CN108949983A - Breast cancer parting gene group and its application - Google Patents
Breast cancer parting gene group and its application Download PDFInfo
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- CN108949983A CN108949983A CN201810810201.6A CN201810810201A CN108949983A CN 108949983 A CN108949983 A CN 108949983A CN 201810810201 A CN201810810201 A CN 201810810201A CN 108949983 A CN108949983 A CN 108949983A
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- 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
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- C12Q2600/00—Oligonucleotides characterized by their use
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Abstract
The present invention provides one group of breast cancer parting gene group, and breast cancer can be divided into three kinds of interstitial type, proliferous type and metabolic pattern hypotypes, and the breast cancer of different subtype has different gene expression profiles.The breast cancer patients of different subtype have different reactions to endocrine therapeutic agents and chemotherapeutics, will greatly improve the survival rate of breast cancer patients using suitable drug accordingly.The present invention can be used for preparing breast cancer parting detecting reagent to breast cancer parting gene group, carries out parting to breast cancer, is suitable for clinical guidance medication, for realizing that the accurate treatment of breast cancer has important application value.
Description
Technical field
The invention belongs to field of biotechnology, and in particular to one group of breast cancer parting gene group and its application.
Background technique
High-throughput cancer gene group confirms that breast cancer is not single disease, but the disease being made of a variety of hypotypes.
At present by gene expression profile to the several hypotypes of breast cancer (PAM50, the patent No. WO2009158143 A1): lumen A type, lumen B
Type, HER2 positive type, basal cell type and class normal cell type.It is this to have comparison accurate prognosis cancer progress parting
Prediction effect.For example, lumen A type, invasion is weaker with metastatic, postoperative recurrence shift risk it is relatively low, to endocrine
It treats more sensitive.Lumen Type B prognosis is medium, needs endocrine therapy combined chemotherapy.HER2 positive type and basal cell type are then
Prognosis is very poor.HER2 positive type, generally with anti-HER2 targeted therapy (Herceptin) combined chemotherapy and (or) endocrine therapy.
Basal cell type prognosis is worst, needs chemotherapeutic treatment.
Another technology (Oncotype Dx) is to the mammary gland specifically for estrogen receptor positive and Lymph Node-negative
Carninomatosis people, recurrence score is calculated with 21 gene expression amounts, and the low patient of recurrence score only needs endocrine therapy, recurrence point
The high patient of number then needs chemotherapy.
However, there are some problems in both the above genotyping technique.PAM50 molecule parting is not accurate enough, for example is
No there are class normal cell types there is also arguement, and the ratio between each hypotype is not known yet.In addition, PAM50 can not be demonstrate,proved accurately
Which kind of real hypotype is needed with specific chemotherapeutics.Oncotype Dx just for estrogen receptor positive breast cancer patients,
And the patient of estrogen receptor negative is not suitable for it.
Summary of the invention
In view of the above technical problems, the present invention provides breast cancer parting gene groups, by the tumour of breast cancer patients point
At three kinds of hypotypes: interstitial type, proliferous type and metabolic pattern.The breast cancer patients of different subtype are to endocrine therapeutic agents and chemotherapeutic
Object has different reactions, according to these three types using suitable drug by the great survival rate for improving breast cancer patients, to the greatest extent
Amount avoids not applicable drug, can reduce the Side effect of chemotherapy in this way.
An aspect of of the present present invention provides one group of breast cancer parting gene group, and the gene group includes interstitial type mastocarcinoma gene
Dactylogram, proliferous type mastocarcinoma gene dactylogram and metabolic pattern mastocarcinoma gene dactylogram, the interstitial type mastocarcinoma gene refer to
Line spectrum includes gene shown in 1 serial number 1-20 of table, and the proliferous type mastocarcinoma gene dactylogram includes shown in 1 serial number 21-40 of table
Gene, the metabolic pattern mastocarcinoma gene dactylogram include 1 serial number 41-60 of table shown in gene.
Further, the breast cancer of the specific expressed interstitial type mastocarcinoma gene dactylogram is interstitial type breast cancer.
Further, the breast cancer of the specific expressed proliferous type mastocarcinoma gene dactylogram is proliferous type breast cancer.
Further, the breast cancer of the specific expressed metabolic pattern mastocarcinoma gene dactylogram is metabolic pattern breast cancer.
Another aspect of the present invention provides above-mentioned breast cancer parting gene group in preparation breast cancer parting detecting reagent
Application, wherein the detection kit includes the primer for expanding the gene of the breast cancer parting gene group.
