Biomarker Discovery in Cancer using Affinity Proteomics - Studies of B-cell lymphomas and Breast Cancer

Sammanfattning: The continual increase in incidence of cancer has created an urgent need for improved methods for diagnosis, prognosis and/or treatment. In this context, the field of biomarker research has expanded immensely during the last few years. This thesis, based on four original papers, revolves around protein biomarker discovery in cancer. For this purpose, an in-house design recombinant antibody microarray technology was used, a proteomic technology which has in the recent years been established as a sensitive, high-throughput method for protein expression profiling of complex samples. In paper I, we presented the first array setup for analysis of formalin-fixed, paraffin-embedded (FFPE) tissue, the traditional method for handling and storing tissue material in clinics, using recombinant antibody microarrays and thus identified an attractive way of addressing the extensive repertoire of retrospective FFPE samples available worldwide. B-cell lymphoma (BCL) is the most common type of hematological malignancy, but diagnosis and prognosis is inherently difficult to establish due to the large heterogeneity of the disease. In paper II, we confirmed the heterogeneity on a plasma protein level for four different BCLs. Moreover, immunoprofiles dividing these BCLs into subgroups were identified, and the subgrouping of one, diffuse large B-cell lymphoma (DLBCL), was correlated with survival. In paper III, the immunoprofiles of DLBCL patients undergoing treatment were investigated, revealing signatures which distinguished DLBCL patients from healthy controls, and moreover, delineated immunoprofiles associated with prognostic measures. In addition, the subgrouping of DLBCL found in paper II was pre-validated, and potential prognostic markers which, in this patient cohort, improved the prediction power of today’s golden standard for prognosis, the International Prognostic Index, were identified. Paper IV was aimed at identifying biomarkers associated with early breast cancer, the most common cancer type to afflict women, using the immune system as an early sensor for disease. In the study, we identified previously known and novel proteins associated with early breast cancer. In addition, anti-tumor and tumor promoting proteins implicated in the process of cancer imunnoediting were identified, demonstrating that a minimally invasive blood sample harbors disease-specific information reflecting early breast cancer and biological process thereof. In summary, this thesis has contributed to the development of the recombinant antibody microarray technology by extending the range of sample formats available for analysis. In addition, immunoprofiles delineating cancer heterogeneity, effects of cancer treatment over time, and the effects on immunoprofiles in the early stages of cancer have been identified, which may potentially, in the long run, come to the benefit of cancer patients through improved diagnosis and prognosis.