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    • 专利摘要:
    Biomarker for the diagnosis, prognosis and follow-up of early onset colorectal cancer. The present invention provides a new biomarker for the diagnosis, prognosis and follow-up of early-onset colorectal cancer, the nomo-1 gene or any of its expression products. Thus, the invention also relates to an in vitro method of diagnosis, prognosis and monitoring of early onset colorectal cancer, in which the quantification of said biomarker in a biological sample comprising tumor cells is necessary. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2619116A1
    申请号:ES201531891
    申请日:2015-12-23
    公开日:2017-06-23
    发明作者:José PEREA GARCÍA；Rogelio GONZÁLEZ SARMIENTO；Miguel URIOSTE AZCORRA；Daniel RUEDA FERNÁNDEZ；María ARRIBA DOMÈNECH；Juan Luis García Hernández；Jéssica PÉREZ GARCÍA
    申请人:Fundacion Instituto De Estudios De Ciencias de la Salud De Castilla Y Leon；Fundacion Centro Nac De Investig Oncologicas (cnio)；Fundacion Inst De Estudios De Ciencias de la Salud De Castilla Y Leon；Universidad de Salamanca；Centro Nacional de Investigaciones Oncologicas CNIO；Fundacion Investigacion Biomedica Hospital Universitario 12 Octubre；
    IPC主号:
    专利说明:

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    In yet another more preferred embodiment, in step (c) the decrease in at least 50% in the number of copies of the NOMO-1 gene with respect to the reference amount, is indicative of a diagnosis, predisposition or risk to develop CCRp .
    5 At the time of determining in a sample of a patient the absence of the NOMO-1 gene
    or the decrease in the number of copies different methodologies are carried out but at the same time complementary. In accordance with preferred embodiments of the in vitro method described in the present invention, the nucleic acid obtained from the isolated sample of the subject can be genotyped, and this will be indicative that there has been complete deletion of the copy (s) of the NOMO-1 gene, and consequently, that there is a predisposition or risk to develop CCRp. If the genotype obtained through the analysis of the NOMO-1 gene is inconclusive (that is, it does not allow to determine that there is a complete absence of NOMO-1), the number of copies present in the patient sample is determined and compared with the number of copies of a
    15 shows control. If it is observed that the number of copies of the NOMO-1 gene in the patient is less than the number of copies of the control, it will imply that one or more copies of the NOMO-1 gene in the individual's sample have been deleted and, consequently, exists predisposition to develop CCRp.
    The expression "totally or partially deleted" means that the entire gene is deleted or a fragment thereof (eg, an exon of NOMO-1). When the expression "absence" relative to the NOMO-1 gene is used in the present invention, it means that when the step (a) is carried out, according to the method described in the present invention, no copy of the gene is detected NOMO-1 in Ia
    25 sample of the individual.
    In another more preferred embodiment, the in vitro method of the invention comprises in step (a) detecting and / or quantifying the level of expression of the NOMO-1 gene, and / or its expression product, in an isolated biological sample of an individual, (b) compare
    30 the amount detected in step (a) with a reference amount, and (c) assign the individual of (a) to the group of patients at risk of developing or suffering from CCRp, when the amount detected in (a) is less than The reference quantity.
    In a more preferred embodiment, the in vitro method of the invention comprises in the
    Step (a) detect and / or quantify the number of copies of the gene and the level of expression of the NOMO-1 gene, and / or its expression product, in an isolated biological sample of an individual, (b) compare the amount detected in stage (a) with a reference amount, and (c) assign the individual of (a) to the group of patients at risk of developing or suffering from CCRp, when the amount detected in (a) is less than the amount reference.
