar effect with RBM14, encoding a member of the family of RNA binding proteins and the HDP-RNP paraspeckle complex. RBM14 is focally amplified on chromosome 11 and results toxic to breast and lung cancer cells when overexpressed.

6/ The well-known cell cycle inhibitor CDKN1A (p21) is an ARGOS gene amplified at the arm-level in chromosome 6p. By creating inducible cell line models, we show that overexpression of CDKN1A impairs the growth of breast cancer cells.

5/ The overlap between “compensated” and “toxic” genes identified eight ARGOS gene candidates across cancers, from which we selected CDKN1A and RBM14 for follow-up validation.

4/ By analyzing data from 17 ORF screens conducted by many of our wonderful collaborators and co-authors
@broadinstitute.org, we identify many genes that result detrimental (i.e. cause growth inhibition or cell death) to cancer cells when overexpressed. We term these “toxic genes”.

3/ The expression of these collaterally altered genes should scale with their copy number. However, by integrating data from >8000 tumors in TCGA & CCLE, we identify amplified genes that are consistently expressed at lower levels than expected, and term them “compensated genes”.

2/ Our study stems from the observation that large chromosomal regions are often gained or lost in cancer. These copy number changes impact not only driver genes but also nearby genes, which become “collaterally altered”.

1/ We describe a new class of cancer genes which we have termed ARGOS. Just like the multi-eyed giant in Greek mythology, ARGOS genes have multiple copies in cancer cells, yet are expressed at lower levels than expected by their copy number and result toxic when overexpressed.