Another aspect of the present invention additionally provides application of the breast cancer parting gene group in breast cancer parting, described
Breast cancer is divided into three kinds of interstitial type breast cancer, proliferous type breast cancer and metabolic pattern breast cancer hypotypes by gene group, wherein specificity
The breast cancer for expressing the interstitial type mastocarcinoma gene dactylogram is interstitial type breast cancer, the specific expressed proliferous type mammary gland
The breast cancer of oncogene dactylogram is proliferous type breast cancer, the mammary gland of the specific expressed metabolic pattern mastocarcinoma gene dactylogram
Cancer is metabolic pattern breast cancer.
The present invention also provides application of the breast cancer parting gene group in breast cancer direction of medication usage, the gene group will be newborn
Gland cancer is divided into three kinds of interstitial type breast cancer, proliferous type breast cancer and metabolic pattern breast cancer hypotypes, wherein between described in specific expressed
The breast cancer of matter type mastocarcinoma gene dactylogram is interstitial type breast cancer, the specific expressed proliferous type mastocarcinoma gene fingerprint
The breast cancer of spectrum is proliferous type breast cancer, and the breast cancer of the specific expressed metabolic pattern mastocarcinoma gene dactylogram is metabolic pattern
Breast cancer.
Further, tamoxifen is suitable for the treatment of the interstitial type breast cancer.
Further, taxol is suitable for the treatment of the proliferous type breast cancer.
Further, Trastuzumab is suitable for the treatment of the proliferous type breast cancer of the HER2 positive.
Further, 5 FU 5 fluorouracil is suitable for the treatment of the metabolic pattern breast cancer.
Beneficial effects of the present invention
The present invention uses one group of breast cancer parting gene group, and breast cancer is divided into interstitial type, proliferous type and three kinds of metabolic pattern
Hypotype, and it was found that for drug to three kinds of hypotypes to therapeutic effect difference, finding has good therapeutic effect to drug three kinds of hypotypes, thus
Realize precisely treatment.The present invention can be used for preparing breast cancer parting detecting reagent to breast cancer parting gene group, to breast cancer
Parting is carried out, for clinical direction of medication usage, there is important application value in the treatment of breast cancer.
Detailed description of the invention
Fig. 1 shows that 125 breast cancer patients of the invention do not have the recurrence-free survival rate of drug therapy；
Fig. 2 shows that 62 breast cancer patients use the recurrence-free survival rate of tamoxifen treatment；
Fig. 3 shows 5 years overall survivals that 327 breast cancer patients treat 5 FU 5 fluorouracil；
Fig. 4 shows 3 years recurrence-free survival rates that the breast cancer patients of 53 HER2 positives treat Trastuzumab；
Fig. 5 shows that the breast cancer patients of 47 HER2 positives are completely slow to the pathology of the operation consent lower rectal cancer of Trastuzumab
Solution rate.
Specific embodiment
Technical solution of the present invention is clearly and completely described below in conjunction with the embodiment of the present invention, it is clear that retouched
The embodiment stated is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, originally
Field those of ordinary skill every other embodiment obtained without making creative work, belongs to the present invention
The range of protection.
Embodiment one, mastocarcinoma gene parting
This technology is to be divided into three kinds of hypotypes: interstitial type, proliferous type and metabolism by detecting the gene expression of breast cancer
Type.
According to the gene expression data (GSE3494, Affymetrix HG-U133A detection platform) of the patient of 251 breast cancer, I
Using obtained based on clustering breast cancer patient three kinds of hypotypes: interstitial type, proliferous type and metabolic pattern.It will be one of
The gene expression of type is compared with other two types, we obtain the genetic fingerprints spectrum of these three types.With interstitial type
For, the gene of the dactylogram is significantly higher than expression value (the expression multiple in other two kinds of hypotypes in the expression value in interstitial type
FC>1.5,p<0.05).Table 1 lists the typical genetic fingerprints spectrum (60 genes) of three kinds of breast cancer hypotypes.
60 genes of 1 breast cancer parting gene group of table
Table 2A-F lists the analysis composed to genetic fingerprints and carry out signal path.
