We reviewed correlations among telomere length, aging and carcinogenesis. Southern blot analysis showed that telomere shortening occurred with aging in all human tissues except for brain and myocardium. We investigated the telomere lengths of individual cell types in human tissues using a Q-FISH method and an original software package, "Tissue Telo". Q-FISH revealed that in squamous epithelia, NTCR corresponding to telomere length was significantly highest in basal cells and lowest in prickle cells, and that telomere length regressed at a certain rate in each cell type except for fibroblasts. Mean telomere length was significantly less in background tissue squamous epithelia of patients with cancer than in normal controls without cancer. We demonstrated telomere shortening and chromosomal instability in the background and normal control with excessively shortened telomeres. The data suggest that cancer arises from epithelial cells with short telomeres.

Imatinib mesylate has significantly improved the outcome of patients with CML. In the IRIS trial, major molecular response (MMR), which is defined as the achievement of > or =3 log reduction in bcr-abl mRNA from the standardized baseline, was observed in 40% of CML patients by 12 months. Achievement of an MMR at 18 months is associated with 100% probability of transformation-free survival at 60 months, and MMR is an important goal of therapy. The nucleic acid quantitative "DNA probe FR Amp-CML" kit based on the transcription-mediated amplification method, can measure major bcr-abl mRNA in peripheral blood leukocytes. In this study, we studied the clinical usefulness of Amp-CML for monitoring minimum residual disease by comparison with the European standard nucleic acid quantitative method and real-time quantitative PCR (RQ-PCR) with GAPDH as an internal control, using peripheral leukocytes obtained from patients receiving imatinib treatment. The results indicated that Amp-CML had a significant correlation with Fusion Quant M-BCR (R>0.971, P<0.01), a standard nucleic acid quantitative method used in Europe and RQ-PCR (R>0.974, P<0.01), especially in samples with more than 100 copies/microg RNA of major bcr-abl mRNA. These data suggest that Amp-CML is reliable for monitoring major bcr-abl mRNA in patients having achieved an MMR.

Cetuximab, an anti-EGFR human/mouse chimeric antibody, has just been approved in Japan for patients with EGFR positive unresectable or recurrent colorectal cancer, as monotherapy or in combination with irinotecan. We reported two cases of unresectable or recurrent colorectal cancer effectively treated by cetuximab after the progression of the prior chemotherapy. Case 1: A51-year-old male suffered from sigmoid colon cancer with synchronous liver metastases. He received cetuximab plus irinotecan combination therapy in the third-line setting. Amonth after the initiation of the chemotherapy, abdominal CT showed tumor shrinkage of liver metastases. Case 2: A57-year-old female suffered from sigmoid colon cancer with metachronous liver, ovarian metastases, ascites and pleural effusion. Her performance status(PS)according to ECOG performance scale was 1, and she complained of dyspnea on exertion. She received cetuximab monotherapy in the fourth-line setting. Five weeks after initiation of chemotherapy, her chest, abdominal and pelvic CT showed tumor shrinkage of the liver metastases and the reduction of both ascites and pleural effusion, together with resolution of her dyspnea on exertion. Before cetuximab administration, we investigated KRAS status on cancer tissue previously resected in the above 2 cases, which showed KRAS wild-type. Cetuximab could be effective for KRAS wild-type colorectal cancer, as well as the previous reports from Western countries.

A genome-wide association study on diffuse-type gastric cancer identified the PSCA gene, whose exact function in the gastric epithelium has been unknown. Immunohistochemical analysis revealed that PSCA is expressed in the region in which gastric epithelial stem cells and precursors are considered to reside. Moreover, the PSCA was downregulated in gastric cancer tissues, and its product showed a cell-growth inhibition activity in vitro. We also identified a functional SNP, the risk allele of which suppressed a promoter activity of the PSCA gene. These findings suggest that the PSCA may contribute to carcinogenesis through the cell-growth regulation of the gastric epithelial precursors. The summary statistics of the 2-stage genome scan is available from a database, GeMDBJ (http://gemdbj.nibio.go.jp/).

Epigenetic modifications, DNA methylation and histone modifications, mark genes to be used and not to be used, and are stably inherited in somatic cells. Epigenome is their genome-wide compilation, and undergoes dynamic changes in development, differentiation, and reprogramming. Epigenomic changes are causally involved in cancer development and progression by inducing silencing of tumor-suppressor genes and genomic instability. Aberrant DNA methylation can accumulate in a large fraction of cells even in tissues without clonal lesions, which indicates that epigenomic changes can potentially affect functions of a tissue. Multiple reports show that epigenomic changes are present in acquired neurological, metabolic, and immunological disorders, and more research in the field is urgently necessary.

Genomic analysis on genetic variation, e.g. SNPs and CNVs, have revealed the phenotype-genotype association for various diseases. Furthermore, recent progress in high throughput sequencing technology should have a great impact in elucidating both genetic and epigenetic mechanisms of human diseases. Several ongoing genome sequencing projects will provide the fundamental information to realize the personalized medicine in next few years. Integration of genomic and clinical information will be crucial to develop biomarkers for early diagnostics and treatment selection.

