title: INPP4B and RAD50 have an interactive effect on survival after breast cancer.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, PO Box 700, 00029 HUS, Helsinki, Finland.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Dai
authors.forename: Rainer
authors.initials: R
authors.lastname: Fagerholm
authors.forename: Sofia
authors.initials: S
authors.lastname: Khan
authors.forename: Carl
authors.initials: C
authors.lastname: Blomqvist
authors.forename: Heli
authors.initials: H
authors.lastname: Nevanlinna
mesh_terms: D017766:Acid Anhydride Hydrolases; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D056915:DNA Copy Number Variations; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D030541:Databases, Genetic; D004843:Epistasis, Genetic; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D019398:Genes, BRCA1; D006801:Humans; D008207:Lymphatic Metastasis; D008875:Middle Aged; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D011379:Prognosis; D014176:Protein Biosynthesis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D014158:Transcription, Genetic; D047368:Tumor Burden
chemical_list: D017766:Acid Anhydride Hydrolases; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D010744:Phosphoric Monoester Hydrolases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase; C112158:RAD50 protein, human