WO2017068402A1 - Procédé permettant de détecter un risque accru de cancer du rein et utilisation des variants génotypiques des gènes grhl1 et/ou grhl2 et/ou grhl3 - Google Patents

Procédé permettant de détecter un risque accru de cancer du rein et utilisation des variants génotypiques des gènes grhl1 et/ou grhl2 et/ou grhl3 Download PDF

Info

Publication number
WO2017068402A1
WO2017068402A1 PCT/IB2015/059225 IB2015059225W WO2017068402A1 WO 2017068402 A1 WO2017068402 A1 WO 2017068402A1 IB 2015059225 W IB2015059225 W IB 2015059225W WO 2017068402 A1 WO2017068402 A1 WO 2017068402A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
grhl2
grhl3
snps
grhl1
Prior art date
Application number
PCT/IB2015/059225
Other languages
English (en)
Inventor
Magdalena PAWLAK
Agnieszka KIKULSKA
Tomasz Wilanowski
Bartosz WILCZYŃSKI
Joanna WESOŁY
Original Assignee
Instytut Biologii Doświadczalnej Im. M. Nenckiego, Polskiej Akademii Nauk
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Instytut Biologii Doświadczalnej Im. M. Nenckiego, Polskiej Akademii Nauk filed Critical Instytut Biologii Doświadczalnej Im. M. Nenckiego, Polskiej Akademii Nauk
Publication of WO2017068402A1 publication Critical patent/WO2017068402A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the invention relates to cancer diagnostics and in particular, the detection of an increased risk of kidney cancer in humans. More specifically, the present invention relates to methods for the identification of persons with an increased risk of renal cell carcinoma based on single nucleotide polymorphisms occurring in the genes Grainyhead-like 1 (GRHL1 ), Grainyhead-like 2 (GRHL2) and Grainyhead-like 3 (GRHL3).
  • the present invention may be used in prognostic genetic studies designed to identify patients at an increased risk for acquiring renal cancer, and in medical diagnostics.
  • Cancer is a disease causing the death more than 8 million people annually (data from the World Health Organization). According to the American Cancer Society, cancer of the kidney is one of the 10 most common types of cancer. The risk of developing kidney cancer is estimated to be 1/63, meaning that 1 .6% of people (16 per 1000) in their lifetime will develop kidney cancer. The most common variant of kidney cancer is a clear cell carcinoma (ccRCC). It represents about 70% of kidney cancer cases.
  • ccRCC clear cell carcinoma
  • Chemotherapy and radiotherapy currently used in the treatment of renal cell carcinoma are inadequate and approved compounds with an immunotherapeutic effect often have serious side effects. If, after surgical removal of the tumor, it is followed by a relapse, patient outcomes are not favorable. In the case of metatastases of the cancer to lymph nodes, the chance of 5-year survival rate ranges from 5 to 15%. If the metastases are to other organs, survival is less than 5%. A complete remission can only be achieved in 12-20% of cases (source: News- Medical. net). There is therefore a strong need for new methods of combating this type of cancer. So far, we have identified a number of potential molecular markers of RCC, but none have so far been validated and implemented into clinical practice (Audenet et al, 2012).
  • kidney cancer at an early stage of development may not cause any symptoms, and therefore the early diagnosis of kidney cancer is very difficult. In its later stages, the symptoms are similar to the symptoms of other diseases such as kidney stones or urinary tract infections. These symptoms include: • fatigue
  • SNP single nucleotide polymorphisms
  • Risk factors for kidney cancer include: smoking obesity
  • VHL gene The occurrence of atypical variants of genes responsible for the proper functioning of the kidney may lead to an increased risk of developing renal cancer.
  • An example of this is the VHL gene. Mutations in this gene cause von Hippel-Lindau disease , also called cerebello-retinal angiomatosis.
  • the VHL gene is a tumor suppressor that controls the rate of cell proliferation. Mutations in this gene can be inherited from parents. A mutant VHL gene is no longer able to suppress the abnormal growth of cells, which increases the risk of kidney cancer. Mutations in other genes are also associated with the risk of developing kidney cancer, such as MET, FH, FLCN, SDHB and SDHC (Clague et al, 2009).
  • This category may include mutations in the GRHL1 and / or GRHL2 and / or GRHL3.
  • GRHL gene expression in non-tumour cell lines often results in acquiring the characteristics of tumour cells, and increased expression of GRHL genes in tumour cell lines results in the loss of the characteristics of tumour cells.
  • genes of the GRHL family provide protection against the development of cancer.
  • the Laryngoscope 201 1 ; 121 (6): 1303-1307 refers to an SNP in the gene GRHL2 in terms of hearing loss and refers to renal cancer.
  • the present invention provides a method of identifying persons with increased risk for renal cell carcinoma based on single nucleotide polymorphisms that occur in the genes GRHL1 , GRHL2 and GRHL3.
  • Methods for the detection of an increased risk of cancer of the kidney are characterized in that they comprise:
  • SNP single nucleotide polymorphism
  • Polymorphisms labeled "+” are present in the patient population in excess of the European population and "-" less frequently.
