Association between genetic variants and the risk of nivolumab-induced immune-related adverse events.

We sought to identify the variants that could predict the risk of nivolumab-induced immune-related adverse events (irAEs) in patients with cancer. We enrolled 622 Japanese patients and carried out a genome-wide association study. The associations for 507 single nucleotide polymorphisms (SNPs) showing p < 0.

Replication Study for the Association of Five SNPs Identified by GWAS and Trastuzumab-Induced Cardiotoxicity in Japanese and Singaporean Cohorts.

Trastuzumab (herceptin) is an effective drug for human epidermal growth factor receptor type 2 (HER2)-positive cancer. However, cardiotoxicity remains a serious complication. In our previous genome-wide association study (GWAS), we identified potential associations for five single nucleotide polymorphisms (SNPs) with trastuzumab-induced cardiotoxicity in a Japanese population.

The association of four genetic variants with myelosuppression in gemcitabine-treated Japanese is not evident in gemcitabine/carboplatin-treated Swedes.

Gemcitabine/carboplatin-induced myelosuppressive adverse drug reactions (ADRs) are clinical problems leading to patient suffering and dose alterations. There is a need for personalised medicine to improve treatment effects and patients' well-being. We tested four genetic variants, rs11141915, rs1901440, rs12046844 and rs11719165, previously suggested as potential biomarkers for gemcitabine-induced leukopenia/neutropenia in Japanese patients, in 213 Swedish gemcitabine/carboplatin-treated non-small cell lung cancer (NSCLC) patients.

Functional Characterization of the Effects of -acetyltransferase 2 Alleles on -acetylation of Eight Drugs and Worldwide Distribution of Substrate-Specific Diversity.

Variability in the enzymatic activity of -acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in -acetylation activities according to NAT2 phenotypes, i.e.

Whole-exome sequencing of 79 xenografts as a potential approach for the identification of genetic variants associated with sensitivity to cytotoxic anticancer drugs.

Chemotherapy response remains unpredictable in most patients with cancer. In this study, we performed whole-exome sequencing of 79 cancer xenografts derived from human cancer tissues to identify genetic predictors of chemosensitivity to nine cytotoxic anticancer drugs. Xenografts were harvested from 12 organs with cancer and implanted into nude mice.

Pharmacogenetics for severe adverse drug reactions induced by molecular-targeted therapy.

Molecular-targeted drugs specifically interfere with molecules that are frequently overexpressed or mutated in cancer cells. As such, these drugs are generally considered to precisely attack cancer cells, thereby inducing fewer adverse drug reactions (ADRs). However, molecular-targeted drugs can still cause characteristic ADRs that, although rarely severe, can be life-threatening.

Determination of novel CYP2D6 haplotype using the targeted sequencing followed by the long-read sequencing and the functional characterization in the Japanese population.

Next-generation sequencing (NGS) has identified variations in cytochrome P450 (CYP) 2D6 associated with drug responses. However, determination of novel haplotypes is difficult because of the short reads generated by NGS. We aimed to identify novel CYP2D6 variants in the Japanese population and predict the CYP2D6 phenotype based on in vitro metabolic studies.

Evaluation of circulating tumor DNA as a biomarker in pancreatic cancer with liver metastasis.

Pancreatic cancer is an aggressive, solid tumor, with a grave prognosis. Despite surgical treatment in patients with pancreatic cancer, the rate of recurrence is high. In addition, although tumor biomarkers are frequently used to confirm advanced pancreatic cancer, this is not accurate and the biomarkers currently used cannot indicate prognosis.

Serial circulating tumour DNA analysis for locally advanced rectal cancer treated with preoperative therapy: prediction of pathological response and postoperative recurrence.

Background: The "watch-and-wait" approach is a common treatment option amongst patients with locally advanced rectal cancer (LARC). However, the diagnostic sensitivity of clinical modalities, such as colonoscopy and magnetic resonance imaging to determine pathological response, is not high. We analysed the clinical utility of circulating tumour DNA (ctDNA) of patients with LARC to predict response to preoperative therapy and postoperative recurrence.

Liquid biopsy for the detection of clinical biomarkers in early breast cancer: new insights and challenges.

