Serum tumor markers are invasive diagnostic tools for malignant tumors and have been commonly used for purposes of screening, prognosis and selection of treatments. In order to develop a new marker, gene expression analysis technologies such as DNA microarray, differential display, cDNA subtraction, and serial analysis of gene expression, which enable investigators to obtain comprehensive data with respect to gene-expression profiles, are progressing rapidly. Several studies have already demonstrated the usefulness of these techniques for identifying novel cancer-related genes and for classifying human cancers at the molecular level. However, significant differences between the abundance ratio of the mRNA transcript and the corresponding protein product are observed for many genes. Also, the protein level in serum is affected by many physiological conditions and related circumstances, not only by mRNA levels in the cell. Therefore, quantitative proteomics technology based on high-resolution two-dimensional gel electrophoresis and mass spectrometric analysis is being developed. One of our goals is the serological evaluation for the new candidate proteins derived from the information of the above transcriptome and/or proteome analysis as a tumor marker. In this report, I will discuss the practical process of the investigation with special regards to a new protein named ALCAN which has been studied through cDNA cloning, preparation of recombinant protein and monoclonal antibodies, construction of immune assay system, and clinical evaluation.

An important pathway of gene transcriptional inactivation is hypermethylation at the CpG islands of promoter regions. Some tumor suppressor genes have been reported to harbor promoter hypermethylation in head and neck cancer. We studied DNA hypermethylation of 4 genes in 42 cases of primary head and neck cancer. We applied methylation specific PCR for p16, RAR-beta, RASSF1A, and Fhit genes. Hypermethylation was detected at p16 in 43%, at RAR-beta in 40%, at RASSF1A in 12%, and at Fhit in none of the cases. Hypermethylation of at least one gene was detected in 26 (62%) of the 42 cases. No significant correlation was seen between methylation status and clinicopathological findings or prognosis. Hypermethylation of several tumor-associated genes plays an important role in tumorigenesis of head and neck cancer. We discuss clinical implications and their application.

Aberrant Wnt pathway signaling is an early progression event in up to 90% of colorectal cancers (CRC). It occurs mainly through mutations of APC or beta-catenin. We have identified frequent promoter hypermethylation and gene silencing of the secreted frizzled-related protein (SFRP) genes in CRC. SFRPs possess a domain similar to one in the Wnt receptor Frizzled proteins and can inhibit Wnt receptor binding to downregulate pathway signaling in development. We next found that restoration of SFRP function in CRC cells attenuates Wnt signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in CRC progression and may, thus, provide constitutive Wnt signaling which is required to complement downstream mutations in the evolution of CRC.

Chronic myelogenous leukemia (CML) is a clonal hematopoietic disorder caused by the reciprocal translocation between chromosome 9 and 22. As a result of this translocation, a novel fusion gene, BCR-ABL, is created on Philadelphia (Ph) chromosome, and the constitutive activity of the BCR-ABL protein tyrosine kinase plays a critical role in the disease pathogenesis. Imatinib mesylate, a selective BCR-ABL tyrosine kinase inhibitor, was first given to a patient with CML in June 1998. Since then, it has continued to demonstrate remarkable efficacy in treating patients with CML. Based upon the results of early phase I and II studies, a phase III study (IRIS Study) that was randomized to first-line imatinib (400 mg/day) or to standard treatment with interferon+low-dose Ara-C, was conducted on 1,106 patients newly diagnosed (within 6 months) with chronic-phase CML. After median follow-up of 30 months, imatinib showed significantly superior tolerability, hematologic and cytogenetic responses (major cytogenetic response, 90%; complete cytogenetic response, 82%), and overall survival (95% without censoring allo-HSCT). Although imatinib is the first-line therapy and has changed the paradigm of CML treatment strategy, questions remain as to the meaning of cytogenetic and molecular response, curability, optimal dose, and relation with allo-HSCT.

Now dozens of genetic abnormalities have been identified in leukemias and lymphomas mainly through breakpoint analyses of the chromosome translocations recurrently observed in these tumors. After analyses on most of the major chromosome translocations have been completed, the current interests of genetic researches on hematopoietic tumors are unbalanced chromosome abnormalities that accompany gene deletions and amplifications among a variety of genetic mutations. In this regard, array based comparative genomic hybridization (CGH) and related techniques provide robust measures that enable high throughput genome-wide estimations of copy number changes for a large number of tumor samples. With these and other innovative techniques, identification of relevant genes for leukemogenesis and lymphomagenesis is being accelerated to provide more comprehensive understandings on development of these hematopoietic neoplasms.

Genetic microarrays applied to hematologic malignancies identified a number of subgroups with a defined gene expression pattern, which were not identified by morphology, cytogenetics or molecular genetics. In many cases, these expression patterns links tumor cells to the normal developmental counterpart, and represent distinct disease subgroups with different clinical presentations and outcomes. Furthermore, genetic microarrays will be useful in predicting prognosis and identifying novel target of therapy.

Prostate cancer is one of the most common cancers in Western men. In Japan, the incidence of this malignancy is increasing. Recent advances in molecular biology brought new biomarkers to prostate cancer diagnosis. In this article, we describe new biomarkers including serum and genetic and histochemical markers for screening, staging and drug selection for the management of prostate cancer patients.

Accumulation of information about genetics and epigenetics has accelerated research investigating the inherent individual variation in cancer susceptibility. Gene polymorphisms, in particular single nucleotide polymorphisms, are being evaluated for their role in various cancers including prostate cancer. Especially, polymorphisms of hormone-related genes such as steroid-hormone receptors in prostate cancer have been recently focused and used in molecular epidemiology. In this article, we present data from the molecular epidemiology about Japanese prostate cancer using polymorphisms of hormone-related genes and offer suggestions for further research.

The molecular and biochemical mechanisms contributing to the development and progression of prostate carcinogenesis are still unknown. Recent technologies such as, real-time PCR, microarray, and laser capture microdissection, have accelerated the study of the molecular events involved in prostate cancer. The expression and function of numerous genes have been shown to be altered in prostate cancer. Such gene regulations are involved in cell cycle, signal transduction pathways, or gene expression. Analysis of the genes during prostate cancer progression has provided a better understanding of the basis of the disease. This review summarises current knowledge of the molecular analysis for prostate cancer.