    In a more preferred embodiment of the in vitro method of the invention, this is characterized in that the NOMO-1 gene comprises the sequence SEQ ID NO: 1 and more preferably, the NOMO-1 gene consists of SEQ ID NO: 1 In another more preferred embodiment, the NOMO-1 gene expression product comprises the
    10 SEQ ID NO: 2 and more preferably still, consists of SEQ ID NO: 2.
    The biological sample from the subject under study is a biological sample that contains a nucleic acid, for example, DNA, genomic DNA (cDNA), complementary DNA (cDNA), RNA, heterogeneous nuclear RNA (mRNA), mRNA, etc., of the 15 subject to evaluate. For the purposes of the present invention, the term "isolated biological sample" refers to, but is not limited to, cell populations and biological tissues and / or fluids of a subject, obtained by any method known to a person skilled in the art that serves for such purpose. finish. The biological sample may contain any suitable material to detect the desired biomarker and may comprise 20 cells and / or non-cellular material of the subject. Preferably, the "isolated biological sample comprises tumor cells", and as used in the description, refers to, but is not limited to, tissues and / or biological fluids of an individual obtained by any method known to a person skilled in the art. Matter that serves this purpose. The biological sample can be a tissue, for example, but not limited to, a
    25 tumor biopsy or a fine needle aspirate. In a more preferred embodiment, the isolated biological sample for the determination of the copy number of the NOMO1 gene and / or the expression levels of the biomarker of the invention is a sample of colon tissue, preferably obtained by biopsy.
    30 On the other hand, the biological sample is a sample of a biological fluid. The terms "biological fluid" and "biofluid" are used interchangeably herein and refer to aqueous fluids of biological origin. The biofluid can be obtained from any location (such as blood, plasma, serum, urine, bile, cerebrospinal fluid, vitreous or aqueous humor, or any body secretion), an exudate
    35 (such as fluid obtained from an abscess or any other site of infection or inflammation), or fluid obtained from a joint (for example, a normal joint or joint affected by a disease such as rheumatoid arthritis). In a preferred embodiment, the biofluid of the invention is preferably blood, leukocyte concentrate, peripheral blood mononuclear cells or peripheral blood lymphocytes.
    5 The sample can be taken from a human, but also from non-human mammals, such as, but not limited to, rodents, ruminants, felines or canines. Therefore, in a preferred embodiment of this aspect of the invention, the "individual" or "subject", used interchangeably throughout this document, from which it proceeds
    The biological sample isolated from step (a) of the in vitro method of the invention is a mammal. In a more preferred embodiment, the mammal is a human, male or female of any age or race.
    The detection and / or quantification of the number of copies of the NOMO-1 gene refers to
    15 determine if gene amplification is detected or not and to what extent. It also includes, therefore, the determination of the level of expression of the NOMO-1 gene and / or of its expression product in the isolated biological sample, refers to the measure of the amount or concentration, preferably in a semi-quantitative or quantitative manner. This measure can be carried out directly or indirectly. The direct measure is
    20 refers to the measurement of the quantity or concentration of both the number of copies in genomic material, and the product of the gene expression, preferably mRNA, based on a signal that is obtained and that is directly correlated with the number of molecules in the product of the expression of the gene present in the sample. This signal - which we can also refer to as an intensity signal
    25 - can be obtained, for example, by measuring an intensity value of a chemical or physical property of the expression product. The indirect measurement includes the measurement obtained from a secondary component (for example, a component other than the product of gene expression) or a biological measurement system (for example, the measurement of cellular responses, ligands, "labels" or reaction products
    30 enzymatic).
    In accordance with the present invention, the detection of the number of copies or the amount of product of the gene expression can be carried out by any method of determining the amount of DNA or the product of the expression of the known genes. by the expert in the field. In a preferred embodiment, the detection of the gene copy number is performed by amplifying a DNA fragment that
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    In a preferred embodiment of the in vitro method of the invention, it is also possible, in addition to the detection of a fragment of the proteins used as biomarkers, the detection and quantification of a functionally equivalent variant thereof.
