Marker of prostate gland cancer

FIELD: chemistry; medicine.

SUBSTANCE: possibility of application in diagnostics of prostate gland cancer, and in differential diagnostics between prostate gland cancer and benign hyperplasia. Marker of prostate gland cancer consists of protein with molecular weight 28.5 kDa and visible isoelectric point 6.92, isolated from tumor tissue of prostate gland. Isolated marker protein includes peptides MPADLPSLAADFVESK; DVFLGMFLYEYAR; VFDEFKPLVEEPQNLIK; FQNALLVR; VPQVSTPTLVEVSR and AVMDDFAAFVEKCCK.

EFFECT: increase of accuracy of prostate gland cancer diagnostics.

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The invention relates to medical diagnosis and can be used for differential diagnosis between prostate cancer man and benign hyperplasia.

One of the important problems of health in the aging populations of modern society - cancer, among which a special place belongs to prostate cancer (PC). It is known that more than 50% of men with age range of 51-60 years have signs of prostate hyperplasia, which is considered as a precancerous condition.

The effective (surgical, chemotherapy and other treatment SPM primarily determined by the timeliness and accuracy of diagnosis, which is of paramount importance to the determination of molecular markers of cancer.

Currently, for the diagnosis of FPW proposed and used a number of completely different clinical and instrumental methods: method of diagnosis by digital rectal exam, a method based on transrectal ultrasound (U.S. Pat. RF 2256924, 2259163), the results of magnetic resonance imaging of the prostate, the analysis of the radio emission of the patient's body (avts 1738261, 1767434, 1655467), color Doppler, x-ray, morphological diagnosis, histology sections of biopsy specimens (U.S. Pat. RF 2156977, 018829), immunohistochemical (U.S. Pat. Of the Russian Federation No. 2276672) and cytological diagnosis (U.S. Pat. RF 2151397), determining the concentration of rubidium and zinc in the prostate secretion (ed. St. No. 764660), infrared spectroscopy (U.S. Pat. Of the Russian Federation No. 2246898, 2018829).

However, these clinical and instrumental methods do not possess the necessary qualities to ensure early and effective diagnosis FPW; it generally allows you to specify the diagnosis only at advanced stages of the disease and for early diagnosis requires the use of molecular markers, as evidenced by the considerable experience gained by Russian and foreign experts (Malignant neoplasms in Russia in 2002. Morbidity and mortality. Ed. Vichissov, TII, Gvera, M., in "Medpress-inform". 2004. P.5-22).

As a result, for the past decades are being actively sought effective molecular markers FPW different nature in the prostate tissues and in biological fluids, and find potential markers are used to develop new ways to diagnose PC.

Quite a long time known neoplastic molecular marker RSP proposed as a universal marker for detection of various tumors, including FPW (U.S. Pat. RF 2025734, filing date 1990).

Describes how differential the diagnosis between benign hyperplasia and FPW (U.S. Pat. Of the Russian Federation No. 2151397, 1999), including the study of biological material on the contents phosphatidylinositol-3-phosphate (FIF); from whole blood secrete the lipid fraction in which the method of running horizontal chromatography determine the level of fit. When the value of 0.1-0.08 nmol of phosphorus fit 1 on 1 mg protein diagnosed with benign hyperplasia, and a value of 0.04-0.01 nmol of phosphorus fit 1 on 1 mg protein diagnose PC.

RF patent №2234942, 1999 protected a number of polynucleotides isolated from tumor tissue of the prostate gland and is able to encode tumor polypeptides of the prostate. The nucleotide sequences of these polynucleotides shown in the patent under the numbers SEQ ID NO: 225 and SEQ ID NO: 326. Described in the patent compositions can be used as markers of cancer progression.

RF patent №2258710, 2000 protected the selected polypeptide is a new cytokine zalpha11 ligand containing a sequence of amino acid residues that is at least 90% identical to residues 41 (Gln) to 148 (Ile) in the sequence shown in the patent under the number SEQ ID NO:2, and the residue at position 44 is Asp, the residue at position 47 is Asp and the residue at position 135 is Glu. The polypeptide binds a zalpha11 receptor shown in the sequence number SEQ ID NO: 115. Alternative polypeptide zalpha1 can serve as an additional marker of cell surface or secreted marker associated with stagespecific expression in tissue. The appearance or disappearance of polypeptides that regulate cell motility, can be used in diagnosis and prognosis of prostate cancer.

Found a human gene (U.S. patent 6300479, publ. 2001), which encodes a new protein from the family of beta timoshkov (hereinafter thymosin β-15); it is shown that this protein has the ability to bind and hold (to arrest) globular actin, like other members of the family of beta timoshkov, but unlike other members of the family of beta timoshkov it directly regulates cell motility in cells carcinoma (cancer) of the prostate. There is a proposal to use thymosin β-15 as a molecular marker for the diagnosis of FPW (Hutchinson L.M. et al. Use of thymosin beta15 as a urinary biomarker in human prostate cancer. Prostate. 2005. V.64. 116-127).