Gene ontology (Gene ontology) path analysis of table 2A interstitial type breast cancer
| Interstitial type gene ontology (Gene ontology) |
| GO:0007155~cell adhesion |
| GO:0030198~extracellular matrix organization |
| GO:0001525~angiogenesis |
| GO:0002576~platelet degranulation |
| GO:0014068~positive regulation of phosphatidylinositol 3-kinase signaling |
| GO:0045766~positive regulation of angiogenesis |
| GO:0016525~negative regulation of angiogenesis |
| GO:0007517~muscle organ development |
| GO:0032355~response to estradiol |
| GO:0007507~heart development |
KEGG (the Kyoto Encyclopedia of Genes and Genomes) access of table 2B interstitial type breast cancer point
Analysis
| Interstitial type KEGG |
| hsa04510:Focal adhesion |
| hsa04512:ECM-receptor interaction |
| hsa04610:Complement and coagulation cascades |
| hsa04151:PI3K-Akt signaling pathway |
| hsa05200:Pathways in cancer |
| hsa04923:Regulation of lipolysis in adipocytes |
| hsa00982:Drug metabolism-cytochrome P450 |
| hsa04974:Protein digestion and absorption |
| hsa04015:Rap1signaling pathway |
| hsa05144:Malaria |
Gene ontology (Gene ontology) path analysis of table 2C proliferous type breast cancer
| Proliferous type gene ontology (Gene ontology) |
| GO:0051301~cell division |
| GO:0006260~DNA replication |
| GO:0000082~G1/S transition of mitotic cell cycle |
| GO:0007067~mitotic nuclear division |
| GO:0006270~DNA replication initiation |
| GO:0008283~cell proliferation |
| GO:0007062~sister chromatid cohesion |
| GO:0006954~inflammatory response |
| GO:0030593~neutrophil chemotaxis |
| GO:0070098~chemokine-mediated signaling pathway |
KEGG (the Kyoto Encyclopedia of Genes and Genomes) access of table 2D proliferous type breast cancer point
Analysis
| Proliferous type KEGG |
| hsa04110:Cell cycle |
| hsa03030:DNA replication |
| hsa05166:HTLV-I infection |
| hsa04115:p53signaling pathway |
| hsa04064:NF-kappa B signaling pathway |
| hsa05323:Rheumatoid arthritis |
| hsa04668:TNF signaling pathway |
| hsa05219:Bladder cancer |
| hsa04060:Cytokine-cytokine receptor interaction |
| hsa03430:Mismatch repair |
Gene ontology (Gene ontology) path analysis of table 2E metabolic pattern breast cancer
KEGG (the Kyoto Encyclopedia of Genes and Genomes) access of table 2F metabolic pattern breast cancer point
Analysis
| Metabolic pattern KEGG |
| hsa05322:Systemic lupus erythematosus |
| hsa05034:Alcoholism |
| hsa04144:Endocytosis |
| hsa04152:AMPK signaling pathway |
| hsa05219:Bladder cancer |
| hsa00280:Valine,leucine and isoleucine degradation |
| hsa01212:Fatty acid metabolism |
| hsa05203:Viral carcinogenesis |
| hsa01100:Metabolic pathways |
| hsa04923:Regulation of lipolysis in adipocytes |
It is composed using genetic fingerprints, we establish prediction model with the machine learning method of support vector machines (SVM) to predict
The hypotype of other breast cancer patients.Specifically, genetic fingerprints modal data is extracted from gene expression profile.For each gene pairs
All patient's samples of the batch are normalized to obtain z value, that is, are directed to each gene, and z value=(gene expression values-are equal
Value)/standard deviation.Parameter needed for obtaining prediction model with 10 cross validations using the e1071 program bag in statistics software R
(parameter gamma and cost).Such as our one group of parameter gamma=0.0078125 and cost=4 finding, with this parameter
Prediction model is established, later patient's tumor specimen hypotype can be predicted.
We observe the relationship of various clinical datas and three kinds of hypotypes, and discovery proliferous type has significant p53 mutation (to be shown in Table
3), and tumor grade is relatively high (being shown in Table 4).
3 proliferous type breast cancer of table is related to p53 mutation (GSE3494)
| p53 | Saltant type | Wild type |
| Interstitial type | 100 | 3 |
| Proliferous type | 30 | 45 |
| Metabolic pattern | 63 | 10 |
4 breast cancer of table, three hypotypes and tumor grade relationship (GSE3494)
| Tumor grade (grade) | 1 | 2 | 3 |
| Interstitial type | 45 | 54 | 2 |
| Proliferous type | 4 | 28 | 43 |
| Metabolic pattern | 18 | 46 | 9 |
The patient of estrogen receptor negative is mainly proliferous type, and interstitial type and metabolic pattern show as estrogen receptor male form
(table 5A-B).
