CN102680597B - Kit for distinguishing colorectal adenomas from colorectal cancer - Google Patents
Kit for distinguishing colorectal adenomas from colorectal cancer Download PDFInfo
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Abstract
The invention discloses a kit for distinguishing colorectal adenomas from colorectal cancer. The kit for distinguishing or assisting in distinguishing the colorectal adenomas from the colorectal cancer comprises a device for detecting phospholipids content and a contrast card established by the phospholipids content, wherein phospholipids are sphingosylphosphorylcholine (SPC), 16:0 sphingomyelin (SM), 18:0SM, 14:0 lysophosphatidylcholine (LPC), 16:0LPC, 18:0LPC, 20:0LPC and 22:0LPC. Saturated LPC, SPC and SM are taken as markers, and a molecular model for distinguishing the colorectal adenomas from the colorectal cancer is established, and has colorectal cancer distinguishing sensitivity of 90 percent and colorectal cancer distinguishing specificity of 93 percent.
Description
Technical field
The present invention relates to biological technical field, relate in particular to a kind of kit of distinguishing knot adenomas and colorectal cancer.
Background technology
Colorectal cancer is one of important malignant tumour, surpasses every year million people and dies from colorectal cancer.Due to generation and the habits and customs of colorectal cancer, particularly eating habit is closely related, and therefore, along with the raising gradually of China's living standards of the people, the incidence of disease and the fatal rate of colorectal cancer are in rising trend in China.Study and show that the early diagnosis of colorectal cancer is particularly crucial, the five-year survival rate of the colorectal cancer patients of early detection is up to 90%, once there is to shift colorectal cancer patients survival rate less than 10%, still current colorectal cancer early detection rate less than 40%." goldstandard " of Colorectal Cancer Diagnosis is Sigmoidoscope, its sensitivity and specificity all surpass 95%, but this detection means can cause larger misery to patient, and expensive, inconvenient, cause patient's interdependency low, be difficult to bring into play due effect in colorectal cancer early screening.In addition,, due to the restriction of medical resource, in China's health check-up, extensively carry out at present Sigmoidoscope and detect unrealistic.
The evaluation of colorectal cancer early diagnosis molecular marked compound becomes one of study hotspot now.Reported successively in recent years some tissue in, the colorectal cancer molecular labeling in ight soil and in serum, but the specificity of these marks and susceptibility are lower.For example, with the special site that methylates of faeces DNA, as diagnosis of colorectal carcinoma mark, when specificity reaches 90%, sensitivity only has 50%.Compare with this marker detection based on fecal sample, blood marker detects more convenient, so people more wish that research and development can be applicable to the blood mark of diagnosis of colorectal carcinoma.Studies have reported that, serum colon cancer specific antigen CCSA-3 and CCSA-4 may become the mark of diagnosis of colorectal carcinoma, but its detection effect also needs further confirmation.
Phosphatide is not only and is formed biomembranous important component, some phospholipid molecules itself or its metabolic product are still as important signaling molecule, lysophosphatidyl choline (lysophosphatidylcholine wherein, LPC), Sphingosylphosphocholine (sphingosylphosphorylcholine, SPC), lysophosphatidic acid (lysophosphatidic acid, LPA), sphingosine-1-phosphate (sphingosine-1-phosphate, S1P) and sphingomyelins (sphingomyelin, SM) etc. can be by the receptors bind of himself or metabolic product and cell surface, activate downstream signal path, participate in cell proliferation, migration, there are and be adsorbed on the regulation and control of interior multiple vital movement in form.These lipid molecules and metabolic product thereof and multiple physiology and pathology process are closely bound up.For example SPC and SM all can be converted into S1P, and LPC can generate LPA by ATX catalysis, and S1P and LPA are very remarkable to tumorigenic regulatory function as functional activity lipid molecule.Along with biologically active lipid molecule and cancer-related understanding deeply and the progress of lipid molecule detection means, some biologically active lipid molecules are considered to may be as the biomarker of early diagnosis of tumor.2007, first the Xu Yan of indiana ,US university professor reports that LPC can be used as the colorectal cancer early diagnosis marker of American population in laboratory, after LPC level determination in Dui100 many cases U.S. colorectal cancer patients He100 many cases U.S. normal person's blood plasma, find that the level of comparing LPC in colorectal cancer patients blood plasma with normal population significantly declines.