    5 In the sense used in this description, the term "variant" refers to proteins substantially homologous to the protein encoded by the NOMO-1 gene. In general, a variant includes additions, deletions or substitutions of amino acids, always with the proviso that said variants are functionally equivalent to the
    10 original protein. The term "variant" also includes proteins resulting from posttranslational modifications such as, but not limited to, glycosylation, phosphorylation or methylation.
    The term "functionally equivalent", as used herein, means that the
    The protein or the fragment of the protein in question essentially maintains the immunological properties described in this document. Such immunological properties can be determined by conventional methods such as those described above.
    The term "fragment", as used in the present description refers to a portion of the protein encoded by the NOMO-1 gene or one of its variants.
    The level of expression of a gene or its expression product, determined in a biological sample from the subject under study, is said to be "greater" than the level or reference amount of said gene or its expression product when , according to the invention, the level of said gene or its expression product in the biological sample of the subject or individual is at least 1.5 times, 2 times, 3 times, 4 times, 5 times, 10 times , 20 times, 30 times, 40 times, 50 times, 60 times, 70 times, 80 times, 90 times, 100 times or even more, with respect to the reference level of said gene or its expression product. Similarly, the level of expression of a gene or expression product, determined in a biological sample from the subject or individual under study, is said to be "lower" than the reference level or quantity of said gene or its product of expression when, according to the invention, the level of said expression product in said biological sample of the subject is at least 1.5 times, 5 times, 10 times, 20 times, 30 times, 40 times, 50 times , 60 times, 70 times, 80 times, 90
    times, 100 times, or even more, lower than the reference level for said expression product of said gene. For the purposes of the present invention, the term "minor" also refers to the complete absence of expression of the gene or its expression product.
    5 The term "reference amount", as used in the present description, refers to any value or range of values derived from the quantification of the NOMO-1 gene and / or its expression product in a biological control sample . The appropriate reference amount may be determined by the method herein.
    The invention is based on a reference sample that can be analyzed, for example, simultaneously or consecutively, together with the problem biological sample. Thus, for example but without limiting ourselves, the reference sample may be the negative control, that is, the amount detected by the method of the invention in samples of individuals not suffering from the disease. Alternatively, it can also be the
    The amount detected by the method of the invention in samples of individuals suffering from CRC, but which is not of early appearance. In a preferred embodiment, the reference amount comes from an isolated biological sample that may or may not comprise tumor cells, where said sample may come from a healthy control individual or not suffering from RCC or from an individual suffering from RCC,
    20 provided it is not of early appearance. A "reference sample", as used herein, refers to a sample obtained from a group of healthy subjects that does not have a particular disease state or phenotype. Preferably, the reference sample may include samples of the colon mucosa of patients who do not suffer from colon cancer or who have no history of colon cancer. Moreover, the sample of
    25 reference could be a sample or a set of colon cancer samples obtained from patients diagnosed with non-early onset CRC.
    Said reference amount, in accordance with the present invention, allows discriminating the presence of CCRp with respect to individuals suffering from RCC of
    30 non-early onset and, therefore, can be used in the diagnosis, prognosis or monitoring of the evolution of a CCRp.
    Steps (a) and / or (b) of the in vitro method of the invention can be fully or partially automated, for example, but not limited to, by robotic equipment for detection and / or quantification, in step (a ), of the number of copies and / or
    of the amount of expression of the NOMO-1 gene, or of its expression product, in the isolated biological sample.
    In addition to the steps specified above, the in vitro method of the invention
    5 may comprise other additional steps, for example, but not limited to, related to the pre-treatment of the isolated biological sample prior to analysis.
    Therefore, the in vitro method of the invention is useful for establishing the diagnosis, prognosis and monitoring of CCRp.
    Another aspect of the invention relates to a kit for the diagnosis, prognosis and / or monitoring of CCRp, hereinafter "kit of the invention", comprising the primers, probes, antibodies, or any combination thereof, necessary for
    15 detect the number of copies and / or the amount of expression of the NOMO-1 gene and / or its expression product, preferably, in an isolated biological sample.
