Gene array testing defined the intrinsic biological subtypes including"luminal A", "luminal B", "HER2-enriched" and "basal" within breast cancer. These subtypes may be approximated using clinicopathological immunochemistry rather than gene expression array criteria. These subtypes have different epidemiological risk factors, different natural histories, and different response to systemic and local therapies. Systemic therapy recommendations follow the subtype classification. "Estrogen receptor", "progesterone receptor", "human epidermal growth factor receptor 2" and "Ki67" are the most important biological markers to classify the subtypes and predict the prognosis and the response to the therapy. The new targeting therapy will require new biomarkers.

Identification of sensitive biomarkers predictive of diagnosis, prognosis and drug sensitivity could have a clinically significant impact on non-small cell lung cancer (NSCLC) treatment strategies. Recently, molecular-targeted therapies have been developed for NSCLC treatment. NSCLC patients with epidermal growth factor receptor (EGFR) gene mutations have shown a dramatic response to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib. In addition, target therapies against echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein present in approximately 5% of the Japanese patients with adenocarcinomas are currently under development. In this paper, we reviewed diagnostic and therapeutic biomarkers for lung cancer patients.

Discovery of usable molecular biomarkers is the step closer to a realization of personalized therapy for patients with colorectal cancer(CRC). Herein we present an update of the most recent data on promising biological prognostic and/or predictive markers, including microsatellite instability(MSI) and KRAS/BRAF mutations. Additionally, we propose a new genetic classification for CRC based on MSI and KRAS/BRAF mutation status (a 2 x 3 matrix). The 2 x 3 matrix is constructed of 6 cells that are made by [MSI/non-MSI] x [BRAF mutant/KRAS mutant/wild type of the both genes]. All of CRC including Lynch syndrome could be classified without overlapping into the 6 cells. More interestingly, each cell has each promising biological prognostic and/or predictive feature, which will help clinicians to make personalized treatment strategy for each CRC patient.

Accumulation of epigenomic aberrations plays a critical role in tumorigenesis, both in tumor initiation and progression. Development of epigenomic markers can therefore be useful in determination of tumor risk of apparently normal cases, or in classifying tumor cases in relation to etiology, prognosis or therapy response. Loss of imprinting of IGF2 is an epigenetic aberration that exists in normal tissues and modifies tumor risk, and is a possible therapy target for tumor risk management. Thanks to development of quantitative and comprehensive analysis tools for DNA methylation, it becomes possible to epigenotype tumors, i.e., classification of tumors using epigenomic information, by unsupervised hierarchical clustering. Gastric cancer is epigenotyped in relation to etiology such as EB virus infection, and colorectal cancer is epigenotyped in relation to oncogene mutation statuses, suggesting distinct molecular mechanisms in colorectal tumorigenesis.

FOLFOX or FOLFIRI are commonly used as first- or second-line chemotherapy for unresectable colorectal cancer or its metastases.Recently, it had become a trend to add bevacizumab or cetuximab(Cmab)limited to the K-ras wild-type or panitumumab(Pmab)limited to the K-ras wild-type.At the present time, a common third-line chemotherapy is CPT-11 plus Cmab limited to the K-ras wild-type, or Cmab/Pmab.However, the results are unsatisfactory.With Cmab plus S-1 we treated a case of remnant liver metastases from rectal cancer which was a K-ras wild-type, after treating 5-FU, L-OHP and CPT-11. The tumor marker dropped and 7 focuses of liver metastases disappeared after 6 courses of treatment(complete response: CR in)and CR was achieved after 9 courses treatment.After 10 courses of treatment, a new lesion appeared on S5 of the liver and we performed percutaneous radiofrequency ablation.