The evolution of having experienced normal-adenoma-tumour of colorectal cancer can there is canceration in some patient after the knot adenomas stage stops 10-15.The existence in adenoma stage is also for early diagnosis and the intervention of colorectal cancer provide an important time window.People's research emphasis is that screening and identification can distinguish the molecular labeling of normal population and tumor patient mostly.Detect at present colorectal cancer process, i.e. adenoma-tumour transition process, molecular marked compound also very deficient.Therefore, evaluation can be distinguished the molecular marker of knot adenomas and colorectal cancer, significant to the early diagnosis of colorectal cancer and intervention.Important physiology and pathology sense in view of biologically active phosphatide molecule, the present invention utilizes mass-spectrometric technique, by detecting and relatively tie the content of biologically active phosphatide molecule in adenomas and colorectal cancer patients blood plasma, having set up, take phospholipid molecule and distinguish the technology of knot adenomas and colorectal cancer as mark.
Summary of the invention
The object of this invention is to provide a kind of differentiation or the auxiliary kit of distinguishing knot adenomas and colorectal cancer.
Kit provided by the invention, comprises for detection of the device of content of phospholipid and the comparison of being set up by described content of phospholipid and blocking;
Described phosphatide is SPC, 16:0SM, 18:0SM, 14:0LPC, 16:0LPC, 18:0LPC, 20:0LPC and 22:0LPC.
In above-mentioned kit, on the described comparison card of being set up by content of phospholipid, be provided with straight line, horizontal ordinate and ordinate;
Described straight line is 0.044 * SM Zong Liang –, 60.1 * SPC Han Liang –, 0.027 * saturated LPC total amount=-1.06;
Described horizontal ordinate is 0.044 * SM Zong Liang –, 60.1 * SPC content;
Described ordinate is saturated LPC total amount.
Also can think that the described comparison card of being set up by content of phospholipid is comprised of straight line, horizontal ordinate and ordinate;
In above-mentioned kit, described SM total amount is the summation of described 16:0SM and described 18:0SM content;
Described saturated LPC total amount is the summation of described 14:0LPC, described 16:0LPC, described 18:0LPC, described 20:0LPC and described 22:0LPC content.
In above-mentioned kit, the described device for detection of content of phospholipid is LC-MS instrument.
In above-mentioned kit, the mobile phase that described detection adopts is that volume ratio is methyl alcohol, water, the ammonia water mixture of 90:10:0.1;
Described content of phospholipid is content of phospholipid described in Blood plasma in vitro.
In above-mentioned kit, described kit is comprised of the described device for detection of content of phospholipid and the described comparison card of being set up by described content of phospholipid.
Above-mentioned kit is distinguished or assisted the application in the product of distinguishing knot adenomas and colorectal carcinoma in preparation is also the scope of protection of the invention.
The content that experiment showed, a plurality of LPC subclass in colorectal cancer patients blood plasma in Chinese population of the present invention is tied adenomas patient conspicuousness and is reduced, and shows that LPCs can be used as the molecular labeling of distinguishing knot adenomas and colorectal cancer.Utilize saturated LPC, SPC, 16:0SM and 18:0SM for mark, can set up the molecular model of distinguishing knot adenomas and colorectal cancer, the sensitivity of this Model checking colorectal cancer and specificity are respectively up to 90% and 92.5%.
Accompanying drawing explanation
Fig. 1 is saturated LPC, total LPC, SPC and (16:0+18:0) variation tendency of total SM content in knot adenomas and colorectal cancer patients blood plasma
Fig. 2 is for utilizing saturated LPC total amount, (16:0+18:0) SM total amount and SPC content to distinguish the model of tying adenomas and colorectal cancer patients in Chinese population
Embodiment
The experimental technique using in following embodiment if no special instructions, is conventional method.
In following embodiment, material used, reagent etc., if no special instructions, all can obtain from commercial channels.
The structure of the kit of embodiment 1, differentiation knot adenomas and colorectal cancer
One, the foundation of molecular model
1, blood is collected, lipid molecule extracts and detection
1) research object
All sample collections are in May, 2007-2010 year May, and sample is from the Second Artillery Force of entire PLA hospital general, Beijing Hospital, the second affiliated hospital of Peking University.Get patient blood on an empty stomach morning and carry out pre-service.This project is examined through Institutional Review Board, all subjects signed Informed Consent Forms.
