A 44-year-old woman complained of headache and palpitation. Magnetic resonance imaging showed bilateral adrenal tumors 10 x 9 cm in size on the left side and 8 x 4 cm in size on the right side. CT scan revealed a 0.7 x 0.7 cm mass in the thyroid. Hormonal examinations showed high values of urinary cathecholamines and serum calcitonin. DNA sequence analysis of peripheral white blood cells revealed that codon 634 in exon 11 of the RET gene was mutated from TGC (Cys) to TAC (Tyr). From these findings, a diagnosis was made of MEN2A with bilateral adrenal pheochromocytomas and medullary thyroid carcinoma. Bilateral adrenalectomy and thyroidectomy were performed. The same mutation of the RET gene was detected in all her 3 children, in two of whom, early stage medullary thyroid carcinoma was detected and thyroidectomy was performed. DNA analysis of the RET gene was useful for the diagnosis of carriers of MEN2A and the early detection of medullary thyroid carcinoma.

In order to define the roles of p53 in acquisition of drug resistance in ATL cell lines, we prepared several ATL cell lines which differed in sensitivity to adriamycin (ADM), and examined their functional p53 statuses, expressions of p53, p21, Bcl-2, Bax, and cell cycles. Our findings demonstrated: (1) Regardless of sensitivity to ADM, most of the cell lines, including ADM-resistant cell lines, carried wild-type p53. (2) Only one cell line, ED-S, which was the most sensitive to ADM carried non-functional mutated-type p53. (3) In the ATL cells carrying wild-type p53, regardless of sensitivity to ADM, ADM-treatment led to an elevation of p53 protein level with concomitant elevations of p21 and Bax protein levels. (4) In the cell line expressing mutated-type p53, ADM-treatment at the concentration of IC50 induced elevations of p53, and Bax protein levels but did not p21 protein level. (5) Expression of Bcl-2 protein did not change in any of the cell lines by treatment with ADM at their respective IC50 levels, but increased in the ADM-resistant cell line when it was treated with ADM at IC50 of its parent cell line. (6) In the cell cycle analysis, ADM-treatment induced G1- and G2-arrest and then apoptosis in the cell lines with wild-type p53, whereas it induced only G2-arrest and then apoptosis in the cell line with mutated-type p53 at the same time course as in those with wild-type p53. These findings suggest that p53 does not play a leading part either in the apoptosis induced by ADM, or in the acquisition of resistance to ADM in ATL cells, and that ADM-induced apoptosis is mediated by multiple pathways leading to the activation of effector molecules.

The resistance of head and neck squamous carcinoma cells (HNSCCs) to cis-Diamminedichloroplatinum(II) (CDDP), which is widely used for the treatment of many malignancies, is a serious problem in the clinic. The mechanism by which cancer cells get resistant to this compound has not been completely understood. To elucidate the mechanism, we compared gene expression in the cells sensitive to CDDP with that in the resistant variants using fluorescent differential display technique. Side-by-side comparison on a sequence gel demonstrated that 105 genes were differentially expressed between KB, a human oral SCC line, and KB/cDDP, which was developed from KB and shows 2.5-fold increases in resistance to CDDP, as well as between HEp2, a human laryngeal SCC line, and its cDDP-resistant variants. Several candidates for the CDDP resistance related genes have been cloned by the following re-amplifications. Northern blot analysis revealed that human chorionic gonadotropin alpha subunit gene and human mitochondrial cytochrome c oxidase subunit II gene were expressed higher in KB/cDDP than in KB parental cells. Our results suggest that these two genes are associated with CDDP resistance and that human chorionic gonadotropin alpha subunit gene product is potentially a clinical biomarker for the resistance to CDDP.

The Wilms tumor gene (WT1) has been reported to be a prognostic factor and a marker for the detection of minimal residual disease (MRD) in acute leukemia. Using competitive polymerase chain reaction procedures, we examined the expression of the WT1 gene in acute leukemia patients with several tumor-specific DNA markers, including bcr/abl, PML/RAR alpha, and AML1/MTG8. A strong correlation was observed between the levels of WT1 and PML/RAR alpha expression. However, AML1/MTG8 transcripts were detected at all stages of the disease even when the expression level of WT1 gene was low. From these findings, we concluded that monitoring the WT1 expression level is a useful means of determining the effectiveness of chemotherapy, and that WT1 is an effective marker for the detection of MRD, especially in acute myeloid leukemia patients with AML1/MTG8.

It is my great pleasure to congradulate the Japanese Journal of Cancer and Chemotherapy on its 25 th anniversary. During this period, great progress has been made in cancer research, mainly owing to the advances in technology in molecular biology. Recently, not only researchers, but lay people as well have come to understand that cancer is mainly a genetic disease. Advances in the human genome project, DNA chip technology and gene technology; including gene targeting and cloning techniques, will enable us to accelerate progress forward the final goal of cancer research in the coming century. Major changes are coming in both cancer research and clinical oncology, which will completely transform the human social environment.