The incidence of endometrial cancer and ovarian cancer has increased in Japan, during the last decade. On the other hand, the incidence of cervical cancer has declined until the middle of the 1990's. However, in recent years it has been increasing slightly. Change of Japanese women's lifestyle may contribute to the increase in gynecologic cancer incidence in Japan. Infection with high-risk oncogenic human papilloma viruses (HPV) play an important role in cervical carcinogenesis. Advances in understanding of the role of HPV in the etiology of cervical cancer have led to the development, evaluation and recommendation of HPV vaccines. Recently environmental factor and genetic factor related carcinogenesis and development have been investigated of gynecologic cancer. This review provides a summary of these studies about the etiology, the treatment and prevention against gynecologic cancer.

A number of promising approaches against human cancer become available in the post genome era. For cancer prevention, a series of genome-wide association study is being performed and several SNPs that could predict susceptibility of cancer, including breast and gastric cancers, have been identified successfully. For cancer treatment, growing numbers of molecular-targeting drugs are being challenged, in which inhibitors of EGFR tyrosine kinase, including gefitinib, have been established for treatment of a subset of lung adenocarcinoma. Detection of the specific EGFR mutations is shown to predict response of individual tumors to gefitinib. Mamma-Print, a microarray-based analysis of breast cancer, is also successfully used for predicting response of breast cancer to Herceptin. Molecular targeting therapy in combination with such genome-based analyses could provide effective personalized medicine against human cancer.

A variety of genomic approaches have been applied to leukemia/lymphoma to identify cancer-promoting genes or to screen for prognostic markers. Gene expression profiling with microarrays has, for instance, succeeded to calculate prognostic scores based on the expression profiles of a subset of genes in acute myeloid leukemia and non-Hodgkin lymphoma. Further, narrowing down the LOH regions with microsatellite markers in the genome of myeloproliferative disorders could identify a mutated JAK2 gene encoding an activated tyrosine kinase. Similarly, a common deletion in the genome of chronic lymphoid leukemia was shown to contain miR-15a/miR-16-1 microRNA genes, loss of expression of which plays an important role in the malignant transformation. Advent of further high-throughput and high-resolution techniques (such as new generation of DNA sequencers) would greatly help to discover leukemia/lymphoma-related genes that may provide promising candidates for molecule-targeted therapies.

Polycythemia vera (PV), essential thrombocythemia(ET), and primary myelofibrosis (PMF) share common clinical features, being clonal disorders of multipotent progenitors. In 2005, a somatic activating mutation in JAK2 (V617F) was identified in most patients with PV and in about half of patients with ET or PMF. The JAK2 mutation causes the constitutive activation of the JAK-STAT signaling pathway, and leads to autonomous cell growth in a cytokine-independent manner. A higher expression of JAK2 V617F would favor erythrocytosis, and a lower one would favor thrombocytosis. This may suggest that the expression levels of JAK2 V617F directly determine which cell lineages increase, possibly leading to the diversity of myeloproliferative diseases. Although only V617F JAK2 may cause myeloproliferative disease (MPD), clonogenic assay, analysis of familial MPD patients, and examination of JAK2 mutation in acute leukemia patients transformed from MPD show that there are additional somatic mutations which contribute to the pathogenesis of V617F JAK2 positive PV, ET, and PMF.

Notch signaling regulates the self-renewal and differentiation of hematopoietic stem cells. Since acute myeloblastic leukemia (AML) originates from dysregulated hematopoietic cells, the Notch system may be involved in the abnormal growth. We found that AML cells express not only Notch proteins but also Notch ligand proteins, which suggests the possibility of autonomous Notch activation. It is known that more than half of T-cell acute lymphoblastic leukemia (T-ALL) cases have activating mutations of the NOTCH1 gene. We report that one out of 20 AML samples and none out of 20 MDS samples showed NOTCH1 mutation. We established an AML cell line, TMD7, which proliferates in response to a Notch ligand, Dll1 protein. Notch activation by ligand stimulation suppressed the cytokine-induced differentiation and apoptosis of U937 cells. For OCI/AML-6 and THP1 cells, Notch ligands suppressed the growth and self-renewal capacity while inducing differentiation into macrophage-like cells. For primary AML cells, the Notch ligands exhibited diverse effects on the short-term growth. The ligands reduced the self-renewal capacity and induced differentiation in some samples. For NOTCH1-mutated T ALL cells, gamma-secretase inhibitors(GSI), which block Notch activation, suppress the growth. We found that GSI suppressed the in vitro growth of some B-cell lymphoma and AML cell lines without NOTCH1 mutations through the induction of apoptosis. GSI may be useful as a novel molecular target therapy for various leukemias. For this purpose, we have to clarify the mechanism behind the effects. Laboratory tests regarding the expression and function of Notch will be important for individualized diagnosis and therapies.

We evaluated retrospectively single-agent S-1 chemotherapy in non-small cell lung cancer patients in clinical practice.