Fanconi anemia (FA) is a genetically heterogeneous inherited disorder characterized by progressive bone marrow failure, development of hematopoietic and solid malignancies and genomic instability. 13 FA proteins, identified to date, closely cooperate with familial breast cancer susceptibility proteins such as BRCA2 and PALB2, thereby forming 'the FA/BRCA molecular network'. Here I summarize our recent understanding of the molecular network and its significance in the pathogenesis of FA. I emphasize that FA provides an excellent genetic model for studying senescence and malignant transformation of human hematopoietic stem cells.

The development and progression of gastric cancer involves a number of genetic and epigenetic abnormalities. The majority of differentiated adenocarcinomas arise from intestinal metaplastic mucosa and exhibit structurally altered tumor suppressor genes (suppressor pathway), typified by p53, which is inactivated via the classic two-hit mechanism, i.e. loss of heterozygosity (LOH) and mutation of the remaining allele. LOH at certain chromosomal loci accumulates during tumor progression. Approximately 20% of differentiated adenocarcinomas show evidence of mutator pathway tumorigenesis due to hMLH1 inactivation via hypermethylation of promoter CpG islands, and exhibit high-frequency microsatellite instability (MSI-H) (mutator pathway). In contrast, undifferentiated carcinomas rarely exhibit structurally altered tumor suppressor genes. For instance, while methylation of E-cadherin in native gastric mucosa is often observed in undifferentiated carcinomas, mutation of this gene is generally associated with the progression from differentiated adenocarcinomas to undifferentiated carcinomas. Hypermethylation of a number of tumor suppressor and tumor-related genes can be detected in both differentiated adenocarcinomas and undifferentiated carcinomas at varying frequencies. Promoter demethylation of specific genes, such as MAGE and Synuclein gamma, can occur during the progressive stages of both histological types, and is associated with patient prognosis. Thus, the molecular pathways of gastric carcinogenesis are dependent on histological background, and specific genetic abnormalities can be used for risk assessment, diagnosis, and prognosis.

Worldwide research on the human genome exerts a major impact on medical science. The growing evidence that genetic polymorphisms in the metabolism, the disposition, and the targets of drugs can have an even greater influence on the efficacy and the toxicity led to the creation of a novel chemotherapeutic strategy, personalized medicine. Much effort has been directed toward identifying the indicators of individual response to drugs, and these studies have provided a variety of potent predictive markers of individual drug response, which include some significant markers in clinical practice with sufficient evidence. Personalized medicine based on the response prediction using genomic marker is increasingly being recognized as a practical treatment approach in cancer chemotherapy, and to be indispensable when molecular targeted drugs are involved in the therapy. Even so, the ingenious and intricate mechanism of individual drug response creates obstacles in predicting chemotherapeutic response: Multiple factors are involved in the mechanisms, and key factors for drug response vary significantly among individuals. DNA chip technology enables us to overview a huge number of gene expressions simultaneously, but gene expression profiles of drug sensitivity vary considerably even for the same drug, which shows the limited value of a static microarray-expression profile as a marker aimed at individualizing patient therapy. Selection of a set of truly significant genomic markers and understanding of their interplay are of key importance in prediction of individual response to drug therapies. Challenges to such biological complexity are now started to identify a better genomic marker. The contribution of genomic marker research to anticancer chemotherapy and problems of the day were reviewed.

Docetaxel, a second-generation taxane, is one of the most powerful anticancer drugs for breast cancer. It has been widely used in the metastatic setting but also in the adjuvant or neoadjuvant setting for breast cancer patients. However, docetaxel is not effective for all breast cancers. The response rate is 40-60% even in first-line chemotherapy and it decreases to 20-30% in the second-or third-line chemotherapy. Therefore, it is very important to predict the sensitivity of docetaxel with high accuracy in order to avoid unnecessary treatment. Docetaxel binds to beta-tubulin and promotes polymerization, resulting in interference with mitosis. Unfortunately, the mechanism of sensitivity or resistance to docetaxel has not been fully understood. Recent studies in this area have demonstrated various mechanisms involved in the anti-tumor activity of docetaxel: (1) efflux (p-glycoprotein), (2) metabolism (CYP3A4), (3) beta-tubulin (isotype class I and III), (4) cell cycle (HER2, BRCA1), (5) apoptosis (p53, Bcl-2, thioredoxin), and (6) cell proliferation (MIB-1, nuclear grade). In addition, recently, gene expression profiling has been applied to the prediction of response to docetaxel in breast cancer. This work has reviewed recent studies, including ours, which have evaluated the association between these biological parameters and response to docetaxel in breast cancer.

CPT-11 is activated by hydrolysis to SN-38 that is primarily inactivated through biotrans-formation into SN-38 glucuronide ( SN-38 G) by UGT1As. Tailoring chemotherapy based on the genetic profile of patients and tumor would increase efficacy and decrease toxicity for patients. The toxicities of CPT-11 have been reported to correlate with the polymorphism of the number of TA repeats in UGT1A1 gene because of its gene transcriptional efficiency. UGT1A1*28 was chosen as the candidate gene to be investigated as a predictor of severe toxicity. Other studies determining predictive markers of CPT-11 efficacy have been highly controversial.