Tuberous sclerosis is associated commonly with renal angiomyolipoma. On the other hand, the relation between tuberous sclerosis and renal cell carcinoma is not widely recognized. We report a case of renal cell carcinoma of the right kidney associated with tuberous sclerosis.

Familial cancers associated with genetic background are of the most intensively investigated diseases in recent years. The phenotype is apparent with most of these diseases and can easily be traced through family history. Induction in familial cancer appears, on current evidence, to be not different from that observed in sporadic cancer. The first suppressor gene Rb gene was cloned from retinoblastoma. There are two representative hereditary colorectal cancers: familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). The gene responsible for FAP (APC gene) was cloned in 1991. The APC gene is a negative regulator of beta-catenin and is considered to play the role of gatekeeper in the adenoma carcinoma sequence. Thereafter a group of genes, human homologues of mismatch repair genes (hMSH2, hMLH1, hPMS1, hPMS2, hMSH6), have been identified as the genes responsible for HNPCC. These are called care taker genes, which serve to maintain genetic stability. Therefore, if one of those genes undergoes mutation, the rate of mutation increases significantly. It has only been in the last 20 years that familial cancer has become an important issue. In association with such advances, predictive testing can now be performed on at risk persons. Persons at risk can thus be accurately counseled and screened for early detection of disease.

In order to elucidate the relationship between tumor growth and various kinds of gene expression and the occurrence of apoptosis in the front portion of neoplastic invasion, 57 advanced colorectal cancers were studied by immunohistochemical staining of p53, c-erb B-2, the TUNEL method and electron microscopy. Light microscopically, the columnar epithelial cells of adenocarcinoma frequently showed a decrease in high and a fall off into the lumen in tumor invasive forefront. Immunohistochemically the positive rate of p53 and c-erb B-2 in tumors with high vascular invasion were higher (p < 0.05) than in those with low vascular invasion. There was a close correlation between the vascular or lymphatic invasion and positive immunoreactivity of p53 and c-erb B-2. The apoptosis index was demonstrated to be related to vessel invasion, over expression of p53 and inflammatory cell infiltration around the front portion of the tumor invasion. These results suggested that p53. c-erb B-2 and the apoptosis index should be evaluated in conjunction with the prognostic factors in colorectal cancer. The infiltrative inflammatory cells may induce apoptosis of the tumor cells.

We have analyzed the effect of polychlorinated biphenyls (PCB, Kanechlor-400) on 1-nitropyrene (1-NP) induced lung tumor. Male A/J mice (6 weeks old) were used for the experiment. A total of 2.5 mg/kg PCB was administered intraperitoneally (PCB group), a total of 0.38 mmol/kg 1-NP was administered intraperitoneally for 17 times (1-NP group), PCB was administered followed by i.p. injection of 1-NP (PCB + 1-NP group), and only vehicle was administered (control group). The lung lesions induced were examined 18 weeks after the final treatment with 1-NP or vehicle. In control group, no neoplastic lesion in the lung was induced. In PCB group, only one lesion with adenoma was induced. In 1-NP group, various kinds of lung neoplastic lesions including hyperplasia, adenoma and adenocarcinoma were induced. In PCB + 1-NP group, both the number and size of tumors induced were significantly more than those in 1-NP group. In addition, the number of adenocarcinoma formed was more in PCB + 1-NP group than in 1-NP group. Each lesion was microdissected to collect and analyze DNA of the targeted tissue. K-ras gene mutation was detected in part of adenoma lesions and all the carcinoma lesions. The mutation was found in either 1-NP or PCB + 1-NP group, but not in control and PCB group. The pattern of K-ras mutation was CAA to CGA in codon 61 or GGT to GAT in codon 12. There was no difference in the pattern of K-ras mutation despite of the pretreatment with PCB. Although the present data are from small sample size, it was suggested that PCB may promote (but not initiate) 1-NP induced lung tumorigenesis, and may not induce K-ras mutation directly in the experimental system.

To examine whether genetic factors influence the prognosis of cancer patients, several microsatellite markers were used to determine the allelic loss of certain areas of the genome. Three microsatellite markers, D3S1067, IFNA and D9S171 were used to study the loss of heterozygosity (LOH) of 3p21 and 9p21 in 93 head and neck squamous cell carcinomas. Of 57 informative cases, LOH was detected in 27 of 57 (47%) DNA samples obtained from cancer specimens when at least one marker was used. The frequency of LOH was not correlated with the clinical factors. However, the frequency of LOH was significantly higher in the recurrent cases than in the non-recurrent cases, and patients with 3p21 and/or 9p21 LOH tended to survive for a shorter period of time. These results suggested that the allelic loss at 3p21 and/or 9p21 could be correlated with the prognosis of the patients, and that it was a novel prognostic factor independent of other clinical factors concerning head and neck cancers. LOH at 3p21 and/or 9p21 may help to identify head and neck cancer patients with a poor prognosis, who need an intensive postoperative follow-up protocol, or who are suitable for novel investigational therapeutic approaches.