Known non-invasive methods for determining the presence of nucleic acids with specific sequences, as well as modifications and damage to nucleic acids in the samples analyzed urine for the presence transrenal renal nucleic acids (U.S. patent 6492144, 2002). The proposed method includes methods for the determination of specific fetal nucleic acid sequences which contain modified nucleotides in the analyzed m the key material to establish the presence of fetal nucleic acid. In addition, this method proposes to use for the diagnosis of not only cancer, but also pathogenic infections, and to determine genetic predisposition to various diseases, for monitoring treatment of cancer and for monitoring the success of the transplantation of cells, tissues and organs.

However, these methods were not sufficiently specific, difficult to reproduce and is not found up to the present time clinical application (Malignant neoplasms in Russia in 2002. Morbidity and mortality. / Ed. Vichissov, TII, Gvera, M., in "Medpress-inform". 2004. P.5-22).

The closest analogue is widely used in the clinic biochemical diagnostic method FPW to determine the level of serum prostatespecific antigen (hereinafter PSA) in plasma or serum (Kuriyama M. Prostate-specific antigen in prostate cancer. // Int. J. Biol. Markers. 1986. 1(2). Page 67-76.; Parekh D.J., Ankerst D.P., Troyer D., Srivastava, S., Thompson I.M. biomarkers are for prostate cancer detection.). However, there is strong evidence of lack of diagnostic value of this marker (Stamey T.A. et al. J. The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years? J. Urol. 2004. 172. 1297-1301), which mainly reflects the degree of hypertrophy. In General, the results of determination of PSA in the blood of patients registered 40-60% lozhnopolojitelny what's tests and about 10% false-negative tests (Kuriyama M Prostate-specific antigen in prostate cancer. // Int. J. Biol. Markers. 1986. 1(2). Page 67-76).

However, over the last 3-4 years using proteomic technologies shows that when FPW in the tumor cells of the prostate detected an increased synthesis of dozens of different proteins, most of which do not exhibit the properties required for specific diagnostic markers, but the search for such proteins are actively continued.

The objective of the invention is to develop a method for the diagnosis of prostate cancer to identify specific protein marker in the malignant tissue with the aim of improving the accuracy of diagnosis.

This goal is achieved through the use as a marker for prostate cancer, consisting of a protein, isolated from the tumor tissue of the prostate gland, the molecular mass of 28.5 kDa and apparent isoelectric point 6,92, which includes peptides MPADLPSLAADFVESK; DVFLGMFLYEYAR; VFDEFKPLVEEPQNLIK; FQNALLVR; VPQVSTPTLVEVSR; AVMDDFAAFVEKCCK.

The authors distinguished the claimed protein from tumor tissue of the prostate technique similar to that described in the article Ahram M. et al. Proteomic analysis of human prostate cancer. Molecular carcinogenesis. 2002. V.33. 9-15. Below this method of analysis.

Proteins from samples of epithelium of prostate cancer (stage by Gleason 8-9) and 12 healthy individuals were extracted lysis-buffer and fractionalise two-dimensional electrophore is ω O' Farrell, using in the first direction (IPG) immobilized strips with nonlinear gradient pH 3-10 and the subsequent separation of SDS-EF SDS page gradient 9-18% staining with silver nitrate or a fluorescent dye Sypro Ruby. Protein spots showing qualitative and quantitative changes in patients with prostate cancer, were cut from the polyacrylamide gels were subjected cryptococcoma hydrolysis and analyzed using HPLC and tandem mass spectrometry. The obtained mass trypticase peptides were used to search for protein candidates for protein sequences using the program PepFrag. Forty-tumor-specific changes were identified, including proteins of cell morphology (tropomyosin beta), metabolism (aldolase a, M-chain lactate dehydrogenase) and signal transduction (laminin receptor 67 kDa protein interactions phosphoserine-threonine-tyrosine).

The authors of this invention have conducted a search using a similar set above proteomic technologies of potential protein markers FPW in comparative studies of proteins in biopsies and operating materials obtained from two groups of patients with postoperative morphologically confirmed diagnosis: prostate cancer (PC, n=20) and hyperplasia (SE, n=18), where n is the number of patients. The research results is presented in table 1. Table 1 shows data on postoperative clinical and morphological diagnoses of these patients and the results of determination they have a DOG, which in most cases corresponded to the so-called "grey zone" (Sz - 4 to 10 ng/ml). Only three patients with polaprezinc a diagnosis of adenocarcinoma of the PSA level exceeded the upper boundary of the "grey zone". With four people surveyed sampling rate of PSA was less than the lower boundary of the "grey zone".

Preoperative clinical and morphological diagnosis in all cases was set using complex instrumental methods, including mnogopolnoe biopsy followed by histological examination of biopsy specimens.