  • the numbering of the items in the column "position” is consistent with the GRCh37/hg19 annotation.
  • the cancer is renal clear cell carcinoma.
  • the cancer is a renal cell cancer of another type.
  • the presence of the variant genotypic is detected based on the analysis of DNA, RNA or proteins.
  • the DNA, RNA or protein test is carried out using any methods which allow the identification of homozygous and heterozygous SNPs in the genomic, gene or protein, sequence including Western blot using specific antibodies, microarrays of SNPs, SNP-RFLP (restriction fragment length polymorphism ), the dynamic hybridization of specific alleles (dynamic allele-specific hybridization - DASH), molecular beacons, probes of the TaqMan type, primer extension, MALDI-TOF (matrix-assisted laser desorption/ionization - time of flight), ELISA (enzyme-linked immunosorbent assay) and the like, an oligonucleotide single-strand conformation polymorphism, gel electrophoresis, temperature gradient gel electrophoresis (TGGE), denaturing high performance liquid chromatography (HPLC), high resolution melting polymerase chain reaction (HRM PCR) SNPlex and/or new generation sequencing (NGS) performed on material isolated from samples of tissue or blood
  • Another subject of the present invention is the use of single nucleotide polymorphisms in GRHL genesl and/or GRHL2 and/or GRHL3 to predict the in vitro or ex vivo increased risk of kidney cancer in humans.
  • variants of genotypes are detected through DNA, RNA or protein analysis.
  • the methods are applicable to samples of tissue or blood collected from a human donor, in which at least one of these SNPs is present at a statistically significant level, indicating the functional disruption of GRHL1 and/or GRHL2 and/or GRHL3 dependent processes.
  • the DNA, RNA or protein test is carried out using any methods which allow the identification of homozygous and heterozygous SNPs in the genomic, gene or protein, sequence including Western blot using specific antibodies, microarrays of SNPs, SNP-RFLP (restriction fragment length polymorphism ), the dynamic hybridization of specific alleles (dynamic allele- specific hybridization - DASH), molecular beacons, probes of the TaqMan type, primer extension, MALDI-TOF (matrix-assisted laser desorption/ionization - time of flight), ELISA (enzyme-linked immunosorbent assay) and the like, an oligonucleotide single-strand conformation polymorphism, gel electrophoresis, temperature gradient gel electrophoresis (TGGE), denaturing high performance liquid chromatography (HPLC), high resolution melting polymerase chain reaction (HRM PCR) SNPlex and/or new generation sequencing (NGS) performed on
  • the cancer is renal clear cell carcinoma.
  • the cancer is a renal cell cancer of another type.
  • the first subject of the present application are the single nucleotide polymorphisms identified in the regulatory sequences and the coding sequences of The GRHL1 , GRHL2 and GRHL3 genes and specific for patients with renal cell carcinoma. Their presence in the DNA sequence can lead to the impaired gene expression of GRHL1 and/or GRHL2 and/or GRHL3 and/or the functioning of the encoded proteins GRHL1 and/or GRHL2 and/or GRHL3 and, therefore, may cause disturbances in the functioning of pathways and pathway signals involving GRHL1 and/or GRHL2 and/or GRHL3 gene products.
  • the second subject of the present application is a method of determining a patient's increased risk of developing kidney cancer, especially cancer of the clear cell, based on the identification of at least one of said single nucleotide polymorphisms in The GRHL1 , GRHL2 and GRHL3 genes.
  • the third subject of the present application is the use of methods of determining patients at increased risk of developing kidney cancer, in particular of the clear cell type, based on the identification of at least one of said single nucleotide polymorphisms in the GRHL1 , GRHL2 and GRHL3 genes in human population screening for the detection of an increased risk of kidney cancer.
  • the fourth subject of the present application is the use of methods of identifying determining an increased risk of developing kidney cancer in patients, in particular the clear cell type, based on the identification of at least one of the said single nucleotide polymorphisms in the GRHL1 , GRHL2 and GRHL3 genes in population prevention programs and early detection of increased risk of cancer of the kidney.
  • RNA sequences GRHL1 and/or GRHL2 and/or GRHL3 tissue or body fluids from patients include, but are not limited to: Western blot using specific antibodies, SNP microarrays, SNP-RFLP (restriction fragment length polymorphism), dynamic allele- specific hybridization (DASH), molecular beacons, TaqMan probes, primer extension, MALDI-TOF (matrix-assisted laser desorption/ionization - time of flight), ELISA (enzyme-linked immunosorbent assay), and the like, oligonucleotide single- strand conformation polymorphism, temperature gradient gel electrophoresis (TGGE), denaturing high performance liquid chromatography (high performance liquid chromatography - HPLC), high resolution melting polymerase chain reaction (HRM PCR), SNPlex and/or New Generation sequencing - NGS) and restriction digestion preceded by a PCR.
  • SNP microarrays SNP-RFLP (restriction fragment length poly
