Publications by authors named "Ituro Inoue"

151 Publications

Genetic variant rs10251977 (G>A) in EGFR-AS1 modulates the expression of EGFR isoforms A and D.

Sci Rep 2021 Apr 22;11(1):8808. Epub 2021 Apr 22.

Department of Genetics, Dr. ALM PG Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India.

Tyrosine kinase inhibitor is an effective chemo-therapeutic drug against tumors with deregulated EGFR pathway. Recently, a genetic variant rs10251977 (G>A) in exon 20 of EGFR reported to act as a prognostic marker for HNSCC. Genotyping of this polymorphism in oral cancer patients showed a similar frequency in cases and controls. EGFR-AS1 expressed significantly high level in tumors and EGFR-A isoform expression showed significant positive correlation (r = 0.6464, p < 0.0001) with reference to EGFR-AS1 expression levels, consistent with larger TCGA HNSCC tumor dataset. Our bioinformatic analysis showed enrichment of alternative splicing marks H3K36me3 and presence of intronic polyA sites spanning around exon 15a and 15b of EGFR facilitates skipping of exon 15b, thereby promoting the splicing of EGFR-A isoform. In addition, high level expression of PTBP1 and its binding site in EGFR and EGFR-AS1 enhances the expression of EGFR-A isoform (r = 0.7404, p < 0.0001) suggesting that EGFR-AS1 expression modulates the EGFR-A and D isoforms through alternative splicing. In addition, this polymorphism creates a binding site for miR-891b in EGFR-AS1 and may negatively regulate the EGFR-A. Collectively, our results suggested the presence of genetic variant in EGFR-AS1 modulates the expression of EGFR-D and A isoforms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-88161-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062556PMC
April 2021

Substantial anti-gout effect conferred by common and rare dysfunctional variants of URAT1/SLC22A12.

Rheumatology (Oxford) 2021 Apr 2. Epub 2021 Apr 2.

Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan.

Objectives: Gout, caused by chronic elevation of serum uric acid levels, is the commonest form of inflammatory arthritis. The causative effect of common and rare variants of ATP-binding cassette transporter G2 (ABCG2/BCRP) on gout risk has been studied, but, little attention has been paid to the effect of common (rs121907892, p. W258X) and rare variants of urate transporter 1 (URAT1/SLC22A12) on gout, despite dysfunctional variants of URAT1 having been identified as pathophysiological causes of renal hypouricemia.

Methods: To address this important but overlooked issue, we investigated the effects of these URAT1 variants on gout susceptibility, using targeted exon sequencing on 480 clinically-defined gout cases and 480 controls of Japanese male in combination with a series of functional analyses of newly-identified URAT1 variants.

Results: Our results show that both common and rare dysfunctional variants of URAT1 markedly decrease the risk of gout (OR 0.0338, reciprocal OR 29.6, p = 7.66 × 1 0 -8). Interestingly, we also found that the URAT1-related protective effect on gout eclipsed the ABCG2-related causative effect (OR 2.30 - 3.32). Our findings reveal only one dysfunctional variant of URAT1 to have a substantial anti-gout effect, even in the presence of causative variants of ABCG2, a "gout gene".

Conclusion: Our findings provide a better understanding of gout/hyperuricemia and its aetiology that is highly relevant to personalized health care. The substantial anti-gout effect of common and rare variants of URAT1 identified in the present study support the genetic concept of a 'Common Disease, Multiple Common and Rare Variant' model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/rheumatology/keab327DOI Listing
April 2021

Analysis of HLA gene polymorphisms in East Africans reveals evidence of gene flow in two Semitic populations from Sudan.

Eur J Hum Genet 2021 Mar 22. Epub 2021 Mar 22.

Human Genetics Laboratory, Department of Genomics and Evolutionary Biology, National Institute of Genetics, Mishima, Shizuoka, Japan.

Sudan, a northeastern African country, is characterized by high levels of cultural, linguistic, and genetic diversity, which is believed to be affected by continuous migration from neighboring countries. Consistent with such demographic effect, genome-wide SNP data revealed a shared ancestral component among Sudanese Afro-Asiatic speaking groups and non-African populations, mainly from West Asia. Although this component is shared among all Afro-Asiatic speaking groups, the extent of this sharing in Semitic groups, such as Sudanese Arab, is still unknown. Using genotypes of six polymorphic human leukocyte antigen (HLA) genes (i.e., HLA-A, -C, -B, -DRB1, -DQB1, and -DPB1), we examined the genetic structure of eight East African ethnic groups with origins in Sudan, South Sudan, and Ethiopia. We identified informative HLA alleles using principal component analysis, which revealed that the two Semitic groups (Gaalien and Shokrya) constituted a distinct cluster from the other Afro-Asiatic speaking groups in this study. The HLA alleles that distinguished Semitic Arabs co-exist in the same extended HLA haplotype, and those alleles are in strong linkage disequilibrium. Interestingly, we find the four-locus haplotype "C*12:02-B*52:01-DRB1*15:02-DQB1*06:01" exclusively in non-African populations and it is widely spread across Asia. The identification of this haplotype suggests a gene flow from Asia, and likely these haplotypes were brought to Africa through back migration from the Near East. These findings will be of interest to biomedical and anthropological studies that examine the demographic history of northeast Africa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-021-00845-6DOI Listing
March 2021

Endogenous retroviruses drive KRAB zinc-finger protein family expression for tumor suppression.

