Hereditary non-polyposis colorectal cancer (HNPCC) is a type of hereditary colorectal cancer with autosomal dominant traits. Its causal genes are mismatch repair genes such as the hMSH2 and hMLH1 genes. Owing to its frequency, juvenile onset, and the outbreaks of multiple colorectal cancers and cancers occurring over multiple organs, it is recognized as a very important disease for the purpose of understanding not only colorectal cancers, but also other digestive cancers, and furthering pathological inquiry into the state of cancers in general.

Familial adenomatous polyposis (FAP) is characterized by more than hundreds of colorectal adenomas, colorectal cancer in early adult life, extracolonic features and genetic inheritance. Not only surgical management of FAP (IAA, IACA and IRA) but also methodology of APC gene test is almost established. Surveillance program and management of extracolonic manifestation is going to contribute to patient's prognosis. And now in Japan, two clinical intervention and chemoprevention trial studies of FAP are going on. As these reasons, FAP is most comprehensive model for understanding status quo and future problem of familial cancer syndromes. However, there are many counseling issues of FAP family members, choice of opportunity and method for diagnosis, surveillance, chemoprevention, surgery and to inform family member about hereditary risk. So, Cancer Genetic Counseling for FAP family members must be provided for their lifetime long.

The criteria for familial gastric cancer are as follows: 1) there should be at least 3 relatives with gastric cancer, 2) one should be a first-degree relative of the other 2, 3) at least 2 successive generations should be affected, 4) at least 1 should be diagnosed before age 50, and 5) other familial tumors should be excluded. There are two types of familial gastric cancer, diffuse type and intestinal type, of which the genetic background seems to be differ. In 1998, an autosomal dominant syndrome of diffuse gastric cancer was reported with germline mutations in the E-cadherin gene and has been identified in approximately 14 families and 50 individuals worldwide. In addition, an inherited mutation in mismatch repair (MMR) genes was found in hereditary non-polyposis colorectal cancer (HNPCC) in 1993. Since there is high frequency microsatellite instability found in familial gastric cancer patients, vigorous efforts have been made to find abnormalities in MMR genes of familial gastric cancer patients. However, to date, there has been little progress in detecting MMR gene mutations in familial gastric cancer patients. It is clinically most important to obtain a detailed family history to identify familial gastric cancer patients. At present, prophylactic total gastrectomy for familial gastric cancer is under careful consideration.

Fifteen (13.3%) and 21 (18.6%) deleterious germline mutations were identified in BRCA1, and BRCA2 genes among 113 Japanese breast cancer families. We found a BRCA1 codon 63 (nucleotide 307) nonsense mutation and a 4-bp deletion at codon 1858 (nucleotide 5802) of BRCA2 in 4 and 7 independent families, respectively. Haplotype analysis has revealed that these two mutations were founder mutations. Lifetime risk of breast cancer in BRCA1 or BRCA2 mutation carriers was estimated at nearly 80%, and that of ovarian cancer in BRCA1 mutation carriers was about 40%. A questionnaire survey as to the genetic testing (BRCA1 and BRCA2) and prevention was carried out with 146 healthy women (hospital workers or medical students) and 84 breast cancer patients. About 80% of healthy women as well as breast cancer patients responded positively to the genetic testing, based on the assumption their's was a breast cancer family, and about 20% of each group answered that they would opt for prophylactic mastectomy and oophorectomy if they were found to be germline mutation carriers. These results indicate that genetic testing and prophylactic surgery would be acceptable among a considerable number of Japanese women, and seem to support the establishment an infrastructure for genetic testing in Japan.

In multiple endocrine neoplasia (MEN) syndromes, tumors appear either synchronously or heterochronously in a combination of 2 or more specified endocrine glands. They are broadly classified as MEN 1 or MEN 2 according to the combination of tumors, and are inherited as an autosomal dominant trait. The genes responsible for these syndromes have been identified, making early diagnosis based on familial screening possible. The gene responsible for MEN 1 is located on the long arm of chromosome 11. It is a tumor suppressor gene that codes for menin. The cause of MEN 2 type is a mutation of the RET proto-oncogene on the long arm of chromosome 10. The present article discusses the diagnosis and treatment of these syndromes.

