Alterations in protooncogenes and tumor-suppressor genes at the DNA and/or protein level indicate the biological properties of individual breast cancers. Information on these genetic and protein alterations is considered to be useful diagnostically and these alterations are now being applied in routine diagnosis or are under investigation for diagnostic application in the areas of: 1) determination of indications for specific therapies for advanced or metastatic breast cancers; 2) prediction of the response of primary tumors to adjuvant or neoadjuvant systemic therapies; and 3) identification of patient groups at high or low risk of recurrence from node-negative breast cancer.

Lung carcinoma is a common malignant disease in adults. Various genetic changes associated with small cell and non-small cell lung carcinoma are now known. There are two types of genetic change which influence tumor growth and patient prognosis. Among oncogenes, c-myc, K-ras, and erbB-2 are considered to play important roles in lung carcinogenesis. The p53 suppressor gene is highly expressed in small and non-small cell carcinoma. To differentiate between double primary lung carcinomas and intrapulmonary metastasis, or between primary lung carcinoma and metastatic lung tumor, the analysis of gene mutations, such as of p53 and K-ras, appears to be very useful.

Pancreatic cancer is an important cause of death from cancer throughout the world. Until recently, pancreatic cancer was a poorly understood disease. Research in the past decade has shown conclusively, however, that pancreatic cancer is primarily genetic in nature. Inactivation with a variety of tumor-suppressor genes such as p53, p16, and DPC4, and genome-maintenance genes such as BRCA2, coupled with the activation of oncogenes such as K-ras, are a few of the mutations that trigger the growth of cancerous cells. The genetic profile of pancreatic cancer has reshaped the nomenclature describing histological progression in pancreatic ductal tumorigenesis. K-ras mutations frequently occur early, whereas changes in the expression and genetic integrity of the p16 gene appear in intermediate lesions, and the inactivation of the p53 and DPC4 genes and activation of telomerase occur late in the neoplastic progression. Although the majority of pancreatic cancers occur sporadically, a minority has been shown to aggregate in families and has aided our understanding of pancreatic tumorigenesis. An improved understanding of the genetics of pancreatic cancer should lead to the development of gene-based screening tests and novel rational therapies.

This paper provides a review of the known genetic diagnostic indicators of liver cancer. The correlation between the genetic diagnosis and clinical outcome in patients with hepatocellular carcinoma (HCC) has been widely reported, based on the detection of liver-specific mRNA or tumor DNA in the blood. Our results suggest that an alteration of alpha-fetoprotein (AFP) mRNA in peripheral blood from HCC patients during the perioperative period might permit the prediction of early recurrence after surgery. The presence of circulating HCC cells may be indicative of metastasis if liver-specific AFP mRNA is detected in the peripheral blood. However, some studies showed that sensitive RT-PCR might possibly give rise to false positivity because nontumor hepatocytes would also express low levels of AFP mRNA. Recently, quantification of AFP mRNA for HCC cell detection using real-time PCR or semiquantitative RT-PCR has proven useful in the prediction of metastasis/recurrence. On the other hand, circulating liver tumor DNA such as p16 and p15 methylation and mitochondrial mutations in the plasma and serum of liver cancer patients might be useful for monitoring, similar to the tumor markers. In future, HCC-specific genes and genes sensitive to radiation and chemotherapy are expected to have wide-spread clinical applications.

Based on the genetic and epigenetic abnormalities of cancer-related genes during the development and progression of gastric cancer, we have established a system of molecular-pathological diagnosis as a routine service in Hiroshima. Approximately 5,000 lesions of the stomach have been diagnosed and useful information on differential diagnosis, grade of malignancy, and tumor multiplicity has been obtained using this system. Further research on systemic gene expression profiles, epigenetic alterations, and genetic polymorphisms will improve the quality and efficiency of diagnosis. With the application of novel knowledge on molecular carcinogenesis and microarray techniques, molecular diagnosis will identify the characteristics of individual cancers and persons, which will lead to the development of personalized medicine.

The clinicopathological characteristics of esophageal cancer have gradually been clarified using molecular biologic methods developed over the past 20 years. For example, amplification of the c-erb B gene is a prognostic factor and predictive of lymph node involvement, while the amplification of the cyclin D1 gene is also a prognostic factor and predictive of distant organ metastasis. Alteration of the p16 gene is also a prognostic factor and predicts lymph node involvement. As telomerase activity is almost a unique phenomenon of cancer cells, highly sensitive detection of esophageal cancer cells in the peripheral blood can be performed. Recently, such new methods as comparative genomic hybridization analysis and cDNA microarray analysis have been used to determine meaningful genetic changes. For therapeutic purposes, although tailor-made therapy has been proposed for several years, the validity of these approaches should be confirmed in a well-designed clinical trial. As molecular targeted therapies, tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR) and monoclonal antibodies against EGFR are being studied in clinical trials in Western countries. A clinical trial of p53 gene therapy against esophageal cancer is also promising.

The basic outlines of the Millennium Genome Project were drawn by the Japanese government on December 19, 1999. In the "Disease gene" team, 5 disease have been chosen as the targets of the Project, Alzheimer's disease, cancer, diabetes, hypertension and asthma. Along with the knowledge-based candidate gene approaches, the complementary strategy of the disease gene hunting, the statistics-based approach, is being deployed. The Project decided to go for a genome-wide, gene-based SNP scan through a close collaboration with another team of the Project, "Standard polymorphism" team, which already discovered c. a. 160,000 SNPs in and around the genes of the Japanese people.

Recent advances in molecular diagnosis in the hematological laboratory have greatly contributed to the diagnosis and treatment of hematologic malignancies, such as leukemia and lymphoma. The pathogenesis of leukemia and lymphoma has been disclosed by the analyses of genetic abnormalities in patients; abnormal gene expression may induce derangement in the control of cellular proliferation. Based on these genetic abnormalities, gene-targeted therapy has been introduced as a new approach to treating hematologic malignancies. We discuss here the usefulness of the molecular diagnosis in clinical hematology.

The HER 2/neu protein is thought to be a unique and useful molecular target for antibody therapy of cancers overexpressing the HER 2/neu gene. The recombinant humanized anti-HER 2 monoclonal antibody trastuzumab (Herceptin) has been available for clinical use in metastatic breast cancer in Japan since June 2001. Some breast cancer patients have responded to trastuzumab alone. A phase III study showed significant efficacy of combination use with paclitaxel compared with paclitaxel alone. Trastuzumab has some toxicities including infusion reaction and cardiotoxicity. It is very rare that infusion reaction manifests lethally. Although trastuzumab should not be concurrently used with an anthracycline, cardiotoxicity was also identified in patients treated with trastuzumab alone. The cumulative dose of anthracycline has not yet been identified as a risk factor, but patients who have received a high cumulative dose should be treated with special caution. In this article, the details of this novel biologic agent are reviewed from basic and clinical studies.

There are two markers, pepsinogen isoenzymes and antibody against Helicobactor pyroli, for screening of high-risk group for gastric cancer. Most of markers are used in diagnosis, staging, monitoring and differentiating subgroups of gastric cancer. Markers in ascitic fluid are used for diagnosing peritoneal invasion of gastric cancer.