Sci Adv 2020 Oct 21;6(43). Epub 2020 Oct 21.

Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 1088639, Japan.

Gene expression aberration is a hallmark of cancers, but the mechanisms underlying such aberrations remain unclear. Human endogenous retroviruses (HERVs) are genomic repetitive elements that potentially function as enhancers. Since numerous HERVs are epigenetically activated in tumors, their activation could cause global gene expression aberrations in tumors. Here, we show that HERV activation in tumors leads to the up-regulation of hundreds of transcriptional suppressors, namely, Krüppel-associated box domain-containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by these adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Increased KZFP expression in cancer cells altered the expression of genes related to the cell cycle and cell-matrix adhesion and suppressed cellular growth, migration, and invasion abilities. Our data suggest that HERV activation in tumors drives the synchronized elevation of KZFP expression, presumably leading to tumor suppression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abc3020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577720PMC
October 2020

APOBEC: A molecular driver in cervical cancer pathogenesis.

Cancer Lett 2021 01 7;496:104-116. Epub 2020 Oct 7.

Department of Genetics, Dr ALM PG Institute of Basic Medical Sciences, University of Madras, Chennai, 600113, India. Electronic address:

Cervical cancer is one of the foremost common cancers in women. Human papillomavirus (HPV) infection remains a major risk factor of cervical cancer. In addition, numerous other genetic and epigenetic factors also are involved in the underlying pathogenesis of cervical cancer. Recently, it has been reported that apolipoprotein B mRNA editing enzyme catalytic polypeptide like (APOBEC), DNA-editing protein plays an important role in the molecular pathogenesis of cancer. Particularly, the APOBEC3 family was shown to induce tumor mutations by aberrant DNA editing mechanism. In general, APOBEC3 enzymes play a pivotal role in the deamination of cytidine to uridine in DNA and RNA to control diverse biological processes such as regulation of protein expression, innate immunity, and embryonic development. Innate antiviral activity of the APOBEC3 family members restrict retroviruses, endogenous retro-element, and DNA viruses including the HPV that is the leading risk factor for cervical cancer. This review briefly describes the pathogenesis of cervical cancer and discusses in detail the recent findings on the role of APOBEC in the molecular pathogenesis of cervical cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539941PMC
January 2021

Identification of ancient viruses from metagenomic data of the Jomon people.

J Hum Genet 2021 Mar 30;66(3):287-296. Epub 2020 Sep 30.

Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan.

Ancient DNA studies provide genomic information about the origins, population structures, and physical characteristics of ancient humans that cannot be solely examined by archeological studies. The DNAs extracted from ancient human bones, teeth, or tissues are often contaminated with coexisting bacterial and viral genomes that contain DNA from ancient microbes infecting those of ancient humans. Information on ancient viral genomes is useful in making inferences about the viral evolution. Here, we have utilized metagenomic sequencing data from the dental pulp of five Jomon individuals, who lived on the Japanese archipelago more than 3000 years ago; this is to detect ancient viral genomes. We conducted de novo assembly of the non-human reads where we have obtained 277,387 contigs that were longer than 1000 bp. These contigs were subjected to homology searches against a collection of modern viral genome sequences. We were able to detect eleven putative ancient viral genomes. Among them, we reconstructed the complete sequence of the Siphovirus contig89 (CT89) viral genome. The Jomon CT89-like sequence was determined to contain 59 open reading frames, among which five genes known to encode phage proteins were under strong purifying selection. The host of CT89 was predicted to be Schaalia meyeri, a bacterium residing in the human oral cavity. Finally, the CT89 phylogenetic tree showed two clusters, from both of which the Jomon sequence was separated. Our results suggest that metagenomic information from the dental pulp of the Jomon people is essential in retrieving ancient viral genomes used to examine their evolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-020-00841-6DOI Listing
March 2021

HLA-B*39:01:01 is a novel risk factor for antithyroid drug-induced agranulocytosis in Japanese population.

Pharmacogenomics J 2021 02 22;21(1):94-101. Epub 2020 Sep 22.

Human Genetics Laboratory, National Institute of Genetics, Mishima, Japan.