Table 1 has been summarized the basic condition of research object: 240 experimenters are Chinese, and 61% is the male sex (147/240), and the male sex's shared ratio in knot adenomas patient and colorectal cancer patients is respectively 63% and 59%.The age of adenoma patient and tumor patient is respectively: 54.5+14.2 and 55.7+11.8, the age does not have significant difference between two groups of samples.
The basic condition of table 1 research object
Table 2 has been summarized the basic condition of the 120 routine tumor samples of getting: be 53%(64/120) colon tumor, all the other samples are comprised of most rectal neoplasms and minority cecal neoplasma.Tumour over 75% is T3/T4 phase (93/120), and only about half of tumour is N0(58/120,48%).From differentiation degree, most tumours are middle height differentiation (82/120,69%).
The basic condition of table 2 tumor patient
| Total amount | |
| Research object | Quantity (number percent |
| Former site | |
| Colon | 64(53) |
| Rectum | 51(43) |
| Other | 5(4) |
| T by stages | |
| T1.T2 | 15(13) |
| T3.T4 | 93(77) |
| Unclear | 12(10) |
| N by stages | |
| N0 | 58(48) |
| N1.N2.N3 | 49(41) |
| Unclear | 13(11) |
| Differentiation degree | |
| Middle high level | 52(69) |
| Low degree | 24(20) |
| Unclear | 14(11) |
2) plasma sample preparation, lipid molecule extract and detect
In containing the pipe of EDTA, collect above-mentioned 1) the in vitro whole blood of sample, room temperature (25 ℃) 1, centrifugal 15 minutes of 750g, is distributed into Blood plasma in vitro on the pipe of silicidation ,-80 degree Refrigerator stores, avoid multigelation.
The extraction of LPC, SPC and SM: add 0.5ml PBS(Hyclone company in glass centrifuge tube, SH30256.01B), add 100 μ l 12:0LPC (avanti polar lipids 855475P, 100mM), add 3ml methyl alcohol/chloroform (volume ratio is 2:1).In above-mentioned solution, add 10 μ l Blood plasma in vitro obtained above, after whirlpool mixes, place on ice 10 minutes.Add 1ml chloroform, 1.3ml distilled water, mixes, room temperature (25 ℃) 1, and centrifugal 10 minutes of 750g, takes off a layer organic phase, and nitrogen dries up, and by 1ml methanol/water (9:1), dissolves, and gets machine testing LPC, SPC and SM and each subclass content on 200 μ l.
Above-mentioned upper machine testing all adopts LC-MS system: LC-MS instrument Applied Biosystems Sciex 3200QtrapTM massspectrometer, Applied Biosystems Sciex, Ontario, Canada, mobile phase is: methanol/water/ammoniacal liquor (90:10:0.1), the flow velocity of described detection content of phospholipid mobile phase is 0.2ml/min.
The standard items of series phosphatide are all purchased from Avanti Polar Lipids company (in Table 3), and the catalog number of portioned product is as shown in table 3 below:
The standard items of table 3 lipid
| Name | Catal0gue N0. |
| 12：0LPC | 855475P |
| 14：0LPC | 855575P |
| 16：0LPC | 855675P |
| 18：2LPC | 790648P |
| 18：1LPC | 845875C |
| 18：0LPC | 855775C |
| 20：0LPC | 855777C |
| 20:4LPC | By the said firm, synthesized |
| 22：0LPC | 855779C |
| 22:6LPC | By the said firm, synthesized |
| SPC | 860600P |
| lyso-PAF | 878119C |
| 14：0LPA | 857120X |
| 16：0LPA | 857123P |
| 18：1LPA | 857130C |
| 18：0LPA | 857128X |
| S1P | 860492P |
| 16：0SM | 860061C |
| 18：0SM | 860062C |
2, experimental result
1) impact of sex on phospholipid molecule content in blood plasma
Due to masculinity proportion higher (61.3%) in whole 240 samples, we detect the relation between the content of phospholipid molecule in blood plasma (μ M) and sex.Testing result is as shown in table 4, if carry out t check using p=0.01 as standard, in all blood plasma, the content of detected phospholipid molecule does not all have significant difference between masculinity and femininity.