Comparative analysis of these two groups of samples showed the presence of specific qualitative differences between tissues with SE and PC, based on the fact that in the past attended the claimed protein with a molecular mass of 28.5 kDa and with an apparent isoelectric point - 6,92. Overall, 19 of the 20 patients with a postoperative diagnosis of adenocarcinoma" in proteomic analysis were recorded inventive protein and the corresponding protein was found only in 1 patient with hyperplasia. In figure 1 the example shows the relevant fragments of the two-dimensional electrophoregrams obtained when PR is teamnum analysis of protein extracts from two patients with PC and one patient with prostatic hyperplasia.

According to the results of MALDI TOF mass-spectrometric analysis trypticase peptides of the claimed protein (arrow number 1 in figure 1) was identified several peptides that are included with albumin-related domains, which allowed to identify the claimed protein as albumin-related carcinomas protein 1 (figure 2).

Thus, the claimed protein is proposed to use as a marker in the diagnosis of PC, determining the presence of the indicated protein in biomaterials using proteomic technologies. The definition of the claimed marker with high specificity (>90%) will reduce the number of false-positive tests with 40-60% (when determining prostatespecific antigen plasma or serum) to 5-10% (in the study declare token).

Claimed marker has never been used for the diagnosis of cancer. Its use is preferred for more accurate diagnosis.

Table 1.
The results of the PSA and the claimed protein in patients with postoperative histological diagnosis.
No.Preoperative clinical and morphological diagnosisDOG The claimed proteinPostoperative morphological diagnosis
1Cancer"NW"cancerAdenocarcinoma
2Cancer"NW"cancerAdenocarcinoma
3Cancer"NW"cancerAdenocarcinoma
4Cancer"NW"cancerAdenocarcinoma
5Cancer"NW"CancerAdenocarcinoma
6Cancer"NW"CancerAdenocarcinoma
7Cancer"NW"CancerAdenocarcinoma
8Cancer"NW"cancerAdenocarcinoma
9CancerCancerCancerAdenocarcinoma
10CancerCancerCancerAdenocarcinoma
11Cancer"NW"cancerAdenocarcinoma
12Cancer"NW"CancerAdenocarcinoma
13hyperplasiaNormaCancerAdenocarcinoma
14hyperplasiaNormaCancerAdenocarcinoma
15Cancer (?)"NW"Cancer Adenocarcinoma
16Cancer (?)"NW"CancerAdenocarcinoma
17CancerCancerCancerAdenocarcinoma
18Cancer"NW"CancerAdenocarcinoma
19Cancer (?)"NW"CancerAdenocarcinoma
20Cancer"NW"Not definedAdenocarcinoma
21Hypertrophy (Hyperplasia)"NW"Not definedHyperplasia
22Hypertrophy (Hyperplasia)"NW"Not definedHyperplasia
23 Hypertrophy (Hyperplasia)"NW"Not definedHyperplasia
24Cancer (?)"NW"Not definedHyperplasia
25Cancer (?)"NW"Not definedHyperplasia
26Cancer (?)"NW"Not definedHyperplasia
27Hypertrophy (Hyperplasia)NormaNot definedHyperplasia
28Hypertrophy (Hyperplasia)"NW"Not definedHyperplasia
29Hypertrophy (Hyperplasia)"NW"Not definedHyperplasia
30genome (Hyperplasia) "NW"Not definedHyperplasia
31Cancer (?)"NW"Not definedHyperplasia
32Cancer (?)"NW"Not definedHyperplasia
33Cancer (?)"NW"Not definedHyperplasia
34Cancer (?)"NW"Not definedHyperplasia
35Hypertrophy (Hyperplasia?)"NW"Not definedHyperplasia
36Hypertrophy (Hyperplasia?)NormaNot definedHyperplasia
37Hypertrophy (Hyperplasia) "NW"Not definedHyperplasia
38Hypertrophy (Hyperplasia?)"NW"CancerHyperplasia

Figure 1. Fragments of two-dimensional electrophoregrams proteins of the human prostate: a - patient "To" with PC; b - the patient "P" with FPW; in - patient With hyperplasia. Arrow No. 1 shows the protein-specific emerging in cancer and identified as unknown protein product of the gene PRO2675 containing C-terminal albumen domain. Arrow No. 2 shows the reference protein, identified as circuit B triosephosphate isomerase.

Figure 2. The results of MALDI TOF mass-spectrometric analysis trypticase peptides extra protein (arrow number 1 in figure 1). Structure determination of peptides identified by mass spectra, using the option “Peptide Fingerprint” of the program Mascot (Matrixscience, USA).

A marker for prostate cancer, consisting of a protein, isolated from the tumor tissue of the prostate gland, the molecular mass of 28.5 kDa and with an apparent isoelectric point 6,92 includes peptides MPADLPSLAADFVESK; DVFLGMFLYEYAR; VFDEFKPLVEEPQNLIK; FQNALLVR; VPQVSTPTLVEVSR; AVMDDFAAFVEKCCK.



 

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