Antithyroid drug (ATD) is a mainstay of Graves' disease (GD). About 0.1-0.5% of patients with GD treated with ATD exhibit ATD-induced agranulocytosis, which is characterized by severe reduction of circulating neutrophils. Immune-mediated responses have been proposed as a possible mechanism for the pathogenesis of ATD-induced agranulocytosis. Although it has been reported that the HLA class II allele (HLA-DRB1*08:03) was associated with ATD-induced agranulocytosis in multiple populations, the entire HLA region have not been explored in Japanese. Therefore, we performed HLA sequencing for 10 class I and 11 class II genes in 87 patients with ATD-induced agranulocytosis and 384 patients with GD who did not show ATD-induced agranulocytosis. By conducting case-control association studies at the HLA allele and haplotype levels, we replicated the association between HLA-DRB1*08:03:02 and ATD-induced agranulocytosis (P = 5.2 × 10, odds ratio = 2.80), and identified HLA-B*39:01:01 as an independent risk factor (P = 1.4 × 10, odds ratio = 3.35). To verify reproducibility of the novel association of HLA-B*39:01:01, we reanalyzed allele frequency data for HLA-B*39:01:01 from previous case-control association studies. The association of HLA-B*39:01:01 was significantly replicated in Chinese (P = 9.0 × 10), Taiwanese (P = 1.1 × 10), and European populations (P = 5.2 × 10). A meta-analysis combining results from the previous and current studies reinforced evidence of the association between HLA-B*39:01:01 and ATD-induced agranulocytosis (P = 1.2 × 10, pooled OR = 3.66, 95% CI; 2.41-5.57). The results of this study will provide a better understanding of the pathogenesis of ATD-induced agranulocytosis in the context of HLA-mediated hypersensitivity reactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41397-020-00187-4DOI Listing
February 2021

AMBRA1 controls antigen-driven activation and proliferation of naïve T cells.

Int Immunol 2020 Sep 10. Epub 2020 Sep 10.

Department of Immunology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

AMBRA1 is a member of the BECN1 (BECLIN1) complex protein, and it plays a role in autophagy, cell death, tumorigenesis, and proliferation. We recently reported that on TCR stimulation, AMBRA1 controlled both autophagy and the cell cycle with metabolic regulation. Accumulating evidence has shown that autophagy and metabolic control are pivotal for T cell activation, clonal expansion, and effector/memory cell fate decision. However, it is unknown whether AMBRA1 is involved in T cell function under physiological conditions. We found that T cells in Ambra1-conditional knockout (cKO) mice induced exacerbated graft versus host response when they were transplanted into allogeneic BALB/c mice. Furthermore, Ambra1-deficient T cells showed increased proliferation and cytotoxic capability towards specific antigens in response to in vivo stimulation using allogeneic spleen cells. This enhanced immune response mainly contributed to naïve T cell hyperactivity. The T cell hyperactivity observed in this study were similar to those in some metabolic factor-deficient mice, but not those in other pro-autophagic factor-deficient mice. Under the static condition, however, naïve T cells were reduced in Ambra1-cKO mice, as same as in pro-autophagic factor-deficient mice. Collectively, these results suggested that AMBRA1 was involved in regulating T cell-mediated immune responses through autophagy-dependent and -independent mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/intimm/dxaa063DOI Listing
September 2020

ARID1A protein expression is retained in ovarian endometriosis with ARID1A loss-of-function mutations: implication for the two-hit hypothesis.

Sci Rep 2020 08 31;10(1):14260. Epub 2020 Aug 31.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ward, Niigata, 951-8510, Japan.

ARID1A loss-of-function mutation accompanied by a loss of ARID1A protein expression is considered one of the most important driver events in endometriosis-associated ovarian cancer. Although our recent genomic study clarified that ARID1A loss-of-function mutations were detected in 13% of ovarian endometriosis, an association between the ARID1A mutation status and ARID1A protein expression in ovarian endometriosis remains unclear. We performed immunohistochemical staining for ARID1A in 78 ovarian endometriosis samples and 99 clear cell carcinoma samples. We revealed that not only 70 endometriosis samples without ARID1A mutations but also eight endometriosis samples with ARID1A loss-of-function mutations retained ARID1A protein expression. On the other hand, most of clear cell carcinomas with ARID1A loss-of-function mutations showed a loss of ARID1A protein expression. In particular, clear cell carcinoma samples which harbor multiple ARID1A loss-of-function mutations or both a single ARID1A loss-of-function mutation and ARID1A allelic imbalance lost ARID1A protein expression. However, ARID1A protein expression was retained in seven clear cell carcinomas with ARID1A loss-of-function mutations. These results suggest that a single ARID1A loss-of-function mutation is insufficient for ARID1A loss in ovarian endometriosis and some clear cell carcinoma. Further driver events may be needed for the malignant transformation of ovarian endometriosis with ARID1A loss-of-function mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-71273-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459315PMC
August 2020

Population genetics: past, present, and future.

Hum Genet 2021 Feb 18;140(2):231-240. Epub 2020 Jul 18.