The widespread use of breast screening programs has contributed to the detection of early stage breast cancer, which is often asymptomatic. Early diagnosis is essential to avoid overtreatment and improve clinical outcomes, as early stage breast cancer is rarely life-threatening if detected quickly. Despite this, tissue biopsy remains the principle method for detecting these cancers.

Early change in circulating tumor DNA as a potential predictor of response to chemotherapy in patients with metastatic colorectal cancer.

The impact of ctDNA changes after chemotherapy on the clinical outcomes of patients with metastatic colorectal cancer (mCRC) remains unclear. The present study evaluated the clinical implications of the early change in ctDNA levels as a predictor of objective response and clinical outcome in mCRC patients who received chemotherapy. We investigated the effects of after/before ratio of ctDNA levels 2 and 8 weeks after initiation of second-line chemotherapy, on objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).

A Genome-Wide Association Study Identifies Five Novel Genetic Markers for Trastuzumab-Induced Cardiotoxicity in Japanese Population.

Trastuzumab has been administered to patients with human epidermal growth factor receptor 2 (HER2)-positive cancer, however, the cardiotoxicity is identified as one of the life-threatening toxicities. Clinically useful biomarker for trastuzumab-induced cardiotoxicity has been expected to be developed. To identify a novel genetic marker(s) determining the risk of trastuzumab-induced cardiotoxicity, we performed a first genome-wide association study (GWAS) in Japanese population.

Whole genome sequencing to identify predictive markers for the risk of drug-induced interstitial lung disease.

Drug-induced interstitial lung disease (DIILD) is a serious side effect of chemotherapy in cancer patients with an extremely high mortality rate. In this study, to identify genetic variants with greater risk of DIILD, we carried out whole genome sequencing (WGS) of germline DNA samples from 26 patients who developed DIILD, and conducted a case-control association study between these 26 cases and general Japanese population controls registered in the integrative Japanese Genome Variation Database (iJGVD) as a screening study. The associations of 42 single nucleotide variants (SNVs) showing P < 0.

Clinical utility of circulating tumor DNA for colorectal cancer.

Colorectal cancer (CRC) is currently the most common type of cancer in Japan, and its prognosis has improved because of development of diagnosis and advancement in treatments including surgery and chemotherapy. However, because of intratumor heterogeneity and clonal evolution, tumors often develop resistance to treatment. Genotyping tumor tissue in search of somatic genetic alterations for actionable information has become routine examination in clinical practice.

Clinical relevance of circulating tumor DNA assessed through deep sequencing in patients with metastatic colorectal cancer.

Because circulating tumor DNA (ctDNA) studies focusing on only one or a few genes to monitor the disease progress or treatment response are unlikely to find its clinical significance, the development of cell-free DNA (cfDNA) panel covering hundreds of mutation hot spots is important for the establishment of clinically practical ctDNA detection system. We enrolled 101 patients with metastatic colorectal cancer (mCRC) who received chemotherapy. Amplicon-based genomic profiling of 14 genes, which are commonly mutated in CRC, in plasma by next-generation sequencing (NGS) was carried out to evaluate the feasibility of this assay and was compared with their clinical parameters and RAS status in matched tissue samples.

A prospective study to examine the accuracies and efficacies of prediction systems for response to neoadjuvant chemotherapy for muscle invasive bladder cancer.

The present study established systems to predict the chemo-sensitivity of muscle invasive bladder cancer (MIBC) for neoadjuvant chemotherapy (NAC) with methotrexate, vinblastine, doxorubicin plus cisplatin (M-VAC) and carboplatin plus gemcitabine (CaG) by analyzing microarray data. The primary aim of the study was to investigate whether the clinical response would increase by combining these prediction systems. Treatment of each MIBC case was allocated into M-VAC NAC, CaG NAC, surgery, or radiation therapy groups by their prediction score (PS), which was calculated using the designed chemo-sensitivity prediction system.

A genome-wide association study identifies three novel genetic markers for response to tamoxifen: A prospective multicenter study.

Purpose: Although association studies of genetic variations with the clinical outcomes of breast cancer patients treated with tamoxifen have been reported, genetic factors which could determine individual response to tamoxifen are not fully clarified. We performed a genome-wide association study (GWAS) to identify novel genetic markers for response to tamoxifen.