  • GRHL family of transcription factors is an evolutionarily conserved, tissue- specific group of proteins. Their role is to regulate transcription (through activation or repression) of genes essential for maintaining the proper structure and function of the epithelium. They control the expression of, among others, genes such as DSG1 , CDH1 , RAB25, CLDN3 and CLDN4, the genes of the EDC complex, hTERT and PCNA. Disturbances in the expression level of GRHL genes may be indirectly associated with multiple kidney diseases and may contribute to tumourigenesis.
  • Quantitative Real-Time PCR - was carried out in the Eco lllumina system. Samples of clear cell renal cancer showed a decrease in the level of gene expression in GRHL1 and GRHL2 compared with surrounding normal tissue (Fig. 2).
  • the decrease in GRHL gene expression is a molecular marker of renal cancer.
  • GRHL expression in kidney cells depends on the cell type and on the state of metabolic and physiological activities. a) Single nucleotide polymorphisms in the promoter and regulatory sequences
  • Next generation sequencing of GRHL genes enabled us to determine single nucleotide polymorphisms in the promoter and regulatory regions of GRHL genes in patients with renal cell cancer (Table 1 ).
  • Table 1 On the basis of the analysis, we made a Manhattan Plot (described earlier) indicating single nucleotide polymorphisms that may be associated with an increased risk of cancer of the kidney. The frequency changes in their occurrence in the patient population with clear cell renal carcinoma compared with the European population was statistically significant.
  • GRHL1 and GRHL2 gene expression In patients with clear cell renal carcinoma, we showed a decrease in the level of GRHL1 and GRHL2 gene expression.
  • the level of gene expression may be dependent on regulation by microRNAs (imiRNA). imiRNAs regulate gene expression levels by binding to a specific 7-nucleotide sequence in the 3'UTR region of imRNA molecules. The reduction of the efficiency of the translation of genetic information into protein, the gene expression is silenced. The dysfunction of gene expression can be crucial in the process of carcinogenesis.
  • One of the causes of the abnormal imiRNA/mRNA interaction may be the presence of single nucleotide polymorphisms in the 3'UTR sequence.
  • Polymorphisms labeled "+” are present in the patient population in excess of the European population and "-" if less frequently.
  • the numbering of the items in the column "position” is consistent with the GRCh37/hg19 annotation.
  • the presence of single nucleotide polymorphisms in the recognition sequence of the miRNA may lead to loss, weakness, enhancement or to the creation of a miRNA/mRNA binding site.
  • the GRHL3 transcription factor directly positively regulates the expression of the PTEN gene whose protein product is an inhibitor of the PI3K/AKT/mTOR pathway (Darido et al, 201 1 ).
  • One of the subjects of the present application is a single nucleotide polymorphism that was identified in the coding sequence of the GRHL3 gene and is specific for patients with renal cell carcinoma. Its presence in the DNA sequence can lead to the impaired function of the GRHL3 protein and thus can affect the reduction of protein activity of PTEN and the activation of the PI3K/AKT/mTOR pathway that promotes cell proliferation and tumour growth.
  • this polymorphism is found in all alternative splice variants of GRHL3 that encode the protein (http://genome.ucsc.edu).
  • the presence of this polymorphism leads to a change in the amino acid sequence and can potentially affect the proper functioning of all isoforms GRHL3.
  • the amino acid residue at the codon which is located in this polymorphism is located in the motif potentially recognized by protein kinases such as GSK-3P, ERK1 , ERK2, and CDK5 (http://kinasephos.mbc.nctu.edu.tw/) . It is very likely that the phosphorylation of GRHL3 by these kinases is essential for its proper functioning.
  • Polymorphisms labeled "+” are present in the patient population in excess of the European population and "-" if less frequently.
  • the numbering of the items in the column "position” is consistent with the GRCh37/hg19 annotation.
  • polymorphism rs41268753 causes the loss of a phosphorylation site in the GRHL3 protein. Its molecular consequences in post-translational modifications and functioning of the GRHL3 protein are the subject of further studies by the authors.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Hospice & Palliative Care (AREA)
  • Biophysics (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne des procédés permettant d'identifier des polymorphismes d'un seul nucléotide (SNP) dans les gènes GRHL1, GRHL2 et GRHL3 et l'utilisation de ces polymorphismes à titre de marqueurs pour identifier les patients ayant une sensibilité accrue au cancer du rein.
PCT/IB2015/059225 2015-10-23 2015-11-30 Procédé permettant de détecter un risque accru de cancer du rein et utilisation des variants génotypiques des gènes grhl1 et/ou grhl2 et/ou grhl3 WO2017068402A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PLP.414469 2015-10-23
PL414469A PL234915B1 (pl) 2015-10-23 2015-10-23 Sposób wykrywania zwiększonego ryzyka zachorowania na raka nerki oraz zastosowania genotypowych wariantów genów GRHL1 i/lub GRHL2 i/lub GRHL3