Laboratory of Statistical Genetics, Rockefeller University, 1230 York Avenue, New York, NY, 10065, USA.

We present selected topics of population genetics and molecular phylogeny. As several excellent review articles have been published and generally focus on European and American scientists, here, we emphasize contributions by Japanese researchers. Our review may also be seen as a belated 50-year celebration of Motoo Kimura's early seminal paper on the molecular clock, published in 1968.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00439-020-02208-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368598PMC
February 2021

Clonal lineage from normal endometrium to ovarian clear cell carcinoma through ovarian endometriosis.

Cancer Sci 2020 Aug 26;111(8):3000-3009. Epub 2020 Jun 26.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Clear cell carcinoma of the ovary is thought to arise from endometriosis. In addition, retrograde menstruation of shed endometrium is considered the origin of endometriosis. However, little evidence supports cellular continuity from uterine endometrium to clear cell carcinoma through endometriosis at the genomic level. Here, we performed multiregional whole-exome sequencing to clarify clonal relationships among uterine endometrium, ovarian endometriosis and ovarian clear cell carcinoma in a 56-year-old patient. Many somatic mutations including cancer-associated gene mutations in ARID1A, ATM, CDH4, NRAS and PIK3CA were shared among epithelium samples from uterine endometrium, endometriotic lesions distant from and adjacent to the carcinoma, and the carcinoma. The mutant allele frequencies of shared mutations increased from uterine endometrium to distant endometriosis, adjacent endometriosis, and carcinoma. Although a splice site mutation of ARID1A was shared among the four epithelium samples, a frameshift insertion in ARID1A was shared by adjacent endometriosis and carcinoma samples, suggesting that the biallelic mutations triggered malignant transformation. Somatic copy number alterations, including loss of heterozygosity events at PIK3CA and ATM, were identified only in adjacent endometriosis and carcinoma, suggesting that mutant allele-specific imbalance is another key factor driving malignant transformation. By reconstructing a clonal evolution tree based on the somatic mutations, we showed that the epithelium samples were derived from a single ancestral clone. Although the study was limited to a single patient, the results from this illustrative case could suggest the possibility that epithelial cells of ovarian endometriosis and clear cell carcinoma were descendants of uterine endometrial epithelium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419022PMC
August 2020

Subtype-specific gout susceptibility loci and enrichment of selection pressure on and identified by subtype genome-wide meta-analyses of clinically defined gout patients.

Ann Rheum Dis 2020 05 1;79(5):657-665. Epub 2020 Apr 1.

Department of Preventive Medicine and Public Health, National Defense Medical College, Tokorozawa, Japan.

Objectives: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years.

Methods: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype.

Results: In addition to the eight loci we reported previously, two novel loci, and , were identified at a genome-wide significance level (p<5.0×10) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, and , from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on in addition to loci for all subtypes except for normal type gout.

Conclusions: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2019-216644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213308PMC
May 2020

XCL1 expression correlates with CD8-positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary.

Oncogene 2020 04 2;39(17):3541-3554. Epub 2020 Mar 2.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan.

Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-020-1237-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176584PMC
April 2020

Germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors.

J Hum Genet 2020 Jul 7;65(7):577-587. Epub 2020 Feb 7.

Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China.

Genetic testing for BRCA1/2 mutations has become the standard clinical practice. Recent findings suggest the clinical significance of multigene panel testing of BRCA1/2 and other cancer-related genes. However, the clinical features of patients with breast cancer with germline mutations identified using multigene panels remain unclear. In this study, DNA samples from 583 Chinese women with breast cancer were subjected to target sequencing for 54 cancer-related genes using a pre-capture pooling method followed by next-generation sequencing. We identified 79 pathogenic germline mutations in 21 cancer-related genes. Forty-five patients (7.7%) harbored BRCA1/2 mutations, and 38 patients (6.5%) carried pathogenic mutations in the remaining 19 genes. PALB2 was the most commonly (1.2%) mutated gene other than BRCA1/2. Most of the identified pathogenic mutations were novel, suggesting mutation screening by using multigene panel testing is important particularly for non-European populations. Mutations in BRCA1/2 and the other cancer-related genes were differentially associated with clinical features. BRCA1 mutation carriers were strongly associated with triple-negative breast cancer (TNBC), whereas BRCA2 mutation carriers were not. Tumors in BRCA1-mutation carriers had a high histological grade. Patients with BRCA2-mutated breast cancers were likely to develop E-cadherin-negative tumors with bone metastases. Furthermore, mutations in PALB2 were strongly associated with TNBC. We demonstrated the usefulness of multigene panel testing and observed that a substantial proportion of patients with breast cancer had hereditary risk factors. Identifying differential associations between mutation status and clinical features will advance our understanding regarding the pathologies of this heterogeneous disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-020-0729-7DOI Listing
July 2020

Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients.

Sci Rep 2019 11 28;9(1):17808. Epub 2019 Nov 28.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan.

