Genetic testing has been widely available and useful in several kinds of familial cancer. Shinshu University Hospital established a division of clinical and molecular genetics as one of its central service departments. We have a staff meeting once a week to discuss each case to provide the suitable counseling and the ethical-legal and social issues. We performed genetic testing in 44 cases, including familial adenomatous polyposis, multiple endocrine neoplasia type 1 and 2, familial breast cancer, von Hippel-Lindau disease, and Li-Fraumeni syndrome. This is the first clinical genetics department in the National University Hospitals in Japan and this system increases the utility of genetic testing.

Cancer is a heritable disorder of somatic cells. Environment and heredity both operate in the origin of human cancer. Hereditary cancers have been important in the understanding of carcinogenesis, and have pointed to the first tumor suppressor genes. Such a hereditary cancer was described in the rat by Reidar Eker in 1954. The Eker rat model of hereditary renal carcinoma is an example of a Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. We identified a germline mutation in the rat homologous to the human tuberous sclerosis gene (TSC2) as the predisposing Eker gene. The Eker rat provides a valuable experimental model for understanding the mechanisms of disease, and the development of the therapeutic treatments.

Li-Fraumeni syndrome(LFS) and its relation to the p53 gene and p53 gene transgenic and targeting mice are reviewed. LFS is a hereditary cancer-prone syndrome mainly with germ line mutation of p53 gene. p53 deficient mice, especially heterozygous mice, may serve as a model for human LFS, although there are several discrepancies between them. Carcinogenesis experiment using p53 deficient mice may be important to clarify the role of p53 in tumorigenesis in vivo.

Apoptosis is a cellular self-destruction mechanism involved in a variety of biological events. Cancer is a disorder of autonomous cell proliferation and accumulation, which is associated with the failure to undergo apoptosis in response to appropriate stimuli. Inhibition of apoptosis may be a prerequisite or acquired biological feature of various cancer cells. Resistance to apoptosis is achieved either by an increase in apoptosis resistance or decrease in apoptosis sensitivity. Some of the hereditary cancer syndrome patients have mutations in the genes to induce apoptosis, eventually leading to inhibition of apoptosis and cancer development.

Mechanisms of carcinogenesis through abnormalities of DNA repair genes are overviewed. Inactivation of DNA mismatch repair(MMR) gene(s) observed in tumors of hereditary non-polyposis colorectal cancer induces frameshift mutator mutation in MMR genes themselves, growth inhibitory genes and apoptosis inhibitory genes providing favorable genetic background for a malignant clone to be expanded. Deficiency of nucleotide excision repair that is usually employed for the removal of pyrimidine dimer formed by ultraviolet-irradiation in xeroderma pigmentosum (XP) causes hypersensitivity of the skin to sunlight as well as increased risk of skin cancer. Strand specificity and absence of hot spots for p53 tumor suppressor gene mutations was reported in ultraviolet induced skin cancers of XP model mice.

Hereditary cancer syndrome is mainly caused by tumor suppressor genes, such as p53 gene in Li-Fraumeni syndrome and p16 gene in familial melanoma. There are 2 signal pathways of regulation of cell cycle, RB pathway and p53 pathway. Cyclin dependent kinase(CDK) was regulated by CDK inhibitor(CDKI) (p16, p15), and CDK-CDKI complex control RB by phosphorylation. p53 regulate RB pathway through p21. p53 is involved in apoptosis through bcl 2 or Bax 3. p19 coded by exon 1 beta and exons 2 and 3 of p16 gene, binds to MDM2 and regulate p53 pathway. Chromosome 9p21 locus, which p16, p15 and p19 genes are assigned, is important to regulate both RB and p53 pathways.

Germline mutations in one of two alleles of c-ret, c-met and c-kit protooncogenes have been revealed to be the causes of three autosomal dominant hereditary tumors; multiple endocrine neoplasia type 2(MEN2), hereditary papillary renal cell carcinoma (HPRCC), and familial gastrointestinal stromal tumor(FGIST), respectively. Patients with MEN2A have missense mutations at extracellular cysteine rich domain of c-ret, those with MEN2B have missense mutations at tyrosine kinase domain of c-ret, those with HPRCC have missense mutations at tyrosine kinase domain of c-met, and those with FGIST have in-frame deletion mutations at juxtamembrane domain of c-kit. All of these mutations are assumed to cause constitutive activation of protooncogenes without binding to ligands, resulting in tumor formation.

Single-nucleotide polymorphism analysis is important in all areas of molecular biology. The causative genes of hereditary cancer syndrome have been isolated. Recently, molecular diagnosis of hereditary cancer syndrome has been performed using methods of single-nucleotide polymorphism analysis and the usefulness has been reported. It is considered that progression of molecular biology will be able to contribute to diagnosis (especially pre-symptomatic diagnosis), prevention and treatment of hereditary cancer syndrome in the future.

A database of mutations in various cancer-related genes has been constructed and named as KMcancerDB (Keio Mutation DataBase for cancer-related genes). This KMcancerDB utilizes a database software called MutationView which we designed to compile various mutation data and to provide graphical presentation of data analysis through the network using ordinary internet browser softwares such as Netscape. Currently, the KMcancerDB accommodates 1261 mutation data of different genes for cancers in 9 different organs/tissues (breast, stomach, uterus, liver, prostate, colon, ovary, thymus and retinoblastoma). KMcancerDB is accessible through http:¿mutview.dmb.med.keio.ac.jp. OMIM is an important document database for human Mendelian traits and hereditary diseases. The information from OMIM is also used in MutationView/KMcancerDB. Some display windows of OMIM and KMcancerDB are presented.