Cancer of unknown primary(CUP)is a heterogenous group of tumors that accounts for 3 to 5 percent of all malignancies. Due to CUP's heterogeneity, clinical trials are difficult to perform and articles published on the disease require careful interpretation. Among CUP's, there are several clinical groups that are treated with specific treatment modalities. Each clinical group has similar treatment effects and prognoses with common malignancies that arise in adjacent locations, such as breast cancer and head/neck cancer. Therefore, accurate histological diagnosis and careful clinical staging are important. However, many CUP's do not belong to these specific clinical groups and generally have a poor prognosis. The treatment is usually directed based upon histology, location of the tumor, and stage. Platinum agents, taxanes and other new cytotoxic drugs are often used for systemic therapy, but their efficacy is often limited. Currently, specific molecular markers and targeted therapy are being explored.

The single-nucleotide polymorphism (SNP)-based genome-wide association study (GWAS) is now widely performed because of the development of new SNP genotyping technologies from 2007 onward. The GWAS provides a powerful approach to identify regions of the genome that harbor genetic variants conferring risk for disease without prior knowledge of location or function. During the past few years, the GWAS has identified numerous robust associations between specific chromosomal loci and different types of cancer. For nearly all regions identified in the GWAS, the per allele effect sizes estimated are < 1.5 and the mechanism of SNP in carcinogenesis was not clear. Consequently, GWAS findings underscore the complex nature of cancer. The combined effects may be sufficiently great to be useful for risk prediction, targeted screening, and prevention, particularly as more loci are identified. Some loci, such as 8q24, were identified as a cancer susceptibility region for many unrelated cancers, and therefore an investigation of those loci may disclose new mechanisms of carcinogenesis or unknown genes including noncoding RNA. Furthermore, the development of new strategies for GWAS analysis is expected.

The role of RNA, as commonly understood, is to carry the genetic code for protein from the DNA to the sites of protein production. Over the years, however, new forms of RNA were discovered, such as microRNA (miRNA) and large intergenic noncoding RNA, and the range of RNA function was extended, miRNA constitutes a large family of small, approximately 20-nucleotide-long, noncoding RNA which controls the expression of target genes at the posttranscriptional level. Recent studies have indicated that miRNA plays an essential role in cancer biology by affecting cell growth, differentiation, and apoptosis as well as the cell cycle. This review summarizes the newly determined role of miRNA in cancer development, discusses some controversies regarding different functions of miRNA, and highlights the prospects for clinical applications of miRNA, such as therapeutic targets and diagnostic markers.

Several oncogenes and tumor suppressor genes are involved in the multistep process of carcinogenesis in many cancer types. Recently, global mutational analyses have revealed that the cancer genome has far greater numbers of mutations than previously thought. Furthermore, the next-generation sequencing method, which has a different principle from conventional Sanger sequencing, has provided more information on the cancer genome such as new cancer-related genes and the existence of many rearrangements in solid cancers. Somatic mutations occurring in cancer cells are divided into "driver" and "passenger" mutations. Driver mutations confer a growth advantage upon the neoplastic clone and are crucial for carcinogenesis. The remaining large majority of mutations are passengers, which, by definition, do not confer a growth advantage. Driver genes with low-frequency mutation rates (less than 10%) are also involved in carcinogenesis along with well-known drivers with high-frequency mutations. There are now several celebrated examples of anticancer drugs of which the efficacy in cancer patients can be predicted based on the genotype of several driver genes, such as EGFR, KRAS, and BRAF on the EGFR signaling pathway. The complete catalogs of somatic mutations provided by the sequencing of the cancer genome are expected to prompt new approaches to diagnosis, therapy, and potentially prevention.

Familial brain tumor syndromes include neurofibromatosis 1, neurofibromatosis 2, tuberous sclerosis, von Hippel-Lindau disease, and multiple endocrine neoplasia type 1, which are hereditary diseases. In these diseases, various tumors develop because of alterations in tumor suppressor genes. Familial brain tumors are mostly benign, but some are malignant. Familial brain tumor syndromes are diagnosed on the basis of guidelines for clinical diagnosis and by DNA test. Unlike sporadic brain tumors, familial brain tumors occur at multiple sites; therefore, a single operation is often not sufficient for treating familial brain tumors, and it is often necessary to treat lesions in other organs. Surgical indications should be considered more prudently for familial brain tumors than for sporadic brain tumors.