We explored the frequency of germline and somatic mutations in homologous recombination (HR)-associated genes in major histological types of ovarian cancer. We performed targeted sequencing to assess germline and somatic mutations of 16 HR-associated genes and 4 mismatch repair (MMR) genes among 207 ovarian cancer patients (50 high-grade serous carcinomas (HGSC), 99 clear cell carcinomas (CCC), 39 endometrioid carcinomas (EC), 13 mucinous carcinomas (MC), and 6 low-grade serous carcinomas (LGSC)). Germline or somatic mutations of HR-associated genes were detected in 44% of HGSC, 28% of CCC, 23% of EC, 16% of MC, and 17% of LGSC patients. The profile of HR-associated gene mutations was remarkably different among each histological type. Germline BRCA1/2 mutations were frequently detected in HGSC and were rarely observed in CCC, EC, and MC patients. ATM somatic mutation was more frequently detected in CCC (9%) and EC patients (18%) than in HGSC patients (4%). There was a positive correlation between MMR gene mutations and HR-associated gene mutations (p = 0.0072). Our findings might be useful in selection of ovarian cancer patients that should be treated with PARP inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-54116-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882827PMC
November 2019

Exploration of intermediate-sized INDELs by next-generation multigene panel testing in Han Chinese patients with breast cancer.

Hum Genome Var 2019 29;6:51. Epub 2019 Oct 29.

3Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, Chongqing, China.

Multigene panel testing via next-generation sequencing focuses on the detection of small-sized mutations, such as single nucleotide variants and short insertions and deletions (INDELs). However, intermediate-sized INDELs have not been fully explored due to technical difficulties. Here, we performed bioinformatics analyses to identify intermediate-sized INDELs in 54 cancer-related genes from 583 Han Chinese patients with breast cancer. We detected a novel deletion-insertion in a translational variant of (also known as ) in one patient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41439-019-0080-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820797PMC
October 2019

Different mutation profiles between epithelium and stroma in endometriosis and normal endometrium.

Hum Reprod 2019 10;34(10):1899-1905

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.

Study Question: Are there common mutation profiles between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium?

Summary Answer: Our study revealed no common mutations between epithelial and stromal cells in ovarian endometriotic tissue and the normal endometrium.

What Is Known Already: Epithelial cells in both ovarian endometriotic tissue and the normal endometrium harbor somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and KRAS proto-oncogene, GTPase (KRAS).

Study Design, Size, Duration: We performed a retrospective study to identify the mutation profiles of stromal cells in endometriotic tissue and the normal endometrium. We collected 11 endometriotic stroma samples and 10 normal endometrial stroma samples between 2013 and 2017 at a tertiary care center.

Participants/materials, Setting, Methods: The laser microdissection method was used to obtain stromal cells in ovarian endometriotic and normal endometrial tissues from patients with ovarian endometriosis and/or other non-invasive gynecological diseases. Target gene sequencing was performed to assess and compare the mutation profiles of stromal cells with those of epithelial cells obtained in our previous study. For target gene sequencing, 76 genes were selected based on previous genomic analyses for ovarian endometriosis, normal endometrium, endometriosis-related ovarian cancer and endometrial cancer.

Main Results And The Role Of Chance: Stromal samples in ovarian endometrioma and normal endometrium harbor somatic mutations (18 mutations in 11 endometriosis samples and 16 mutations in 10 normal endometrial samples) but did not share any mutations with paired epithelial samples. The mutant allele frequency of stromal samples was significantly lower than that of epithelial samples in ovarian endometrioma (P = 6.0 × 10-11) and normal endometrium (P = 1.4 × 10-7).

Limitations, Reasons For Caution: The number of genes evaluated in the mutational analysis was limited. Additionally, the functional roles of somatic mutations in stromal cells remain unclear.

Wider Implications Of The Findings: Different mutation profiles between paired epithelial and stromal cells in both ovarian endometrioma and normal endometrium suggest that origins of epithelial and stromal cells would be independent of each other in both normal endometrium and ovarian endometrioma; however, the theory of epithelial-mesenchymal transition is proposed in ovarian endometrioma.

Study Funding/competing Interest(s): This work was supported in part by the Japan Society for the Promotion of Science KAKENHI grant number JP15H02373 (Grant-in-Aid for Scientific Research A for I.I.), JP16H06267 (Grant-in-Aid for Young Scientists A for K.Y.), JP17K08688 (Grant-in-Aid for Scientific Research C for H.N.) and JP16H06279 (Grant-in-Aid for Scientific Research on Innovative Areas-Platforms for Advanced Technologies and Research Resources for H.N. and K.Y). There are no conflicts of interest to declare.

Trial Registration Number: Not applicable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/humrep/dez155DOI Listing
October 2019

Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese.

J Neuroinflammation 2019 Aug 5;16(1):162. Epub 2019 Aug 5.

