Biological Convergence of Cancer Signatures

Abstract

Gene expression profiling has identified cancer prognostic and predictive signatures with superior performance to conventional histopathological or clinical parameters. Consequently, signatures are being incorporated into clinical practice and will soon influence everyday decisions in oncology. However, the slight overlap in the gene identity between signatures for the same cancer type or condition raises questions about their biological and clinical implications. To clarify these issues, better understanding of the molecular properties and possible interactions underlying apparently dissimilar signatures is needed. Here, we evaluated whether the signatures of 24 independent studies are related at the genome, transcriptome or proteome levels. Significant associations were consistently observed across these molecular layers, which suggest the existence of a common cancer cell phenotype. Convergence on cell proliferation and death supports the pivotal involvement of these processes in prognosis, metastasis and treatment response. In addition, functional and molecular associations were identified with the immune response in different cancer types and conditions that complement the contribution of cell proliferation and death. Examination of additional, independent, cancer datasets corroborated our observations. This study proposes a comprehensive strategy for interpreting cancer signatures that reveals common design principles and systems-level properties.

Upregulation of adenylate cyclase 3 (ADCY3) increases the tumorigenic potential of cells by activating the CREB pathway

“…ADCY3 expression may be affected by promoter CpG methylation, a well-known epigenetic mechanism for cancer-specific changes in gene expression. According to the encyclopedia of DNA elements (ENCODE) annotation [36], the region of the ADCY3 promoter analyzed in our study harbors binding sites for critical transcription factors, including early growth response protein 1 (Egr-1), E2F, and activating protein 2 (AP-2), which are known to promote the development of an environment conducive for tumor formation [37,38]. It is possible that environmental factors alter the methylation status of the ADCY3 promoter region, upregulating the expression of ADCY3 in gastric tissue.…”

Identification of a panel of ten cell surface protein antigens associated with immunotargeting of leukemias and lymphomas by peripheral blood T cells

“…28 Our analyses led to the identification of a large panel of genes differentially expressed between "γδ-susceptible" and "γδ-resistant" tumors. Importantly, we verified that there was no correlation between intrinsic anti-apoptotic properties and resistance to γδ-PBL cytotoxicity, both in terms of gene expression and response to a death stimulus.…”

Translating Tumor Antigens into Cancer Vaccines

“…These studies have been performed in breast, colorectal, pancreatic, and lung cancers and glioblastoma and, overall, have identified almost 400 candidate cancer genes (CANgenes) (48,83,134,199). Interestingly, systems-level analyses show that, despite the low degree of overlap in terms of gene identity, cancer signatures converge on specific biological processes, as defined by significant molecular and functional associations between genes and/or proteins (68, 163,170).…”