Here we reviewed the molecular genetic mechanism in the development of 4 types of human hereditary kidney cancers. These include von Hippel-Lindau (VHL) disease, hereditary papillary renal carcinoma, familial renal cancers with translocation of chromosome 3, and Tuberous sclerosis. Loss of function of the VHL disease gene is responsible for the von Hippel-Lindau disease and major portion of sporadic clear cell renal carcinoma. Activated c-Met oncogene is responsible for the development in some cases of hereditary papillary renal cell carcinomas and sporadic papillary renal carcinomas. There are several cases of familial renal carcinoma in that translocations of chromosome 3 p are demonstrated. The molecular genetic mechanism of this disease is not known. Several reports show the development of renal cell carcinoma in Tuberous sclerosis patients. TSC 1 or TSC 2 gene may be responsible for these tumors. The detail in this disease not well known. Molecular genetic analyses for hereditary renal cancer identified several oncogenes and tumor suppressor genes in hereditary as well as sporadic renal carcinomas. Future studies may reveal new category of oncogenes or tumor suppressor genes that are involved in the human kidney cancer development.

Patients with Barrett's columnar-lined esophagus are at increased risk of developing esophageal adenocarcinoma, the incidence of which has increased rapidly especially in the USA. Although the number of patients with Barrett's adenocarcinoma is fewer in Japan than in the USA, all gastroenterologist should know its multistep carcinogenic process. Tumor suppressor genes (p53, p16), oncogenes (c-erbB-2, H-ras, K-ras, cyclin D1, src), and growth factor/receptor (TGF-alpha, EGFR) seem to cause the malignant transformation of Barrett's esophagus. Because detection of these molecular alterations is feasible, more accurate diagnosis of Barrett's esophageal biopsy specimens should be made by adding the molecular examination to the conventional pathologic examination.

Alterations of the p53 tumor suppressor gene are the most common genetic change detected in human cancers. The incidence of p53 gene mutation in bladder tumor patients were studied and were compared with clinicopathological findings, smoking history and prognosis.

An 88-year-old Japanese woman with splenomegaly, but without lymphadenopathy, was admitted because of epigastric distress. Laboratory data disclosed an RBC of 310 x 10(4)/microliter, Hb of 10.1 g/dl, Ht of 30.6%, Plt count of 9.8 x 10(4)/microliter, and WBC of 4,470/microliter with 38% abnormal lymphocytes. Peripheral blood films revealed lymphocytes with thin, short cytoplasmic villi, condensed nuclear chromatin, and small nucleoli. The lymphocytes stained negative for tartrate-resistant acid phosphatase. Also, immunophenotyping was positive for expression of the cell surface markers CD19, CD20, IgG, kappa and HLA-DR, but not for CD5, CD10, CD11c, CD23, CD25, CD38, or CD103 antigens. Chromosomal analysis of peripheral blood cells disclosed the 46, XX, del(7), (q32) aberration. A splenectomy was performed simultaneously with partial colon resection because of a mucinous carcinoma found in the transverse colon. Histologic examination of resected spleen tissues revealed a distinctive pattern of white pulp infiltration by lymphoma cells. The histologic findings and clinical data were consistent with the features of splenic lymphoma with circulating villous lymphocytes. Our patient exhibited a relatively benign clinical course, and was being followed on an outpatient basis with no additional therapy.

Reverse transcriptase-polymerase chain reaction (RT-PCR) methods often detect the AML1/MTG8 fusion transcript even in acute myelogenous leukemia (AML) patients with t(8;21) who have been in long-term remission. We encountered 2 hypoplastic leukemia patients with t(8;21) who achieved cytogenetic remission with short-term conventional chemotherapy. Patient 1 was a 42-year-old woman. Chromosomal analysis detected t(8;21) (q22;q22) and PCR analysis (35 cycles PCR amplification; detection limit 1 x 10(-5) cells) detected the AML1/MTG8 fusion transcript. Complete remission was obtained with 1 course of chemotherapy consisting of low-dose cytarabine (20 mg x 14 days) and etoposide (50 mg x 14 days). After 2 courses of consolidation chemotherapy consisting of conventional-dose cytarabine and mitoxantrone, the RT-PCR findings were negative for the AML1/MTG8 fusion transcript. Patient 2 was a 67-year-old man. Cytogenetic analysis detected t(8;21) (q22;q22), and was positive for the AML1/MTG8 fusion transcript. After 2 courses of induction chemotherapy comprising low-dose cytarabine (20 mg x 14 days) and etoposide (50 mg x 14 days), and 3 courses of conventional consolidation chemotherapy, RT-PCR analysis confirmed the disappearance of the AML1/MTG8 fusion transcript.