Department of Neurology, Osaka University Graduate School of Medicine, Suita, 565-0871, Japan.

Background: The spectrum of classical and non-classical HLA genes related to the risk of multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) in the Japanese population has not been studied in detail. We conducted a case-control analysis of classical and non-classical HLA genes.

Methods: We used next-generation sequencing (NGS)-based HLA genotyping methods for mapping risk for 45 MS patients, 31 NMOSD patients, and 429 healthy controls. We evaluated the association of the HLA variants with the risk of MS and NMOSD using logistic regression analysis and Fisher's exact test.

Results: We confirmed that HLA-DRB1*15:01 showed the strongest association with MS (P = 2.1 × 10; odds ratio [OR] = 3.44, 95% confidence interval [95% CI] = 1.95-6.07). Stepwise conditional analysis identified HLA-DRB1*04:05, HLA-B*39:01, and HLA-B*15:01 as being associated with independent MS susceptibility (P < 8.3 × 10). With respect to amino acid polymorphisms in HLA genes, we found that phenylalanine at HLA-DQβ1 position 9 had the strongest effect on MS susceptibility (P = 3.7 × 10, OR = 3.48, 95% CI = 2.23-5.43). MS risk at HLA-DQβ1 Phe9 was independent of HLA-DRB1*15:01 (P = 1.5 × 10, OR = 2.91, 95% CI = 1.79-4.72), while HLA-DRB1*15:01 was just significant when conditioned on HLA-DQβ1 Phe9 (P = 0.037). Regarding a case-control analysis for NMOSD, HLA-DQA1*05:03 had a significant association with NMOSD (P = 1.5 × 10, OR = 6.96, 95% CI = 2.55-19.0).

Conclusions: We identified HLA variants associated with the risk of MS and NMOSD. Our study contributes to the understanding of the genetic architecture of MS and NMOSD in the Japanese population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-019-1551-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683481PMC
August 2019

Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout.

Ann Rheum Dis 2019 10 8;78(10):1430-1437. Epub 2019 Jul 8.

Laboratory for Mathematics, National Defense Medical College, Tokorozawa, Saitama, Japan.

Objective: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout.

Methods: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia).

Results: This new approach enabled us to identify two novel gout loci (rs7927466 of and rs9952962 of ) and one suggestive locus (rs12980365 of ) at the genome-wide significance level (p<5.0×10). The present study also identified the loci of , and . One of them, rs671 of , was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (, and ) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level.

Conclusions: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2019-215521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788923PMC
October 2019

Concurrent isolated retroperitoneal HGSC and STIC defined by somatic mutation analysis: a case report.

Diagn Pathol 2019 Feb 11;14(1):17. Epub 2019 Feb 11.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Niigata, 951-8510, Japan.

Background: Retroperitoneal high-grade serous carcinoma (HGSC) is extremely rare and the origin remains unclear. We present a case of retroperitoneal HGSC and coexisting serous tubal intraepithelial carcinoma (STIC), which is considered as the main origin of ovarian HGSC. We reviewed the available literature and discussed about the origin of this rare disease.

Case Presentation: A 58-year-old female with a 93 × 65 × 62 mm-solid tumor with a cystic part was located immediately dorsal to the rectum underwent bilateral salpingo-oophorectomy, total abdominal hysterectomy, and en bloc resection of the retroperitoneal tumor together with lower anterior resection of the rectum. Histological diagnosis was retroperitoneal HGSC and STIC at the right fallopian tube. Two deleterious somatic mutations in TP53 and BRCA2 genes were shared between retroperitoneal HGSC and STIC.

Conclusions: In addition to clinical features in the previous reports, our genetic findings suggest the origin of retroperitoneal HGSC might be STIC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13000-019-0795-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371506PMC
February 2019

Genetic and phenotypic landscape of the major histocompatibilty complex region in the Japanese population.

Nat Genet 2019 03 28;51(3):470-480. Epub 2019 Jan 28.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.

To perform detailed fine-mapping of the major-histocompatibility-complex region, we conducted next-generation sequencing (NGS)-based typing of the 33 human leukocyte antigen (HLA) genes in 1,120 individuals of Japanese ancestry, providing a high-resolution allele catalog and linkage-disequilibrium structure of both classical and nonclassical HLA genes. Together with population-specific deep-whole-genome-sequencing data (n = 1,276), we conducted NGS-based HLA, single-nucleotide-variant and indel imputation of large-scale genome-wide-association-study data from 166,190 Japanese individuals. A phenome-wide association study assessing 106 clinical phenotypes identified abundant, significant genotype-phenotype associations across 52 phenotypes. Fine-mapping highlighted multiple association patterns conferring independent risks from classical HLA genes. Region-wide heritability estimates and genetic-correlation network analysis elucidated the polygenic architecture shared across the phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0336-0DOI Listing
March 2019

Novel MXD4-NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma.