Publications (1)

Publication Number Publication Date
WO2017068402A1 true WO2017068402A1 (fr) 2017-04-27

Family

ID=55359545

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/059225 WO2017068402A1 (fr) 2015-10-23 2015-11-30 Procédé permettant de détecter un risque accru de cancer du rein et utilisation des variants génotypiques des gènes grhl1 et/ou grhl2 et/ou grhl3

Country Status (2)

Country Link
PL (1) PL234915B1 (fr)
WO (1) WO2017068402A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050130193A1 (en) * 2003-09-10 2005-06-16 Luxon Bruce A. Methods for detecting, diagnosing and treating human renal cell carcinoma
WO2013029116A1 (fr) 2011-08-31 2013-03-07 Monash University Méthode de prédiction de réactivité à un traitement
WO2015093998A1 (fr) * 2013-12-19 2015-06-25 Instytut Biologii Doświadczalnej Im. M. Nenckiego Polskiej Akademii Nauk Procédé de détection d'un risque accru de développer un cancer de la peau et utilisation d'un variant de génotype du gène grhl3

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050130193A1 (en) * 2003-09-10 2005-06-16 Luxon Bruce A. Methods for detecting, diagnosing and treating human renal cell carcinoma
WO2013029116A1 (fr) 2011-08-31 2013-03-07 Monash University Méthode de prédiction de réactivité à un traitement
WO2015093998A1 (fr) * 2013-12-19 2015-06-25 Instytut Biologii Doświadczalnej Im. M. Nenckiego Polskiej Akademii Nauk Procédé de détection d'un risque accru de développer un cancer de la peau et utilisation d'un variant de génotype du gène grhl3

Non-Patent Citations (22)

