14-gene immunoglobulin (IGG) and proliferation signatures and association with overall survival across cancer-types

2636 Background: The HER2DX prognostic assay in early-stage HER2-positive breast cancer integrates clinical variables and 4 gene expression signatures (GES) tracking IGG, tumor proliferation, luminal cell differentiation, and the expression of the HER2 amplicon. Here, we assessed the prognostic value across cancer-types of each of these four individual GES and a research-based version of the HER2DX risk-score. Methods: RSEM batch normalized RNA-sequencing gene expression data from The Cancer Genome Atlas (TCGA) project were downloaded from cBioPortal. The association between a research-based version of the HER2DX risk-score, and each GES, with overall survival (OS) was assessed as continuous variables using univariate Cox regression model. The research-based version of the HER2DX risk-score tested did not include clinical variables. The Cox model was applied to estimate hazard ratios (HR) with 95% confidence intervals. The threshold for statistical significance was set at p< 0.05. Results: Gene expression data from 9,852 patients representing 30 different cancer-types were evaluated. The proliferation, IGG, luminal and HER2 amplicon GES were significantly associated with OS in 40.0%, 33.3%, 23.0% and 6.7% of the cancer-types tested, respectively. The IGG GES was found significantly associated with a favorable OS in breast cancer (HR: 0.73, p < 0.001), cervical and head & neck squamous cell carcinomas (HR: 0.75, p = 0.021 and HR: 0.78, p < 0.001), lung adenocarcinoma (HR: 0.84, p = 0.020), skin melanoma (HR: 0.73, p < 0.001) and sarcomas (HR: 0.78, p = 0.029). Conversely, association of IGG GES with unfavorable OS was observed in uveal melanoma (HR: 1.74, p = 0.008), kidney clear cell and papillary cell carcinomas (HR: 1.29, p < 0.001 and HR: 1.44, p = 0.017, respectively), as well as brain low-grade gliomas (LGG) (HR: 1.56, p < 0.001). Finally, the research-based HER2DX risk-score was found significantly associated with OS in 11 of 30 (36.7%) cancer-types, including breast (HR: 1.42, p < 0.001) cervical and head & neck squamous cells cancers (HR: 1.36, p = 0.018 and HR: 1.30, p < 0.001), lung adenocarcinoma (HR: 1.34, p < 0.001), skin melanoma (HR: 1.34, p < 0.001), sarcomas (HR: 1.41, p = 0.003), adrenocortical carcinoma (HR: 2.31, p < 0.001), endometrial carcinoma (HR: 1.36, p = 0.005), hepatocarcinoma (HR: 1.26, p = 0.012), LGG (HR: 1.37, p = 0.001) and mesothelioma (HR: 1.48, p = 0.005). Conclusions: The 14-gene IGG and proliferation signatures are strong prognostic biomarkers across cancer-types. The opposite association of IGG with OS depending on the cancer-type warrants further investigation.