Over the last decade, significant progress has been made in understanding glioma on a molecular level. However, optimal incorporation of molecular markers into clinical care is still controversial. Here, the potential utility of genetic alterations found in gliomas in refining histological diagnosis, prognosis, and predictive values for treatment selection is reviewed. Among all, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, 1p/19q codeletion, and isocitrate dehydrogenase 1 (IDH1) mutations have been identified as favorable prognostic markers. MGMT promoter methylation is the only potential predictive marker for response to temozolomide and alkylating agents in glioblastoma (GBM), but it is not of assistance in diagnostics. IDH1 mutations and 1p/19q codeletion are also useful for classifying and grading gliomas, since 1p/19q codeletion is tightly linked to oligodendroglial lineage, and IDH1 mutations are restricted to grade II/III gliomas, while not to primary GBM. BRAF fusion is a good marker for pilocytic astrocytoma. High-throughput profiling techniques for gene expression and epigenetic modification have provided new subtype classifications for GBM as well as lower grade gliomas, which may be of prognostic and predictive values. Efforts to identify molecular markers that predict the benefits of novel molecularly targeted treatments will enable better patient stratification and individualization of treatment.

Androgen and estrogen are sex steroid hormones, which bind to it own nuclear receptors, such as androgen receptor (AR) and estrogen (ER) , and exert its action through regulation of target gene expressions, and contribute to the maintenance of various homeostasis. However, the mode of binding of AR and ER binding site on the genome DNA and their intracellular behavior are diverse in various cells. From genome-wide analysis studies with the advent and remarkable development of next-generation sequencer in recent years, it has been clarified that new features and mechanism of action of sex hormone receptors in breast cancer and prostate cancer. In this paper, we focus on the AR, together with recent findings on genome-wide analysis, and we also introduce the current application for bone metabolism.

Leukemias including acute myeloid leukemia (AML), acute lymphocytic leukemia, and chronic myeloid leukemia as well as myelodysplastic syndrome (MDS), male non-Hodgkin lymphoma and MGUS are statistically significant radiation-associated hematopoietic neoplasms. Recently, MDS has been confirmed to increase among atomic bomb survivors. AML/RUNX1 is a critical transcription factor of differentiation and proliferation of hematopoietic stem cells. AML1 point mutations, especially N-terminal RUNT domain in-frame type, are frequently detected in radiaton-associated and therapy-related (rad-t-) MDS/AML. In addition, the point mutations, are frequently associated with additional mutations in receptor tyrosine kinase (RTK)-RAS pathway, including FLT3, N-RAS, SHP2 and NF1. The combination of AML1/RUNX1 mutation and RTK-RAS pathway mutation in hematopoietic stem cells is considered responsible for the oncogenesis of rad-t- MDS/AML.

Intense research after Hiroshima and Nagasaki atomic bomb (A-bomb) tragedy and Chernobyl nuclear plant accident revealed that ionizing radiation (IR) more than 100 mSv induces cancers that are indistinguishable from sporadic tumors. It remains controversial whether low dose IR (less than 100 mSv) is oncogenic or not. Among IR-induced malignancies, leukemia (A-bomb) and thyroid cancers (Chernobyl), in which chimeric(fusion) oncogenes formed by chromosome translocations play a critical role, develop with relatively short latency. All other cancers develop after long latency. Age-related epigenetic changes, as well as additional genetic alterations, would contribute to IR-induced carcinogenesis.