* Cited by examiner, † Cited by third party
Title
AUDENET F; YATES DR; CANCEL-TASSIN G; CUSSENOT 0; ROUPRET M: "Genetic pathways involved in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine", BJU INTERNATIONAL, vol. 109, 2012, pages 1864 - 1870
BHANDARI I WSP: "The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1", ONCOGENE, vol. 32, pages 1497 - 1507
CLAGUE J; LIN J; CASSIDY A; MATIN S; TANNIR NM; TAMBOLI P; WOOD CG; WU X: "Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research", vol. 18, 2009, AMERICAN SOCIETY OF PREVENTIVE ONCOLOGY, article "Family history and risk of renal cell carcinoma: results from a case-control study and systematic meta-analysis", pages: 801 - 807
DARIDO C; GEORGY SR; WILANOWSKI T; DWORKIN S; AUDEN A; ZHAO Q; RANK G; SRIVASTAVA S; FINLAY MJ; PAPENFUSS AT: "Targeting of the Tumor Suppressor GRHL3 by a miR-21-Dependent Proto-Oncogenic Network Results in PTEN Loss and Tumorigenesis", CANCER CELL, vol. 20, 2011, pages 635 - 648
DARIDO I WSP.: "Targeting of the Tumor Suppressor GRHL3 by a miR-21-Dependent Proto-Oncogenic Network Results in PTEN Loss and Tumorigenesis", CANCER CELL, vol. 20, no. 5, 2011, pages 635 - 648
FABIAN J; LODRINI M; OEHME; SCHIER MC; THOLE TM; HIELSCHER T; KOPP-SCHNEIDER A; OPITZ L; CAPPER D; VON DEIMLING A: "GRHL1 Acts as Tumor Suppressor in Neuroblastoma and Is Negatively Regulated by MYCN and HDAC3", CANCER RES, vol. 74, 2014, pages 2604 - 2616
H. BUTZ ET AL: "Integrative Bioinformatics Analysis Reveals New Prognostic Biomarkers of Clear Cell Renal Cell Carcinoma", CLINICAL CHEMISTRY., vol. 60, no. 10, 19 August 2014 (2014-08-19), WASHINGTON, DC., pages 1314 - 1326, XP055279561, ISSN: 0009-9147, DOI: 10.1373/clinchem.2014.225854 *
HEMMINKI K; LI X: "Familial renal cell cancer appears to have a recessive component", JOURNAL OF MEDICAL GENETICS, vol. 41, 2004, pages E58
HUMAN GENETICS, vol. 122, no. 3-4, 2007, pages 397 - 407
LIN I WSP.: "The grainyhead-like 2 gene (GRHL2) single nucleotide polymorphism is not associated with age-related hearing impairment in Han Chinese", THE LARYNGOSCOPE, vol. 121, no. 6, 2011, pages 1303 - 1307
MLACKI M; DARIDO C; JANE SM; WILANOWSKI T: "Loss of Grainy head-like 1 is associated with disruption of the epidermal barrier and squamous cell carcinoma of the skin", PLOS ONE, vol. 9, 2014, pages E89247
MLACKI MICHAL ET AL: "Recent discoveries concerning the involvement of transcription factors from the Grainyhead-like family in cancer.", EXPERIMENTAL BIOLOGY AND MEDICINE (MAYWOOD, N.J.), vol. 240, no. 11, 10 June 2015 (2015-06-10), pages 1396 - 1401, XP009190483, ISSN: 1535-3699 *
PANIS I WSP: "Putative circulating markers of the early and advanced stages of breast cancer identified by high-resolution label-free proteomics", CANCER LETTERS, vol. 330, no. 1, 2013, pages 57 - 66
PETERS I WSP: "Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28", HUMAN MOLECULAR GENETICS, vol. 11, no. 23, 2002, pages 2877 - 2885
PETROF I WSP: "Mutations in GRHL2 Result in an Autosomal-Recessive Ectodermal Dysplasia Syndrome", AJGH, vol. 95, no. 3, 2014, pages 308 - 314
PEYRARD-JANVID I WSP: "Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development", THE AMERICAN JOURNAL OF HUMAN GENETICS, vol. 94, no. 1, 2014, pages 23 - 32
PURDUE MARK P ET AL: "Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3 (+ online methods)", NATURE GENETICS, vol. 43, no. 1, January 2011 (2011-01-01), pages 60 - 65+2PP, XP002758705, ISSN: 1061-4036 *
QUAN Y; JIN R; HUANG A; ZHAO H; FENG B; ZANG L; ZHENG M: "Downregulation of GRHL2 inhibits the proliferation of colorectal cancer cells by targeting ZEB1", CANCER BIOLOGY & THERAPY, vol. 15, 2014, pages 878 - 887
TANAKA Y; KANAI F; TADA M; TATEISHI R; SANADA M; NANNYA Y; OHTA M; ASAOKA Y; SETO M; SHIINA S: "Gain of GRHL2 is associated with early recurrence of hepatocellular carcinoma", J HEPATOL, vol. 49, 2008, pages 746 - 757
VAN LAER I WSP: "The grainyhead like 2 gene (GRHL2), alias TFCP2L3, is associated with age-related hearing impairment", HUMAN MOLECULAR GENETICS, vol. 17, no. 2, 2008, pages 159 - 169
WERNER S; FREY S; RIETHDORF S; SCHULZE C; ALAWI M; KLING L; VAFAIZADEH V; SAUTER G; TERRACCIANO L; SCHUMACHER U: "Dual roles of the transcription factor grainyhead-like 2 (GRHL2) in breast cancer", J BIOL CHEM, vol. 288, 2013, pages 22993 - 23008
XIANG J; FU X; RAN W; CHEN X; HANG Z; MAO H; WANG Z: "Expression and role of grainyhead-like 2 in gastric cancer", MEDICAL ONCOLOGY, vol. 30, 2013, pages 714