Three hypotypes of table 5A breast cancer and estrogen receptor relationship (GSE3494)
| Estrogen receptor | It is negative | It is positive |
| Interstitial type | 4 | 96 |
| Proliferous type | 30 | 45 |
| Metabolic pattern | 0 | 72 |
Three hypotypes of table 5B breast cancer and estrogen receptor relationship (GSE41998)
| Estrogen receptor | It is negative | It is positive |
| Interstitial type | 17 | 67 |
| Proliferous type | 112 | 18 |
| Metabolic pattern | 9 | 56 |
Embodiment two, drug are to the therapeutic effects of three kinds of hypotypes of breast cancer
1, interstitial type breast cancer patients significantly benefit from tamoxifen
The gene expression data and clinical data of the patient of 189 breast cancer downloads (GSE2990) from GEO database,
In 2 patients without clinical data.Patient data is from the John Radcliffe Hospital of England Oxford and Sweden crow
The Uppsala University Hospital of Pu Sala.As shown in Figure 1,125 breast cancer patients are in no drug therapy
In the case where, the recurrence-free survival rate of the breast cancer patients of three kinds of hypotypes has no marked difference, wherein several 54 people of interstitial type patient,
Several 38 people of proliferous type patient, several 33 people of metabolic pattern patient.
As shown in Fig. 2, interstitial type patient number 17, proliferous type patient number 19, metabolic pattern patient number 26, interstitial type breast cancer disease
After using endocrine therapy (tamoxifen), recurrence-free survival rate is significantly increased people than other two kinds of hypotypes.It is specific next
It says, in 17 interstitial type patients, only one patient is recurred after 9 years half.This shows that only interstitial type breast cancer patients are aobvious
Write the treatment for benefiting from tamoxifen.
2, proliferous type breast cancer patients significantly benefit from taxol
The gene expression data and clinical data of the patient of 279 breast cancer downloads (GSE41998) from GEO database, number
According to the clinical trial (NCT00455533) for deriving from Bristol-Myers Squibb Co..Patient uses new adjuvant chemotherapy before surgery, first
It is administered once with Doxorubicin joint cyclophosphamide (AC) within first every 21 days, makees as a treatment course, treated 4 courses for the treatment of.Such as table 6A
Shown, the complete reactivity of the pathology of three kinds of hypotype patients has no significant difference (p=0.419).Then 121 patients therein
It is primary with administering paclitaxel weekly again, make as a treatment course, has treated 12 courses for the treatment of.As shown in table 6B, the disease of proliferous type patient
It manages complete reactivity and reaches 43%, the complete reactivity of pathology only has 15% and the patient of other two kinds of hypotypes is averaged.Proliferous type disease
The complete reactivity of the pathology of people significantly improves (p=0.002).This shows that the breast cancer patients of proliferous type benefit from controlling for taxol
It treats.
Pathological reaction of the table 6A breast cancer patients to Doxorubicin joint cyclophosphamide
Fisher's Exact test:P=0.419
Table 6B breast cancer patients combine the pathological reaction of cyclophosphamide+taxol to Doxorubicin
Fisher's Exact test:P=0.002
The gene expression data and clinical data of the patient of 14 breast cancer downloads (GSE22513) from GEO database, disease
People uses taxol new adjuvant chemotherapy before surgery.As shown in table 7, the complete reactivity of the pathology of proliferous type patient reaches 50%,
And the patient of other two kinds of hypotypes is averaged, the complete reactivity of pathology only has 0%.In summary two groups of clinical data (GSE41998
And GSE22513) show that the breast cancer patients of proliferous type benefit from the treatment of taxol.
Pathological reaction of 7 breast cancer patients of table to taxol
Fisher's Exact test:P=0.070
Note: wherein there is a patient can not be to its correct classification
3, metabolic pattern breast cancer patients significantly benefit from 5 FU 5 fluorouracil
The gene expression data and clinical data of the patient of 327 breast cancer downloads (GSE20685) from GEO database, number
According to from TaiWan, China and letter central hospital for cancer.In this group of patient, patient also receives taxanes chemotherapy, ER sun
Venereal disease people also receives endocrine therapy.Data analysis shows metabolic pattern breast cancer patients significantly benefit from 5 FU 5 fluorouracil (p <
0.05).It is interesting that Lei et al (Identification of Molecular Subtypes of Gastric
Cancer with Different Responses to PI3-Kinase Inhibitors and 5-Fluorouracil,
Lei, Zhengdeng et al.Gastroenterology, Volume 145, Issue 3,554-565 (2013)) exist
Confirm that metabolic pattern Patients with Gastric Cancer benefits from 5 FU 5 fluorouracil in multiple groups Patients with Gastric Cancer.