Recent developments in molecular biology have increased our understanding of the genetics of familial tumor syndromes. Isolation of the responsible genes has made it possible to identify gene carriers before they manifest clinical symptoms, which enables early detection of disease and at times prophylactic surgery. Indications for genetic testing of susceptible family members, however, should be carefully considered. Genetic counseling must be provided to clients before genetic tests. Patients should be provided with the latest knowledge on the disease and appropriately informed of the benefits and possible problems associated with genetic test, as such information is essential for clients to decide whether they will undergo such tests. Genetic medicine is not sufficiently available at present in Japan. Establishment of genetic services that deal with genetic counseling, family support and ethical, social and legal issues is strongly desired.

Esophageal cancer carries one of the poorest prognoses among digestive tract malignancies. Recent evidence suggests that the addition of nonsurgical treatment to surgery may improve resection rates, reduce the risk of recurrence, and improve survival.

Gene expression of human ovarian carcinoma cell lines and epithelial ovarian tumors was examined by oligonucleotide microarray for about 6000 human cDNAs. (1) Comparison of gene expression between CDDP-sensitive human ovarian serous adenocarcinoma cell lines and CDDP-resistant cell lines revealed that gamma-glutamylcysteine synthetase, glutathione peroxidase-like protein, dehydrogenase (UGDH), NAD(P)H: quinoneoxireductase, glucose-6-phosphatase, ornithine decarboxylase and dihydrodiol dehydrogenase were associated with a mechanism of CDDP-resistance. Comparison of gene expression between taxol-sensitive human ovarian cell lines and taxol-resistant cell lines showed that up-regulation of 30 kinds of gene expression including MDR and semaphorin E in taxol-resistant cell lines. (2) Comparison of gene expression among serous adenocarcinomas, clear cell adenocarcinomas and non-cancerous ovarian tissues by hierarchical clustering demonstrated that clear difference between carcinomas and non-cancerous ovarian tissues but not obvious difference between serous and clear adenocarcinomas. Genes that were up- and down-regulated specifically in these two types of ovarian carcinomas were further selected by the criteria that difference in the mRNA level by more than 4-fold between tumors and non-cancerous tissues. Tissue type specific alterations of gene expression are likely to play important roles in the carcinogenesis of epithelial ovarian tumors. cDNA microarray is a powerful and high-throughput tool to analyze gene expression of cancer development.

An 84-year-old man was admitted with pleural lymphomatous effusion and bone marrow infiltration. The abnormal cells from the effusion showed abundant basophilic cytoplasm, large atypical nuclei, and small nucleoli with frequent mitosis. The abnormal cells were found to be CD5+, CD10+, CD19+, and CD20+ by flow cytometry, and had clonal rearrangements of the IgH-JH gene, indicating the existence of a clonal B-cell population. No bcl-1, bcl-2, bcl-6, or c-myc rearrangement was found. Neither human herpesvirus 8 (HHV-8) nor Epstein-Barr virus was detected in the abnormal cells. Tetraploid chromosomal abnormality was present. After administration of prednisolone, transient disappearance of the effusion was obtained.

cDNA microarray technology permits the simultaneous measurement of the expressions of thousands of genes. The technology is now an indispensable research tool in molecular biology, and the challenge is its development and usage as clinical diagnostic tools. cDNA microarray can be used to identify gene expression profiles in tumor cells which correlate strongly with the treatment responsiveness such as drug resistance and clinical outcome of the disease despite similar phenotypes. For the introduction of cDNA microarray into laboratory examination, many issues need to be resolved. Design of a diagnostic array must be developed with defined sequences based on interpretation of huge quantities of data from experimental arrays to predict treatment responsiveness. Assay quality must be improved in terms of detection sensitivity, reproducibility, and linear dynamic range for RNA quantitation. Generally available instruments, which are much less expensive and more practical, need to be developed. Along with the improvement of the assay as a laboratory examination method, cDNA microarray will facilitate the integration of diagnosis and therapeutics, and the introduction of individual medicines.