Also Published As

Publication number Publication date
PL234915B1 (pl) 2020-05-18
PL414469A1 (pl) 2017-04-24

Similar Documents

Publication Publication Date Title
Danielsen et al. Portrait of the PI3K/AKT pathway in colorectal cancer
Marzese et al. Epigenome-wide DNA methylation landscape of melanoma progression to brain metastasis reveals aberrations on homeobox D cluster associated with prognosis
Visone et al. DNA methylation of shelf, shore and open sea CpG positions distinguish high microsatellite instability from low or stable microsatellite status colon cancer stem cells
Krishnan et al. A minimal DNA methylation signature in oral tongue squamous cell carcinoma links altered methylation with tumor attributes
Pavlidou et al. Diagnostic significance and prognostic role of the ARID1A gene in cancer outcomes
Nogueira et al. Association between genetic polymorphisms in DNA mismatch repair‐related genes with risk and prognosis of head and neck squamous cell carcinoma
Chen et al. Pri-miR-34b/C and Tp-53 polymorphisms are associated with the susceptibility of papillary thyroid carcinoma: a case–control study
van Geelen et al. Clinical implications of prospective genomic profiling of metastatic breast cancer patients
Nassar et al. microRNA expression in ethnic specific early stage breast cancer: an integration and comparative analysis
Wilhelm et al. Epigenetic silencing of AKAP12 in juvenile myelomonocytic leukemia
Jia et al. CeRNA expression profiling identifies KIT-related circRNA-miRNA-mRNA networks in gastrointestinal stromal tumour
Jovčevska Sequencing the next generation of glioblastomas
Barros-Filho et al. Oncogenic drivers in 11q13 associated with prognosis and response to therapy in advanced oropharyngeal carcinomas
Jha et al. Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation
Wang et al. Effects of KRAS mutation and polymorphism on the risk and prognosis of oral squamous cell carcinoma
Cheng et al. Identification of key genes in invasive clinically non-functioning pituitary adenoma by integrating analysis of DNA methylation and mRNA expression profiles
Vymetalkova et al. Epigenome-wide analysis of DNA methylation reveals a rectal cancer-specific epigenomic signature
Abdel-Rahman et al. Somatostatin receptor expression in hepatocellular carcinoma: prognostic and therapeutic considerations
Zhang et al. Up-regulation of CRKL by microRNA-335 methylation is associated with poor prognosis in gastric cancer
Yu et al. LncRNA H19 gene rs2839698 polymorphism is associated with a decreased risk of colorectal cancer in a Chinese Han population: a case‐control study
Silva et al. DNA repair system and prostate cancer progression: the role of NBS1 polymorphism (rs1805794)
He et al. Seven-microRNA panel for lung adenocarcinoma early diagnosis in patients presenting with ground-glass nodules
Chiacchiarini et al. Role of tissue and circulating microRNAs and DNA as biomarkers in medullary thyroid cancer
Liang et al. Identification of DNA methylation-regulated differentially-expressed genes and related pathways using Illumina 450K BeadChip and bioinformatic analysis in gastric cancer
Zhao et al. Identification of a NFKBIA polymorphism associated with lower NFKBIA protein levels and poor survival outcomes in patients with glioblastoma multiforme

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15834720

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15834720

Country of ref document: EP

Kind code of ref document: A1