TGF-beta is a multifunctional cytokine which regulates cell growth, extracellular matrix deposition, cell differentiation, and immunosuppression etc. The signal is mainly mediated through Smad pathway to inhibit epithelial cell growth. In 50% of pancreatic cancer, Smad4/DPC4 gene is deleted or mutated, which might cause pancreatic carcinogenesis and be associated with highly invasive and metastatic character of the disease. On the other hand, TGF-beta signal itself has recently been shown to act in favor of cancer cells, especially in the late phase of tumor progression. In Smad4-inactivated pancreatic cancer cells, TGF-beta signal regulates a number of genes involved in tumor suppression and progression. The regulated genes and signaling pathways of TGF-beta signal should be investigated to obtain an effective therapeutic target molecule for pancreatic cancer.

Cancer development is considered by the dysregulated proliferation of transformed cells. In recent years, dramatic and remarkable insight into the molecular mechanisms of this phenomenon have come from basic cancer research. Detailed knowledge of the molecular mechanisms and pathophysiology of cancer allows therapeutic agents to be designed that specifically target aberrant cellular processes. There are currently a number of targeted treatment strategies with less toxicity being evaluated. In the future, it is likely that this mechanistic and targeted approach will have a significant impact on clinical oncology and the diagnostic evaluation of tumors.

Cancer metastasis involves the complicated steps of tumor growth, angiogenesis, invasion and adhesion. At present new drugs targeting particular molecule (s) responsible for such cancer progression and metastasis have been developed in clinics. Major endpoints for cancer treatment should be prolongation of survival and maintenance of QOL. However, clinical development of such molecular-target based drugs is associated with difficulties in evaluating the efficacy in phase I/II studies prior to entering phase III study, because many of the targeted drugs seem cytostatic rather than cytocidal to tumors. New approaches incorporating technologies of genomics and proteomics may provide an expanding repertoire of molecular targeted therapeutics for clinical evaluation. In this review, the significance and problems of biomarkers available for clinical evaluation of molecular targeted drugs are discussed.

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) have been identified as a predictor of response to 5-fluorouracil (5-FU). Danenberg et al. developed a technology to evaluate gene expressions in formalin-fixed paraffin-embedded (FFPE) specimens (DTP; Danenberg tumor profile). In this study, TS and DPD gene expressions were measured in 47 primary colorectal cancer tumors and 12 metastatic tumors using FFPE specimens. In primary tumors, expression of TS genes in cancerous tissues was statistically higher than in stromal tissues, while DPD gene expressions in stromal tissues were higher than those in cancerous tissues. The median TS mRNA level was 0.86 in hepatic metastasis and 1.95 in lymph node metastasis. The median DPD mRNA level was 0.86 in hepatic metastasis and 1.96 in lymph node metastasis. Both gene expressions differed among primary tumors and metastatic tumors, especially in metastatic sites. DTP might be useful to evaluate the 2 gene expressions in colorectal cancer. Further studies would be needed to clarify the mechanisms of difference of gene expressions in cancerous and stromal tissues, or in primary tumors and metastatic tumors.

While hereditary disease genes have a high lifelong cumulative incidence rate (penetrance), the penetrance for polymorphism genotypes is not high. Polymorphisms relating to cancer incidence are classified into 1. carcinogen metabolizing enzymes (CYPs, GSTs, NQO1, etc.), 2. DNA repair enzymes (OGG1, XRCC1, XPD, etc.), 3. DNA synthesis and methylation (MTHFR, MS, etc.), 4. cytokines and inflammation-related enzymes (IL-1B, TNF-A, MPO, etc.), and 5. sex hormone metabolizing enzymes and the receptors (CYP19, SRD5A2, ER, etc.). Since genotypes cannot be manipulated, they are not the factors subject to prevention. However, the finding that the strength of association between lifestyle and disease occurrence is influenced by genotypes (gene-environment interaction), opens the door to genotype applications for disease prevention practice.

Wilms' tumor gene WT1 mRNA is a new marker of leukemic blast cells for AML, ALL, and CML. The minimal residual disease(MRD) of leukemia can be detected at frequencies as low as 1 in 10(3) to 10(4) normal bone marrow cells and 1 in 10(5) normal peripheral blood mononuclear cells by means of the quantitation of WT1 mRNA (WT1 assay) using reverse transcriptase-polymerase chain reaction. Thus, the WT1 assay makes it possible to rapidly assess the effectiveness of treatment and to evaluate the degree of eradication of leukemic cells in individual leukemia patients. Furthermore, the WT1 assay can continuously assess the disease progression of myelodysplastic syndrome(MDS) and predict the evolution of MDS to overt AML within 6 months. Moreover, WT1 protein is highly immunogenic, thus, WT1 peptide-based cancer immunotherapy is effective.