    The primers, probes and / or antibodies included in the kit of the invention have complementarity, and therefore, hybridization capacity, with the gene
    20 NOMO-1 and / or with at least one expression product thereof. In general, the kit of the invention comprises all those reagents necessary to carry out the method of the invention described above. The kit can also include, without any limitation, buffers, enzymes, such as, but not limited to, polymerases, cofactors for optimal activity of these, agents for
    25 prevent pollution, etc. On the other hand, the kit can include all the supports and containers necessary for its start-up and optimization. The kit may also contain other molecules, genes, proteins or probes of interest, which serve as positive and negative controls. Preferably, the kit further comprises instructions for carrying out the method of the invention. Preferably, the kit of the
    The invention comprises the oligonucleotides of SEQ ID NO: 4 and SEQ ID NO: 5.
    Another aspect of the invention relates to the in vitro use of the kit of the invention for the diagnosis, prognosis and / or monitoring of CCRp, preferably in an isolated biological sample, as described throughout the present document.
    Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the
    5 invention. The following examples are provided by way of illustration, and are not intended to be limiting of the present invention. EXAMPLES
    The invention will now be illustrated by tests carried out by the inventors, which demonstrates the effectiveness of the method of the invention in the diagnosis, prognosis and monitoring of CCRp. These specific examples provided serve to illustrate the nature of the present invention and are included for illustrative purposes only, and therefore should not be construed as
    15 limitations to the invention claimed herein. Therefore, the examples described below illustrate the invention without limiting its scope of application. Example 1. Determination of the NOMO-1 gene as a biomarker in the diagnosis and characterization of patients suffering from CRPC compared to patients suffering from CRC.
    A total of 34 tumor tissue samples were collected from individuals diagnosed consecutively with CCRp, at the age of 45 years or less. In addition, 17 samples of tumor tissue were also collected from individuals diagnosed consecutively with 25 CRC but at the age of 70 years or older, in order to compare them with the group of young individuals presenting CCRp. The clinical characteristics of both groups of patients included in the study are shown in Table 1. The microsatellite instability (IMS) and the mutations related to Lynch syndrome were also analyzed for all individuals (Table 1). Track them all
    30 was continued for at least five years after surgery. All patients included in the study signed the informed consent.
    In the samples of young subjects under 45 years of age, the hereditary origin of the presence of CCRp was ruled out, as well as the presence of other solid tumors, such as endometrial cancer and glioblastoma.

    Table 1. Clinical characteristics of the patients included in the present study.
    CCRp n (%) RCC elderly n (%)
    Patients 3. 417
    Mean age (DS) 1 38.65 (5.2)79.5 (5.2)
    Male Female Sex 19 (56) 15 (44)7 (41.2) 10 (58.8)
    Location Right colon Left colon Right 11 (32.4) 17 (50) 6 (17.6)7 (41.2) 3 (17.6) 7 (41.2)
    Tumor differentiation2 Poorly differentiated 2/27 (7.4)0/16 (0)
    Mucinous tumors2 Cells in "Seal Ring" 2 10/27 (37) 0 (0)1/16 (6.3) 0/16 (0)
    Astler Coller staging modified A B C D 7 (20.6) 17 (50) 3 (8.8) 7 (20.6)3 (17.6) 6 (35.3) 6 (35.3) 2 (11.8)
    Associated polyps Average number of polyps (DS) 1 Type Adenomatous Hyperplastic Mixed 21 (61.8) 2.3 (3) 7 (33.3) 3 (14.3) 11 (52.4)12 (70.6) 2.8 (3.5) 6 (50) 2 (16.7) 4 (33.3)
    Synchronous or metachronous RCC Recurrence3 Related mortality Disease-free survival (DS) 1 Global survival (DS) 1 3 (8.8) 4 (14.8) 7 (20.6) 57.7 (43.6) 67.5 (37.2)3 (17.6) 2 (20) 3 (17.6) 27.2 (37.8) 27.3 (32.3)
    IMS Mutations in MMR genes 7 (20.6) 6 (17.6)1 (5.9) 0 (0)
    Family history of cancer Families Amsterdam II Positive. Sporadic cases. 9 (26.5) 12 (35.3)0 (0) 10 (58.8)
    1 Statistical analysis carried out by Student's t. 2 The proportions shown are
    5 based on the variable total number of cases since those in which only cases biopsy was obtained (stages D, for example) 3 The cases that show recurrence are those with initial stages C or less. DS: Standard deviation. CCR: Colorectal Cancer; CCRp: Early onset colorectal cancer. IMS: microsatellite instability. MMR: DNA error repair system.