In Japan, awareness of hereditary breast and ovarian cancer (HBOC) has gradually increased among health care workers and the general population. We focus on two current topics: genetic testing and risk-reducing surgery for HBOC. Genetic testing for BRCA1 and BRCA2, the genes responsible for HBOC, is performed to diagnose HBOC. PCR-direct sequencing is a standard method used for BRCA1/2 mutation analysis. Recently, genetic rearrangement of BRCA1 was reported in a Japanese patient with HBOC. Therefore, MLPA tests are also being included in routine genetic testing for the disease. The result of "uncertain significance, " which indicates unclear pathogenic significance, is obtained in about 3% of all patients who undergo BRCA1/2 genetic tests. Furthermore, novel candidate genes for HBOC, such as RAD51C, PALB2, and BRIP1, were recently identified. Prophylactic surgical intervention for HBOC includes procedures such as risk-reducing bilateral salpingo-oophorectomy (RRSO) and risk-reducing mastectomy(RRM). In Japan, RRSO is performed in very few patients at present. Increasing evidence from overseas indicates that RRSO contributes to a decreased incidence of ovarian/breast cancers and lowers overall mortality. Therefore, a system for performing RRSO was established in our institute. RRSO was approved to be performed as a clinical examination by our Institutional Review Board. The clinical significance of ipsilateral complete mastectomy and RRM remains unclear. Based on the NCCN guidelines, conservative mastectomy with radiation therapy is relatively contraindicated in patients with HBOC. However, several studies have reported that conservative mastectomy with radiation the rapydoes not increase the incidence of recurrent or metachronous breast cancers in the ipsilateral breast of mutation-positive patients when compared to mutation-negative or control patients. However, more aggressive malignancies seem to be included in the mutation-positive group(especially BRCA1 -mutation-positive cases). RRM clearly reduced the incidence of breast cancers. RRM may also be allowed as a treatment option for HBOC in Japan.

Familial ovarian cancer occurs as part of two genetically distinct syndromes: hereditary breast and ovarian cancer (HBOC) and hereditary nonpolyposis colorectal cancer (HNPCC). HBOC caused by inherited mutations of BRCA1/2 and HNPCC caused by mismatch-repair genes are considered responsible for about 65 to 75% and 10 to 15% of familial ovarian cancers, respectively. Germline mutations of BRCA1 are considered responsible for about 50% of ovarian cancer families and 80% of breast-ovarian cancer families. BRCA2 mutations are less common than BRCA1 mutations in ovarian cancer families. A high proportion of serous adenocarcinomas at an advanced stage has been reported with BRCA-related ovarian cancers in several studies. It is controversial whether BRCA-related ovarian cancer patients carry a better prognosis despite the aggressive tumor-pathological characteristics of their disease, compared to sporadic cases. However, a good therapeutic response may be attributable to platinum-based chemotherapy. Recently in Japan, gene testing of BRCA1/2 has been available as a routine clinical test for diagnosing ovarian cancer families. Because the mutation spectrum of BRCA1/2 in Japanese was different from that of non-Ashkenazi individuals, the clinical application of BRCA1/2 gene testing for Japanese has been advocated. Approximately 1-5% of ovarian cancer patients in Japan are thought to have a family history of breast and/or ovarian cancer. The prevalence of deleterious mutations of BRCA1/2 in Japanese was reportedly significantly higher than that of non-Ashkenazi individuals despite the low frequency of familial cases in Japan. Although the age at diagnosis of ovarian cancers with BRCA1/2 mutation in the United States was earlier than those of the sporadic cases, there were no differences among Japanese. These results suggest that clinical and genetic aspects of BRCA-related ovarian cancer of the Japanese are different from those of Caucasians. A serious issue in this field is how the results will lead to a basis for the clinical application of a cancer prevention strategy targeting BRCA mutation carriers in Japanese.

The clinical features of familial breast cancer are characterized by early onset, high frequency of bilateral breast cancer, and multiple malignancies of other organs. It is strongly suggested that genetic factors contribute to familial breast cancer. The causative genes now identified are BRCA1 and BRCA2. This disease is called hereditary breast ovarian cancer syndrome (HBOC)because breast cancer and ovarian cancer are clustered in the kindred confirmed BRCA mutation. As for BRCA related breast cancer, early onset and highly frequent bilateral breast cancer are characteristic. In addition, the histological grade is high and the positive rate of estrogen receptors is low in BRCA1-related breast cancer. Gene diagnosis of BRCA is useful when choosing a surgical method, chemotherapy, or a surveillance of mutation carriers. The problem in Japan is that the treatment is very expensive, with poor understanding of HBOC of by clinicians and as yet immature genetic counseling system.