Genes Chromosomes Cancer 2018 11;57(11):557-563

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Primary ovarian sarcomas are extremely rare tumors, and their genomic and transcriptomic alterations remain to be elucidated. We performed whole exome sequencing of primary tumor and matched normal blood samples derived from one patient with ovarian undifferentiated small round cell sarcoma. We identified 8 nonsynonymous somatic mutations, and all mutations were missense or nonsense changes. Next, we performed RNA sequencing of the tumor sample and identified two in-frame fusion transcripts: MXD4-NUTM1 and ARL6-POT1. Most NUTM1 exons were retained in the MXD4-NUTM1 fusion transcript, and we confirmed an increase in NUTM1 mRNA and protein expression in tumor tissue. Further genomic and transcriptomic analyses might lead to the development of new therapeutic strategies based on the molecular characteristics of ovarian undifferentiated small round cell sarcoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/gcc.22668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221051PMC
November 2018

Exome and copy number variation analyses of Mayer-Rokitansky-Küster- Hauser syndrome.

Hum Genome Var 2018 27;5:27. Epub 2018 Sep 27.

1Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara, Kanagawa Japan.

Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital absence of the vagina and uterus. We conducted genome-wide SNP analyses and exome sequencing to detect the causes of MRKH syndrome. We identified de novo variants of , , and in three families and a variant of in a sporadic case. Here, we demonstrated the partial genetic makeup of Japanese MRKH syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41439-018-0028-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160444PMC
September 2018

High Order Formation and Evolution of Hornerin in Primates.

Genome Biol Evol 2018 12 1;10(12):3167-3175. Epub 2018 Dec 1.

Department of Genetics School of Life Sciences, SOKENDAI (Graduate University for Advanced Studies), Mishima, Japan.

Genomic duplication or loss can accelerate evolution because the number of repeats could affect molecular pathways and phenotypes. We have previously reported that the repeated region of filaggrin (FLG), a crucial component of the outer layers of mammalian skin, had high levels of nucleotide diversity with species-specific divergence and expansion and that it evolved under the birth-and-death model. We focused on hornerin (HRNR), a member of the same gene family that harbor similar tandem repeats as FLG, and examined the formation process of repeated regions and the evolutional model that best fit the HRNR repeated region in the crab-eating macaque (Macaca fascicularis), orangutan (Pongo abelii), gorilla (Gorilla gorilla), and chimpanzee (Pan troglodytes) and compared them with the human (Homo sapiens) sequence. Paar et al. (2011) and Takaishi et al. (2005) have different theories as to the formation of the repeated region of HRNR; both groups share the longest repeat length of 1,404 bp (quartic or longest unit), but they differed in the process. We identified the formation described by Paar et al. {[("39 bp (primary) × 9" × 2 (secondary)) × 2 (tertiary)] × 5 (quartic)} to be conserved in all species except the crab-eating macaque. We detected high nucleotide diversities between the longest repeats, which fits the birth-and-death model. We concluded that the high order repeat formation of HRNR was conserved in primates except the crab-eating macaque. As previously identified in FLG, the longest repeats have high levels of nucleotide diversity, which could contribute to phenotypic differences between closely related species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gbe/evy208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280949PMC
December 2018

Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium.

Cell Rep 2018 08;24(7):1777-1789

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. Electronic address:

Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.07.037DOI Listing
August 2018

Long non-coding RNA p10247, high expressed in breast cancer (lncRNA-BCHE), is correlated with metastasis.

Clin Exp Metastasis 2018 03 8;35(3):109-121. Epub 2018 Jun 8.

Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China.

Recent studies have shown that long non-coding RNAs (lncRNAs) have key functions during breast cancer development. Considering the complexity of IncRNAs regulatory network, the identification of novel and functional lncRNAs associated with breast cancer is thus very important. By using Agilent LncRNA Human Gene Expression Microarray, we identified a number of lncRNAs that were differentially expressed in breast cancer compared to their corresponding adjacent tissues. According to the microarray, the expression of p10247, henceforth named as lncRNA-BCHE (standing for lncRNA high expressed in breast cancer), was found to be uniformly higher in all the five breast cancer tissues tested, and this was further confirmed in 56 breast cancer tissues by real-time RT-PCR. The function of lncRNA-BCHE in breast cancer cells was tested by knockdown and over-expression experiments in vitro. We also analyzed the public cohorts of breast cancer patients on the Kaplan Meier plotter platform. Clinical analysis revealed that the expression of lncRNA-BCHE was significantly correlated with advanced clinical stage and lymph node metastasis. Our data indicate that lncRNA-BCHE regulates the growth, migration and invasion of breast cancer cells. In addition, we found that these functions are mediated, at least in part, by the regulation of integrin subunit beta 1 (ITGB1) levels. The expression of ITGB1 serves as a negative prognostic factor and metastasis risk predictor in breast cancer, irrespective of subtype and therapeutic regimen. In summary, our results suggest that lncRNA-BCHE is an oncogenic lncRNA enhancing the growth and metastatic potential of breast cancer cells, and a potential predictor of breast cancer metastatic progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10585-018-9901-2DOI Listing
March 2018

No novel, high penetrant gene might remain to be found in Japanese patients with unknown MODY.