Experimental Design: We prospectively collected 347 blood samples from patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative, invasive breast cancer receiving preoperative tamoxifen monotherapy for 14 to 28 days.

Targeted sequencing reveals genetic variants associated with sensitivity of 79 human cancer xenografts to anticancer drugs.

Although there has been progress moving from a 'one-size-fits-all' cytotoxic approach to personalized molecular medicine, the majority of patients with cancer receive chemotherapy using cytotoxic anticancer drugs. The sequencing analysis of 409 genes associated with cancer was conducted in the present study using 59 DNA sequences extracted from human cancer xenografts implanted into nude mice, of which sensitivity to 9 cytotoxic anticancer drugs [5-fluorouracil, nimustine, adriamycin, cyclophosphamide, cisplatin, mitomycin C (MMC), methotrexate, vincristine (VCR), and vinblastine] was examined. The present study investigated the association between the sensitivities of the xenografts to the 9 anticancer drugs and the frequency of single nucleotide variants (SNV).

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy.

Tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and 4-hydroxy N-desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype.

Whole exome sequencing to identify genetic markers for trastuzumab-induced cardiotoxicity.

Although trastuzumab-induced cardiotoxicity is an important determinant to limit the use of this drug, the molecular mechanism of risk for this toxicity is not well understood. To identify genetic variants determining the risk of trastuzumab-induced cardiotoxicity, we carried out whole exome sequencing of germline DNA samples from 9 patients with trastuzumab-induced cardiotoxicity, and conducted a case-control association study of 2258 genetic variants between 9 cases (with trastuzumab-induced cardiotoxicity) and general Japanese population controls registered in the Human Genetic Variation Database (HGVD). The top variant which showed the lowest P-value in the screening study was rs139503277 in PHD Finger Protein 3 (P = .

Breast cancer: The translation of big genomic data to cancer precision medicine.

Cancer is a complex genetic disease that develops from the accumulation of genomic alterations in which germline variations predispose individuals to cancer and somatic alterations initiate and trigger the progression of cancer. For the past 2 decades, genomic research has advanced remarkably, evolving from single-gene to whole-genome screening by using genome-wide association study and next-generation sequencing that contributes to big genomic data. International collaborative efforts have contributed to curating these data to identify clinically significant alterations that could be used in clinical settings.

The prediction models for postoperative overall survival and disease-free survival in patients with breast cancer.

The goal of this study is to establish a method for predicting overall survival (OS) and disease-free survival (DFS) in breast cancer patients after surgical operation. The gene expression profiles of cancer tissues from the patients, who underwent complete surgical resection of breast cancer and were subsequently monitored for postoperative survival, were analyzed using cDNA microarrays. We detected seven and three probes/genes associated with the postoperative OS and DFS, respectively, from our discovery cohort data.

Silencing PRDM14 expression by an innovative RNAi therapy inhibits stemness, tumorigenicity, and metastasis of breast cancer.

PR domain zinc finger protein 14 (PRDM14) maintains stemness in embryonic stem cells via epigenetic mechanisms. Although PRDM14 is elevated in several cancers, it is unclear if and how PRDM14 confers stem cell-like properties and epigenetic changes to cancer cells. Here, we examined the phenotypic characteristics and epigenetic and gene expression profiles of cancer cells that differentially express PRDM14, and assessed the potential of PRDM14-targeted cancer therapy.

Overview of BioBank Japan follow-up data in 32 diseases.

Background: We established a patient-oriented biobank, BioBank Japan, with information on approximately 200,000 patients, suffering from any of 47 common diseases. This follow-up survey focused on 32 diseases, potentially associated with poor vital prognosis, and collected patient survival information, including cause of death. We performed a survival analysis for all subjects to get an overview of BioBank Japan follow-up data.

Cross-sectional analysis of BioBank Japan clinical data: A large cohort of 200,000 patients with 47 common diseases.

Background: To implement personalized medicine, we established a large-scale patient cohort, BioBank Japan, in 2003. BioBank Japan contains DNA, serum, and clinical information derived from approximately 200,000 patients with 47 diseases. Serum and clinical information were collected annually until 2012.