Genes sharing similar genomic landscape have the potential to interactively orchestrate certain clinicopathological features of a disease. Deletion of the RAD50 gene is a common event particularly in basal-like breast cancer, and often occurs together with deletions of BRCA1, RB1, TP53, PTEN, and INPP4B. In this study, we investigate whether these co-deleted genes have interactive effects on survival in breast cancer. Using publicly available TCGA data, we employed Cox’s proportional hazards models to test whether genomic deletions of these genes, or reduced protein or transcript levels associate with breast cancer patient survival in an interactive manner. Further validation was obtained at the transcriptional level by including 1,596 additional cases from 13 publicly available gene expression data sets from the KM-plotter database. Our results indicate that RAD50 and INPP4B associate interactively with breast cancer survival at the transcriptional, translational, and genomic levels in the TCGA data set (p (interaction) < 0.05). While neither of the genes was independently prognostic on its own, low INPP4B levels in combination with above median RAD50 abundance associated with increased hazard, both at the mRNA (HR 2.39, 95 % CI 1.20–4.76) and protein (HR 2.92, 95 % CI 1.42–6.00) levels, whereas concomitant deletion or low expression of both genes associated with unexpectedly improved survival. A similar pattern was observed in the KM-plotter data set (p (interaction) = 0.0067). We find that RAD50 and INPP4B expression levels have a synergistic influence on breast cancer survival, possibly through their effects on treatment response.
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The Cancer Genome Atlas
Copy number variation
Reverse-phase protein microarray
Lymph node metastasis
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This work was supported by the Helsinki University Central Hospital Research Fund, the Finnish Cancer Society, the Sigrid Juselius Foundation, and the Academy of Finland (266528). The results shown in this study are in part based upon data generated by the TCGA Research Network (http://cancergenome.nih.gov/) and the Kaplan–Meier Plotter database (http://kmplot.com/). We thank the specimen donors and research groups who have provided these data and made this study possible.
Conflicts of interest
All authors declare no conflicts of interest.
Xiaofeng Dai and Rainer Fagerholm have contributed equally to this work.
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Dai, X., Fagerholm, R., Khan, S. et al. INPP4B and RAD50 have an interactive effect on survival after breast cancer. Breast Cancer Res Treat 149, 363–371 (2015). https://doi.org/10.1007/s10549-014-3241-y
- Breast cancer