In order to develop a new therapeutic intervention for pancreatic cancer, we have examined the effect of gene therapy for pancreatic disease. The transfection of the gene for UPRT, a 5-FU-converting enzyme, resulted in a significant change in the sensitivity of pancreatic cancer cells against 5-FU, resulting in the decrease of the tumor volume disseminated in the abdominal cavity of mice. Although the production levels of vascular endothelial growth factor (VEGF) in pancreatic cancer cell lines are different, anti-angiogenesis gene therapy using a soluble form of VEGF receptor (flt-1) has been demonstrated to be a promising strategy for pancreatic cancer. The transfection efficacy is the crucial point for the success of gene therapy; therefore, it is necessary to develop a vector system for solid tumors. It has been revealed that replication-competent adenoviruses are not only a strong weapon themselves, but are also useful carriers of genes possessing anti-tumor activities as virus vectors specific to tumors without normal p53 function or intact Rb pathway. Determining whether these experimental results are universally true will require clinical trials in the future.

Owing to the recent advances in surgical techniques and postoperative care, the operative indication for adenocarcinoma of the pancreas has been widened in Japan. In our institution, we have extended lymphatic and connective tissue clearance during surgical resection of this cancer. As a result, the 5-year survival rate has increased from 8% to 25% due to a significant decrease in the incidence of locoregional recurrence. The prognostic benefit gained by this procedure is seen mainly in those patients with stage III cancer or in whom no positive nodes were detected beyond the pancreatic head region. Thus, our extended surgery seems to have been useful due to eradicating the microinvasion in the peripancreatic connective tissues, rather than dissecting the positive lymph nodes. More advanced cancers should be treated by effectively combining chemo- and/or radiation-therapies with surgery. In order to cure the patients more easily with less-invasive surgery in the future, we should develop both an early diagnosis system and sensitive examinations of micrometastases or microinvasions.

Herceptin has provided the first proof that tyrosine kinase modulation, through monoclonal antibodies can translate into improved clinical outcomes in cancer therapy. The development of Herceptin was encouraged by the biologic significance of HER2 overexpression. Although the number of patients affected by the targeted molecular abnormality(30% of breast cancer patients) is small and the response rate observed in patients after treated with single agent Herceptin is rather low, the ability to document overexpression of the target in breast biopsies, and a growing interest in biologic therapy facilitated the rapid accrual of patients to clinical trials. The challenges of applying research techniques of molecular biology to routine clinical testing have been demonstrated by the experiences with the HER2/neu oncogene. Immunohistochemistry and fluorescence in situ hybridization yielded discrepant results regarding the frequency and degree of HER2 alterations even within the same sample. In order to make the complexity of interpretation of the discrepancy simple, it is wise to build an algorithm to help clinicians follow the ideal sequence of laboratory testings. The experience gained in the testing of Herceptin has provided important lessons for the future testing of molecularly targeted compounds.

The HER2/neu protein is thought to be a unique and useful target for antibody therapy of cancers overexpressing the HER2/neu gene. The recombinant humanized anti-HER2 monoclonal antibody, trastuzumab(Herceptin) has recently been available for clinical use in Japan. In this paper, the details of this novel biologic agent are reviewed in conjunction with the results of the clinical trials for breast cancer.

A 47-years-old woman (case 1) was admitted to our hospital because of a mediastinal mass. We performed an operation by VATS under the diagnosis of a mediastinal neurinoma. The histology of it was a neurinoma. Her father (case 2) had undergone a resection of a mediastinal neurinoma at the age of 42. Her brother (case 3) also had undergone a resection of mediastinal and intrathoracic neurinomas at the age of 37. A few years later, he underwent operations for neurinomas in limbs 2 times. We suppose patients with a mediastinal neurinoma have little complaints in many cases, so there are a number of patients who have a mediastinal neurinoma without being discovered and treated. Although the neurinoma is not considered as a hereditary disease inherently, the cases, we experienced, might have some genetic disorders. In this concern, our cases are very rare and have a great interest.