The gender differences of content of phospholipid in table 4 blood plasma
2) detection of phospholipid molecule content in knot adenomas and colorectal cancer patients blood plasma
Detected the content (μ M) of following phospholipid molecule in whole 240 samples and subclass thereof: SPC, lyso-PAF, 14:0LPC, 16:0LPC, 18:2LPC, 18:1LPC, 18:0LPC, 20:4LPC, 20:0LPC, 22:6LPC, 22:0LPC, 16:0SM and 18:0SM.
Result is as shown in Fig. 1 and table 5, compare with knot adenomas group, most LPC hypotypes, comprise 14:0LPC, 16:0LPC, 18:2LPC, 18:1LPC, 18:0LPC, 20:4LPC, 20:0LPC, 22:6LPC and 22:0LPC, the content in colorectal cancer patients blood plasma all significantly reduces (table 5).Saturated LPC, total LPC content and SPC significantly decline in colorectal cancer patients blood plasma, however the significantly increase in colorectal cancer patients blood plasma of 16:0SM, 18:0SM and total SM content (table 5, Fig. 1).
The content of phospholipid molecule in table 5 knot adenomas patient and colorectal cancer patients blood plasma
3, set up the model of distinguishing knot adenomas and colorectal cancer
Based on above-mentioned phospholipid molecule plasma content, in difference, detect the difference in group, set up the molecular model of distinguishing knot adenomas and colorectal carcinoma:
The formula of model: 0.044 * SM Zong Liang –, 60.1 * SPC Han Liang –, 0.027 * saturated LPC total amount=-1.06
SM total amount is the summation of 16:0SM and 18:0SM content;
Saturated LPC total amount is the summation of 14:0LPC, 16:0LPC, 18:0LPC, 20:0LPC and 22:0LPC content.
Two, distinguish the structure of the kit of knot adenomas and colorectal cancer
1) set up comparison card
Comparison card is comprised of formula (straight line), horizontal ordinate and the ordinate of model;
Horizontal ordinate is 0.044 * SM Zong Liang –, 60.1 * SPC content;
Ordinate is saturated LPC total amount.
2) structure of kit
Kit comprises above-mentioned comparison card and LC-MS instrument Applied Biosystems Sciex 3200QtrapTMmassspectrometer, Applied Biosystems Sciex, Ontario, Canada.
The application of the kit of embodiment 2, differentiation knot adenomas and colorectal cancer
1, sensitivity and the specificity of distinguishing knot adenomas and colorectal cancer detect
Get the blood of 120 knot adenomas (all passing through clinical identification) and 120 routine colorectal cancer patients (all making a definite diagnosis through clinical identification); According to embodiment 1 one 1 2) method carry out Blood plasma in vitro preparation, lipid extraction, LC-MS instrument and detect, obtain SPC in blood plasma, 16:0SM, 18:0SM, 14:0LPC, 16:0LPC, 18:0LPC, 20:0LPC and 22:0LPC content;
0.044 * SM Zong Liang –, 60.1 * SPC content of take is horizontal ordinate, and the saturated LPC total amount of take is ordinate, with the formula [0.044 * SM Zong Liang –, 60.1 * SPC Han Liang –, 0.027 * saturated LPC total amount=-1.06] of model, makes straight line, maps.
Result is as shown in the right figure of Fig. 2, for 0.044 * SM Zong Liang –, 60.1 * SPC content in the blood plasma of each adenoma patient (a) and colorectal cancer patients (c), saturated LPC total amount is mapped, figure cathetus is: [0.044 * SM Zong Liang –, 60.1 * SPC Han Liang –, 0.027 * saturated LPC total amount=-1.06].It is knot adenomas patient that straight line left side is determined, and right side is judged to be colorectal cancer patients.Amount to 120 knot adenomas patients and 120 colorectal carcinoma patients.
By analysis, have 124 samples in straight line left side, 116 samples are on straight line right side.In 116 samples on straight line right side, have 108 samples to derive from colorectal cancer patients (116/120), 8 samples derive from knot adenomas patient (8/120); In 124 samples in straight line left side, 112 samples derive from knot adenomas patient (112/120), and 12 samples derive from colorectal cancer patients (12/120);
108 patients on straight line right side are correctly diagnosed as (and survey and make a definite diagnosis through intestines microscopy) colorectal carcinoma patient, and 112 patients in straight line left side are correctly diagnosed as (and survey and make a definite diagnosis through intestines microscopy) knot adenomas patient.