    10
    Total DNA was extracted from tumor tissue samples using techniques
    conventional. The quantity and purity of the DNA samples were made in the
    Nanodrop (Thermo Scientific D-1000).
    For the detection of the presence or absence of the NOMO-1 gene (SEQ ID NO: 1) in the samples obtained from said patients, a RT-qPCR was carried out to quantify the number of relative alleles of said gene in each patient. RT-qPCR was performed using the FastStart Universal SYBR Green Master (ROX) (2x with.) In 5 StepOnePlusTM Real-Time PCR System (Life Technologies-Invitrogen, California, U.S.A.). Briefly, a fragment of the NOMO-1 gene (SEQ ID NO: 1) was amplified in the DNA obtained from the isolated samples of the subjects included in the study using the following primers: direct primer 5`-agctccatgtggatggagtc-3` (SEQ ID NO: 4) and reverse primer: 5`-acggatgaagtacagagttc-3´ (SEQ ID NO: 5). As an internal control for the normalization of gene expression levels, the gene 36b4 (SEQ ID NO: 6) was amplified in the same DNA using the following primers: direct primer: 5`-cagcaagtgggaaggtgtaatcc-3` (SEQ ID NO: 8) and reverse primer 5`cccattctatcatcaacgggtacaa-3´ (SEQ ID NO: 9). For the qRT-PCR reaction, a concentration of 15 ng of DNA and a final reaction volume of 10 utilizó were used. SYBR Green (Roche, FastStart Universal SYBR Green Master (ROX) Applied Science, Germany) was used for the detection of PCR products. One-step RT-PCR reactions were carried out in 96-well plates covered with an adhesive film (MicroAmp Optical Adhesive Film, Life Technologies-Invitrogen, California, U.S.A) to prevent evaporation of the samples. The conditions of the 20 RT-qPCR were 10 minutes at 95 ° C followed by 40 cycles at 95 ° C for 15 seconds, then at 58 ° C for 45 seconds and at 72 ° C for 15 seconds. These reactions were carried out in an Applied Biosystems StepOnePlus thermal cycler and the results were obtained with the RQ Manager software (Applied Biosystems). Data were analyzed according to the method of analysis.
    25 relative expression ddCt previously described by Pfaffl (Pfaffl et al., 2002. Nucleic Acids Res. May 1; 30 (9): e36). The data of the presence or absence and / or of the levels of expression of the NOMO-1 gene in the samples of the analyzed patients are normalized in Log10 scale.
    30 All results are expressed as mean values ± standard deviation (SD) and categorical variables are expressed in the form of number of cases and their percentage. The differences were considered significant when the p value <0.05. All statistical analyzes were carried out using the SPSS v.11.5 program for Windows (SPSS, Inc., Chicago, IL).