Pharmacogenetics has been widely studied to predict the clinical outcome including response, survival, and toxicity in patients treated by fluoropyrimidines based on a candidate approach. Several "candidate" gene expressions or polymorphisms in 5-fluorouracil pathway have been selected and identified retrospectively to correlate closely with the clinical outcome in small patient cohorts. Because of the lack of prospective confirmation, these candidate genes have not yet been applied in clinical practice as the predictive biomarker. Further studies by the pathway approach which overview the entire 5-fluorouracil pathway and that by the global approach using array are warranted.

In this review, pathogenesis and genetic alterations of urologic malignancies and their therapeutic target molecule are summarized briefly. In bladder cancer, only a little has been revealed. Loss of heterozygosity of 9p/q is frequently observed in low grade, low stage tumors. In invasive or carcinoma in situ tumors, alteration of p53 and Rb tumor suppressor gene is frequently found. In prostate cancer, the process of carcinogenesis from normal epithelium to cancer hypothesized by Nelson et al. (N Engl J Med 24; 349 : 366-381) seems to be logic. Androgen independency of tumor cells is associated with androgen receptor gene mutation and amplification, however, the mechanism is not well clarified. It is a turning point, therapeutic strategy is changing from cytokine immunotherapy to molecular targeting therapy in metastatic renal cell carcinoma. The pathway from growth factors such as vascular endothelial growth factor and platelet derived growth factor, and their receptors to mTOR is a central controller of tumor angiogenesis and proliferation.

The quantity and quality of circulating DNA fragments was analyzed by quantitative real-time polymerase chain reactions (qPCR) in plasma from patients with esophageal and gastric cancer, in order to assess their diagnostic value. Plasma was collected preoperatively from 24 patients with esophageal cancer 53 patients with gastric cancer and from 21 healthy controls. qPCR was performed using two primer sets for the BETA-actin gene, amplifying short (102 bp) and long (253 bp) segments. The DNA concentrations in both the short and long segment assays of both cancer patients were significantly higher than the controls. The difference of concentrations between disease group and controls was more significant in esophageal cancer patients. The area under the receiver-operating characteristic curve was 0.83 (short) and 0.91 (long) for esophageal cancer patients, and 0.75 (short) and 0.67 (long) for gastric cancer versus the controls. There was also a significant difference in DNA integrity (short/long) between esophageal cancer patients and the control group (p = 0.001). qPCR assays for plasma DNA concentrations and their integrity can serve as new diagnostic markers for screening and monitoring patients with esophageal and gastric cancer.

Prostate cancer is the most common non-cutaneous malignant neoplasm in men in Western countries. In Japan, the number of afflicted men has been increasing although it is still low compared with Western countries. One of the most important problems in prostate cancer patients is treatment for hormone-refractory prostate cancer (HRPC). Although docetaxel is considered as a first-line chemotherapeutic option in patients with HRPC in the USA, it is still necessary to search and develop new drugs. Spheroid culture models have an invaluable role in tumor biology or drug screening. Characteristics of cancer cells in three-dimensional (3D) culture, especially spheroid culture, differ dramatically from those in two-dimensional (2D) culture. Spheroid culture models appear to be an ideal tool, however, their models have not been incorporated in drug screening. In this article, we demonstrate characterization of prostate cancer spheroids including chemo-resistance compared with 2D culture and xenograft models. Prostate cancer cells except PC-3 formed E-cadherin-mediated spheroids. An immunocytochemical analysis of the spheroids revealed that cells showing Ki-67 were localized in the peripheral layer and the intermediate zone cells showed p27 and poly (ADP-ribose) polymerase-1 (PARP-1), suggesting quiescent cell character. Prostate cancer cells acquired resistance to most agents when grown as spheroids, but not to all of the anticancer agents tested. This article also attempts to provide up-to-date information about spheroids, especially quiescent cells as therapeutic targets and the involvement of genetics and epigenetics in forming spheroids.

Chromosomal aberrations have been shown to significantly affect survival in multiple myeloma (MM), but few cytogenetic analyses among Japanese MM patients have been reported. Using a commercial laboratory, we performed interphase fluorescent in situ hybridization (FISH), as well as a conventional metaphase cytogenetic study (G-banding), among 106 of 131 patients between April 1997 and February 2007. Karyotype abnormalities were found in 21.2% (21 of 99 patients). Del(13q), del(17p), del(11q), t(11;14) and t(4;14) were detected by FISH in 36.0% (31/86), 24.7% (19/77), 7.6% (5/64), 18.2% (12/66) and 10.4% (7/67) of patients, respectively. The prevalence of abnormalities detected by G-banding was lower than that reported in European countries, but when compared with FISH studies, no difference was observed. Prognostic analyses of patients with these abnormal chromosomes revealed that those with abnormal karyotype and del(13q), t(4;14), as detected by FISH, had significantly poorer survival. This study suggests that the prevalence of chromosome abnormalities among Japanese patients is similar to that for European populations, and that chromosome studies by G-banding and FISH are essential to predict survival.