4, HER2 positive proliferative type breast cancer patients significantly benefit from Trastuzumab
The gene expression data and clinical data of the patient of 53 HER2+ breast cancer is downloaded from GEO database
(GSE55348), data source is in the IRCSS Istituto Nazionale Tumori of Italy.As shown in figure 4, relative to
Interstitial type and metabolic pattern patient, the breast cancer patients of proliferous type are significantly benefited from Trastuzumab (p < 0.05), and other two groups of hypotypes
Patient be benefited to the targeted therapy of Trastuzumab and bad even HER2+.
The gene expression data and clinical data of the patient of 47 HER2+ breast cancer downloads (GSE62327 from GEO database
And GSE66305), data source is in IRCSS Istituto Nazionale Tumori and the University of of Italy
Modena and Reggio Emilia.As shown in figure 5, relative to interstitial type and metabolic pattern patient, for the new auxiliary of Trastuzumab
Treatment is helped, the pathology complete remission rate of proliferous type breast cancer patients is significantly higher than the patient (p < 0.05) of other two groups of hypotypes.
Claims (11)
1. one group of breast cancer parting gene group, the gene group includes interstitial type mastocarcinoma gene dactylogram, proliferous type breast cancer
Genetic fingerprints spectrum and metabolic pattern mastocarcinoma gene dactylogram, the interstitial type mastocarcinoma gene dactylogram include 1 serial number 1-20 of table
Shown in gene, the proliferous type mastocarcinoma gene dactylogram includes gene shown in 1 serial number 21-40 of table, metabolic pattern cream
Gland cancer genetic fingerprints spectrum includes gene shown in 1 serial number 41-60 of table.
2. breast cancer parting gene group according to claim 1, which is characterized in that the specific expressed interstitial type mammary gland
The breast cancer of oncogene dactylogram is interstitial type breast cancer.
3. breast cancer parting gene group according to claim 1, which is characterized in that the specific expressed proliferous type mammary gland
The breast cancer of oncogene dactylogram is proliferous type breast cancer.
4. breast cancer parting gene group according to claim 1, which is characterized in that the specific expressed metabolic pattern mammary gland
The breast cancer of oncogene dactylogram is metabolic pattern breast cancer.
5. application of the breast cancer parting gene group according to claim 1 in preparation breast cancer parting detecting reagent,
Wherein, the detection kit includes the primer for expanding the gene of the breast cancer parting gene group.
6. application of the breast cancer parting gene group according to claim 1 in breast cancer parting, the gene group will be newborn
Gland cancer is divided into three kinds of interstitial type breast cancer, proliferous type breast cancer and metabolic pattern breast cancer hypotypes, wherein between described in specific expressed
The breast cancer of matter type mastocarcinoma gene dactylogram is interstitial type breast cancer, the specific expressed proliferous type mastocarcinoma gene fingerprint
The breast cancer of spectrum is proliferous type breast cancer, and the breast cancer of the specific expressed metabolic pattern mastocarcinoma gene dactylogram is metabolic pattern
Breast cancer.
7. application of the breast cancer parting gene group according to claim 1 in breast cancer direction of medication usage, the gene group
Breast cancer is divided into three kinds of interstitial type breast cancer, proliferous type breast cancer and metabolic pattern breast cancer hypotypes, wherein specific expressed institute
The breast cancer for stating interstitial type mastocarcinoma gene dactylogram is interstitial type breast cancer, the specific expressed proliferous type mastocarcinoma gene
The breast cancer of dactylogram is proliferous type breast cancer, and the breast cancer of the specific expressed metabolic pattern mastocarcinoma gene dactylogram is generation
Thank to type breast cancer.
8. application according to claim 7, which is characterized in that tamoxifen is suitable for controlling for the interstitial type breast cancer
It treats.
9. application according to claim 7, which is characterized in that taxol is suitable for the treatment of the proliferous type breast cancer.
10. application according to claim 7, which is characterized in that Trastuzumab is suitable for the proliferous type cream of the HER2 positive
The treatment of gland cancer.
11. application according to claim 7, which is characterized in that 5 FU 5 fluorouracil is suitable for the metabolic pattern breast cancer
Treatment.
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