Cancer affects millions of people worldwide. Tumor mortality is substantially due to diagnosis at stages that are too late for therapies to be effective. Advances in screening methods have improved the early diagnosis, prognosis, and survival for some cancers. Several validated biomarkers are currently used to diagnose and monitor the progression of cancer, but none of them shows adequate specificity, sensitivity, and predictive value for population screening. So, there is an urgent need to isolate novel sensitive, specific biomarkers to detect the disease early and improve prognosis, especially in high-mortality tumors. Proteomic techniques are powerful tools to help in diagnosis and monitoring of treatment and progression of the disease. During the last decade, mass spectrometry has assumed a key role in most of the proteomic analyses that are focused on identifying cancer biomarkers in human serum, making it possible to identify and characterize at the molecular level many proteins or peptides differentially expressed. In this paper we summarize the results of mass spectrometry serum profiling and biomarker identification in high mortality tumors, such as ovarian, liver, lung, and pancreatic cancer. 1. Introduction Cancer-related mortality is one of the leading causes of death worldwide. The most effective treatment to fight cancer is still early diagnosis. On the other hand, it is known that the correct classification of the tumor, coupled to a suitable therapy and to a stringent follow-up, helps to prevent and detect relapses. Cancer is a very heterogeneous disease, and, at the diagnostic level, is defined by many indexes such as histological grade, tumor stage, patient age, sex and, more importantly, genetic background and profiles. Histological evaluation of tumor specimens obtained from tissue biopsy is the gold standard of diagnosis, but often tumors with the same histopathological features respond differently to the same therapy. New generation diagnostic platforms, previously unavailable, have enabled to better characterize transcriptomic signatures that predict tumor behaviour, helping to define diagnosis, prognosis, and the most appropriate therapies [1–3]. Tumor biomarker discovery in biological fluids, such as serum, plasma, and urine, is one of the most challenging aspects of proteomic research [4]. Many researchers have attempted to identify biomarkers in serum that reflect a particular pathophysiological state. Since the expressed proteins, native, fragmented, or posttranslationally modified, quickly change in response to environmental
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