J Hum Genet 2018 Jul 18;63(7):821-829. Epub 2018 Apr 18.

Department of Diabetes and Endocrinology, Graduate School of Medicine, Gifu University, Gifu, Japan.

MODY 5 and 6 have been shown to be low-penetrant MODYs. As the genetic background of unknown MODY is assumed to be similar, a new analytical strategy is applied here to elucidate genetic predispositions to unknown MODY. We examined to find whether there are major MODY gene loci remaining to be identified using SNP linkage analysis in Japanese. Whole-exome sequencing was performed with seven families with typical MODY. Candidates for novel MODY genes were examined combined with in silico network analysis. Some peaks were found only in either parametric or non-parametric analysis; however, none of these peaks showed a LOD score greater than 3.7, which is approved to be the significance threshold of evidence for linkage. Exome sequencing revealed that three mutated genes were common among 3 families and 42 mutated genes were common in two families. Only one of these genes, MYO5A, having rare amino acid mutations p.R849Q and p.V1601G, was involved in the biological network of known MODY genes through the intermediary of the INS. Although only one promising candidate gene, MYO5A, was identified, no novel, high penetrant MODY genes might remain to be found in Japanese MODY.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s10038-018-0449-4DOI Listing
July 2018

The Relationship between Gene Status and Carboxylesterase 2 Expression in Human Colorectal Cancer.

Dis Markers 2018 31;2018:5280736. Epub 2018 Jan 31.

Department of Biochemistry, Juntendo University School of Medicine, Tokyo, Japan.

Irinotecan (CPT-11) is an anticancer prodrug that is activated by the carboxylesterase CES2 and has been approved for the treatment of many types of solid tumors, including colorectal cancer. Recent studies with cell lines show that CES2 expression is regulated by the tumor suppressor protein p53. However, clinical evidence for this regulatory mechanism in cancer is lacking. In this study, we examined the relationship between gene status and CES2 expression in human colorectal cancer. Most colorectal cancer specimens (70%; 26 of 37) showed lower CES2 mRNA levels (≥1.5-fold lower) than the adjacent normal tissue, and only 30% (12 of 37) showed similar (<1.5-fold lower) or higher CES2 mRNA levels. However, gene sequencing revealed no relationship between CES2 downregulation and mutational status. Moreover, while colorectal cancer cells expressing wild-type p53 exhibited p53-dependent upregulation of CES2, PRIMA-1, a drug that restores the transcriptional activity of mutant p53, failed to upregulate CES2 expression in cells with missense mutations. These results, taken together, suggest that CES2 mRNA expression is decreased in human colorectal cancer independently of p53.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/5280736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831679PMC
September 2018

Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions.

Oncogenesis 2018 Jan 23;7(1). Epub 2018 Jan 23.

Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

We previously found that therapeutic targetable fusions are detected across various cancers. To identify therapeutic targetable fusion in uterine cervical cancer, for which no effective gene targeted therapy has yet been clinically applied, we analyzed RNA sequencing data from 306 cervical cancer samples. We detected 445 high confidence fusion transcripts and identified four samples that harbored FGFR3-TACC3 fusion as an attractive therapeutic target. The frequency of FGFR3-TACC3-fusion-positive cervical cancer is also 1.9% (2/103) in an independent cohort. Continuous expression of the FGFR3-TACC3 fusion transcript and protein induced anchorage-independent growth in the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) but not in that from endocervix (End1/E6E7). Injection of FGFR3-TACC3 fusion-transfected-Ect1/E6E7 cells subcutaneously into NOG mice generated squamous cell carcinoma xenograft tumors, suggesting the association between FGFR3-TACC3 fusion and squamous cell carcinogenesis. Transfection of a FGFR3-TACC3 fusion transcript into four cervical cancer cell lines (SiHa, ME180, HeLa, and Ca Ski) induced activation of the MAPK pathway and enhancement of cell proliferation. Transcriptome analysis of the FGFR3-TACC3 fusion-transfected cell lines revealed that an IL8-triggered inflammatory response was increased, via activation of FGFR3-MAPK signaling. Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations. Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status. Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA. Additionally, TACC3 inhibitor, KHS101, suppressed FGFR3-TACC3 fusion protein expression and showed antitumor effect against FGFR3-TACC3 fusion-transfected cell lines. FGFR3-TACC3 fusion-positive cancer has frequent genetic alterations of the PI3K/AKT pathway and selection of appropriate treatment based on PI3K/AKT pathway status should be required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41389-017-0018-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833787PMC
January 2018