Therefore, the sensitivity of this Model checking colorectal cancer is the number 108/ tumor patient sum 120=90% being correctly diagnosed in 90%(tumor patient), specificity is the number 116 that number 108/ that 93%(is diagnosed as actual tumor patient in the sample of tumor patient is diagnosed as tumor patient).
The left figure of Fig. 2 serve as reasons differentiation knot adenomas patient that right figure sets up and colorectal carcinoma patient's ROC curve.
Therefore LPC, SPC and SM can be used as the diacritics thing of tying adenomas patient and colorectal cancer patients in Chinese population.
The above-mentioned model that LPC, SPC and SM set up as mark of take can accurately be distinguished knot adenomas and colorectal cancer, and the judgement of colorectal cancer is had to good sensitivity and specificity.
Claims (6)
1. distinguish or an auxiliary kit of distinguishing knot adenomas and colorectal cancer, comprise for detection of the device of content of phospholipid and the comparison of being set up by described content of phospholipid and blocking;
Described phosphatide is SPC, 16:0SM, 18:0SM, 14:0LPC, 16:0LPC, 18:0LPC, 20:0LPC and 22:0LPC;
On the comparison card of being set up by described content of phospholipid, be provided with straight line, horizontal ordinate and ordinate;
Described straight line is 0.044 * SM Zong Liang –, 60.1 * SPC Han Liang –, 0.027 * saturated LPC total amount=-1.06;
Described horizontal ordinate is 0.044 * SM Zong Liang –, 60.1 * SPC content;
Described ordinate is saturated LPC total amount.
2. kit according to claim 1, is characterized in that:
Described SM total amount is the summation of described 16:0SM and described 18:0SM content;
Described saturated LPC total amount is the summation of described 14:0LPC, described 16:0LPC, described 18:0LPC, described 20:0LPC and described 22:0LPC content.
3. kit according to claim 1 and 2, is characterized in that:
The described device for detection of content of phospholipid is LC-MS instrument.
4. kit according to claim 3, is characterized in that:
The mobile phase that described detection adopts is that volume ratio is methyl alcohol, water, the ammonia water mixture of 90:10:0.1;
Described content of phospholipid is content of phospholipid described in Blood plasma in vitro.
5. kit according to claim 1, is characterized in that:
Described kit is comprised of the described device for detection of content of phospholipid and the described comparison card of being set up by described content of phospholipid.
6. in claim 1-5, the application in the product of distinguishing knot adenomas and colorectal cancer is distinguished or assisted to arbitrary described kit in preparation.
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| EP3250708B1 (en) * | 2015-01-30 | 2021-08-11 | BGI Shenzhen | Biomarkers for colorectal cancer related diseases |
| CN106370834B (en) * | 2016-09-07 | 2018-01-19 | 辽宁润生康泰生物医药科技有限公司 | A kind of kit for the carcinoma of the rectum that come to an end using common molecular sieve |
| CN106872590B (en) * | 2017-01-03 | 2019-05-07 | 中国人民解放军第四军医大学 | The method and diagnosis of colorectal carcinoma kit of Liquid Chromatography-Tandem Mass Spectrometry detection tissue linoleic acid content |
| CN113939737A (en) * | 2019-04-01 | 2022-01-14 | 创新生物有限公司 | Solid cancer diagnosis device and method for providing solid cancer diagnosis information |
| CN112915093A (en) * | 2021-03-16 | 2021-06-08 | 山东大学 | Application of sphingosylphosphorylcholine in inducing apoptosis of tumor cells |
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| CN101498700A (en) * | 2009-02-16 | 2009-08-05 | 桑建利 | Production and use of reagent kit for measurement of lipide molecule content in human blood sample and colorectal carcinoma diagnosis |
| CN102147396A (en) * | 2010-02-10 | 2011-08-10 | 桑建利 | Preparation and application of kit used for testing content of lipid molecules in human blood sample and diagnosing colorectal adenomas |
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| CN101498700A (en) * | 2009-02-16 | 2009-08-05 | 桑建利 | Production and use of reagent kit for measurement of lipide molecule content in human blood sample and colorectal carcinoma diagnosis |
| CN102147396A (en) * | 2010-02-10 | 2011-08-10 | 桑建利 | Preparation and application of kit used for testing content of lipid molecules in human blood sample and diagnosing colorectal adenomas |
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