RET genetic testing affords valid clinical strategies in the diagnosis and management of MEN 2. For at risk family members, the test provides accurate diagnosis of gene carriers and best chance of cure of medullary thyroid carcinoma by prophylactic total thyroidectomy. The test results, however, may have medical, psychological, ethical, and social effects on the individuals as well as their families, it is important for an individual to know the potential consequences and to give an informed consent before having the genetic test. Health care providers should make efforts to be aware of these potential effects and to support a tested individual throughout the entire screening process.

There are many observation of genetic alterations in pancreatic carcinoma. Mutation of codon 12 of K-ras gene relating to cell growth signaling was reported as high as 90%, and p16/CDKN2 gene regulating cell cycle are frequently altered by point mutation, homozygous deletion, or methylation in pancreatic carcinoma. Mutations of K-ras and p16 gene in endocrine pancreatic carcinomas were reported 15-58% in insulinomas or gastrinomas. The alterations of K-ras and p16 gene was detected early event of carcinogenesis, to detect of the alteration with high sensitivity in pancreatic juice and serum, therefore, these alterations are very important for the early diagnosis of endocrine pancreatic carcinomas.

Multiple endocrine neoplasia types 2A and 2B(MEN 2A and MEN 2B), and familial medullary thyroid carcinoma(FMTC) are autosomal, dominantly inherited syndromes involving endocrine tumors. MEN 2A is characterized by medullary thyroid carcinoma(MTC), pheochromocytoma(pheo), and parathyroid hyperplasia; MEN 2B is characterized by MTC, pheo, mucosal ganglioneuroma, and marfanoid habitus. Affected individuals in FMTC families develop MTC without any other abnormalities. MEN 2A and MEN 2B and FMTC are caused by germline mutations in the RET proto-oncogene. To investigate the spectrum of RET mutations among Japanese patients, we analyzed the RET gene 118 patients with MEN 2 or FMTC.

It has been thought that endocrine tumors occurred through interactions of multiple environments factors and a personal genetic factor. A normal somatic cell having an intrinsic function is able to obtain the character of a malignant cell by influence of many factors. Several percent of all tumors have obvious familial aggregation. These entity are called familial cancer. Familial cancer syndrome is well defined for colorectal cancer and breast cancer, but an endocrine neoplasia is the one, too. Ectopic hormone producing tumors are kinds of endocrine tumors, and have the characteristics, which they generate in many organs multicentrically. The phenomena suggest that the patient with these disorders may possess strong genetic predisposition. Among endocrine neoplasia, multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease(VHL) are well defined genetic disorder with autosomal dominant inheritance, and the reliable genes were previously identified as MEN1, RET, and VHL, respectively. At this opportunity, we interpret for these three disorders.

Atomic bombs were dropped on Hiroshima and Nagasaki in August 1945. Within a few months, the bomb blast, heat and radiation emitted by the atomic explosions led to approximately 114,000 fatalities in Hiroshima and about 70,000 in Nagasaki. The radiation in particular continued to exert effects on the human body over a long period of time, resulting in the development of tumors and functional abnormalities in various organs. This paper briefly outlines the diseases caused by radiation as well as the biological late-effects on the survivors without any specific diseases, and stresses the necessity of our enthusiastic opposition to the use of any kind of nuclear weapons.

We encountered a 12-year-old girl with acute promyelocytic leukemia (APL) that occurred 21 months after a living donor partial orthotopic liver transplantation from her father for ornithine transcarbamylase deficiency. FK-506 had been administered for prophylaxis against graft-versus-host reaction. The bone marrow specimen revealed a massive infiltration of promyelocytic blasts (M3 by FAB classification) with chromosome 46, XX, t (15; 17) (q22; q12), being the recipient origin. A PML/RAR alpha chimeric gene was detected by RT-PCR. The patient was diagnosed as having APL and successfully induced to complete remission by chemotherapy including daunorubicin (DNR), cytarabine (araC), and all-trans retinoic acid (ATRA). She has been in continuous remission for 12 months after the treatment. Leukemia after liver transplantation is generally taken as a rare complication. However, recent advances in the survival rate of patients who have undergone liver transplantation will lead to an increase of such cases.