    35
    The results of the detection of the presence or absence of the NOMO-1 gene in the group of young patients suffering from CCRp, has shown that the 34 individuals analyzed showed residual amplification of said gene, always much less than half of the copies detected in healthy tissue, that is, 100% of the 5 analyzed individuals showed homozygous loss of the NOMO-1 gene, since the presence of said gene could not be detected. In contrast, of the 17 elderly patients with CRC, only two cases showed homozygous loss of NOMO-1, while five presented heterozygous loss, and in the other 10 cases, the NOMO-1 gene showed normal presence. Therefore, within the elderly population that were
    10 diagnosed with RCC, only 2 of 17 individuals showed absence of the NOMO1 gene, showing that only 11.7% of the elderly population with RCC presented homozygous deletion of said gene.
    To validate the results obtained in that first group of patients, the
    15 shows an independent CCRp group of 41 individuals in total, representative of three independent institutions: Salamanca University Hospital (Salamanca, Spain), Family Cancer Clinical Unit of the National Oncology Research Center (CNIO) (Madrid, Spain) and Hospital October 12 (Madrid, Spain). All patients signed the informed consent before being included in the
    20 study.
    For the analysis of the detection of the presence or absence (preferably analyzing the presence of the number of alleles of the gene) and / or the levels of expression of NOMO-1, in the new group of patients, we proceeded as it was explained 25 previously. Therefore, the presence of the NOMO-1 gene (SEQ ID NO: 1) was analyzed by RT-qPCR in the tumor tissue samples obtained from the new group of young patients presenting CCRp (validation group). The results obtained show that of the total of 41 new cases, 27 showed homozygous loss (total absence of expression of the NOMO-1 gene); 7 showed loss
    30 heterozygous (50% amplification of the NOMO-1 gene with respect to the CRC group of elderly individuals), and 7 showed normal expression of the NOMO-1 gene.
    Next, all the results obtained were grouped, both from the first group of patients, and from the second group (validation group), obtaining a total of 35 75 individuals suffering from early onset RCC. This grouping, as observed in Table 2, confirmed that 61 individuals (81.3% of the total population
    analyzed) showed loss of the NOMO-1 gene, thus confirming that these patients have homozygous deletion of the NOMO-1 gene. On the other hand, 7 individuals (9.3% of the total population analyzed) presented heterozygous deletion of the NOMO-1 gene, and the remaining 7 individuals (9.3% of the total population analyzed),
    5 showed a normal expression of said gene. These results show the usefulness of the NOMO-1 gene as a specific biomarker for the diagnosis, prognosis and / or monitoring of patients suffering from CCRp.
    Subsequently, we wanted to determine if the IMS phenotype could influence the
    10 diagnosis of CCRp, also associated with the absence in greater or lesser degree of expression of the NOMO-1 gene. Patients were subdivided according to the IMS phenotype they presented (Table 2). Thus, young patients who presented an EMS phenotype showed the most homozygous loss of the NOMO-1 gene (54 of 59) (91.5%), while only 7 of 16 patients who had an IMS phenotype showed
    15 homozygous loss of the gene (43.74%) (Table 2). Therefore, the heterozygous loss of the NOMO-1 gene appears to be rare in cases of individuals with CCRp who show EMS phenotype (3.3%, 2/59), and much more frequent in cases of individuals with CCRp who show IMS phenotype. (31.2%, 5/16) (Table 2).
    20 Table 2. Analysis of the expression of the NOMO-1 gene in the groups of patients with early onset CRC regarding the presence of the EMS or IMS phenotype.
    CCRp Original Group (n: 34) CCRp Validation Group (n: 41)Total CCRp (n: 75)
    EMS IMS EMSIMS EMSIMS
    NOMO-1 homozygous deletion 3132. 34547
    NOMO-1 heterozygous deletion 002525
    NOMO-1 normal expression 003434
    CCRp: Early onset colorectal cancer. IMS: microsatellite instability. EMS: Stability of microsatellites.
    To confirm that the absence of expression of the NOMO-1 gene, both in homozygosis and in heterozygosis, is a specific marker in the diagnosis of CCRp, alleles of said gene were quantified in different samples of tumor tissue from
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    权利要求:
    Claims (1)
    [1]
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