The genes responsible for hereditary cancers such as retinoblastoma, colorectal cancer and breast cancer have been identified through application of positional cloning from human molecular genetics. Linkage analysis is a powerful method to locate a disease gene, however a precise genetic model, detailing the mode of inheritance, gene frequencies and penetrance, is required for parametric methods, but not for nonparametric methods. The nonparametric methods ignores unaffected people, and looks for alleles that are shared by affected individuals within nuclear families as well as extended families. Hence the methods usually have been performed to identify disease genes in many hereditary diseases. In this paper, we describe the rationale and strategy of linkage analysis in detail for genetic mapping of hereditary cancers.

The discovery of microsatellite instability (MSI) and its association to hereditary nonpolyposis colorectal cancer (HNPCC) in 1993 gave rise to a new criterion in tumor biology. By using five microsatellite markers, colorectal carcinomas (CRC) may be classified either as high frequency-MSI (MSI-H) if two or more of the five markers show instability, or as low frequency-MSI (MSI-L)/microsatellite stable (MSS) if one or less shows instability. MSI-H tumors which comprise about 15% of total CRC show distinctive clinicopathologic features: proximal colon location, mucinous and undifferentiated histology, presence of tumor-infiltrating lymphocytes, and a less aggressive clinical course. Mismatch repair gene mutations, transcription loss of a mismatch repair gene associated with promoter region hypermethylation, or loss of imprinting have been proposed as some of the causes for MSI.

With the cloning of cancer-predisposing genes many responsible genes have been identified from hereditary tumor syndrome over the past 10 years. Cancer is a genetic disease, arising from accumulation of mutations that promote clonal selection of cells and tumor progression. An individual who carries a mutant allele of an inherited cancer gene has a variable cancer risk. The proteins encoded by inherited cancer genes have been implicated in diverse cellular function, including proliferation, differentiation, apoptosis, and maintenance of genomic integrity. Concept and classification of hereditary tumor syndrome are discussed from genetic aspect.

A 72-year-old man was referred to our department with the chief complaint of painless swelling of the left scrotum in May 1997. Left high orchiectomy was performed under the diagnosis of primary testicular tumor. Histological findings revealed non-Hodgkin's lymphoma (NHL) of diffuse, mixed type, B cells. No evidence of tumors in any other site was detected by further examinations. About 3 years and a month earlier, he had undergone right high orchiectomy and postoperative radiotherapy (inverted Y irradiation) and chemotherapy (CHOP 5 cycles) for a right testicular tumor whose histological findings were NHL of diffuse, large cell type, B cells. Metachronous bilateral primary malignant lymphoma of the testis is very rare and we discussed each tumor origin by using IgH gene (IgJHDNA) rearrangement as a tumor specific marker of B cell lineage malignant lymphoma. We discussed the clonality of IgJHDNA rearrangement using polymerase chain reaction (PCR) in each paraffin fragment diagnosed pathologically as NHL of B cell origin.

We retrospectively analyzed treatments and outcomes for 83 acute myelogenous leukemia (AML) patients aged 60 years or more (median age 71) admitted to our hospital between August 1984 and January 1998. Complete remission was achieved in 36% of 78 patients who received anti-leukemic therapy, and median overall survival was 227 days. In addition to abnormal karyotypes involving chromosome 5 or 7, administration of less than 120 mg/m2/course of daunorubicin (DNR) during the initial treatment phase was an unfavorable prognostic factor for both CR and survival. Only 41% of all patients received 120 mg/m2/course of DNR or more, and had a significantly higher CR rate (56%) and longer survival, with a median of 389 days. It was suggested that intensive chemotherapy was effective for selected elderly AML patients who were relatively younger and had good performance status, although the number of such patients was limited in our study.

In order to characterize clinical and biological characteristics of elderly patients with acute myelogenous leukemia (AML), we retrospectively analysed 83 elderly patients aged 60 years or more and, as a control, 114 younger patients aged 15 to 59 years who were admitted to our hospital between August 1984 and January 1998. There was a significantly higher incidence of preceding myelodysplastic syndromes in the elderly patients. They also had a significantly higher incidence of unfavorable cytogenetic abnormalities (loss or partial deletion of chromosome 5 or 7) and a significantly lower incidence of favorable cytogenetic abnormalities, such as t(15:17), t(8:21), or inv(16). With regard to FAB subtypes in de novo AML, the incidence of M3 subtype was significantly lower in the elderly group. Myeloperoxidase positivity of AML cells in the elderly group was lower than that in the younger group. Laboratory data at presentation disclosed a lower peripheral leukemic cell count, a higher fibrinogen level, a lower serum protein level, and a higher serum creatinine level in the elderly group. They also had poorer performance status and more frequent concomitant diseases at presentation, including liver diseases, heart diseases, or documented infections. It was concluded that elderly AML patients 60 years or older had a higher incidence of poor prognostic factors compared to younger patients.