Tgfbr1 HAPLOINSUFFICIENCY MODIFIES RISK FOR CANCER

• US 20100267028A1
• Filed: 12/24/2009
• Published: 10/21/2010
• Est. Priority Date: 12/24/2008
• Status: Active Grant

• Current Assignee: Boris Pasche
• Original Assignee: Boris Pasche
• Inventors: Pasche, Boris
• Granted Patent: US 8,492,096 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/172 Haplotypes

Abstract

The present invention provides methods for assessing a genetic susceptibility to cancer in a subject which includes measuring allele specific expression or presence of at-risk haplotypes of TGFBR1, where a difference in expression or the presence of at-risk haplotypes is indicative of a cancer or susceptibility to a cancer. Methods to screen for agents that modify expression of TGRBR1 are also provided.

Claims

1. A method for the identification of susceptibility to cancer in an individual, comprising:

screening a sample from the individual to be diagnosed for at least one allele or SNP associated with allele specific expression (ASE) in the transforming growth factor beta type 1 receptor gene (TGFBR1) wherein the allele or at-risk haplotype increases the risk of developing cancer in the individual.

2. The method of claim 1, wherein the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, breast cancer, and non-small-cell lung cancer.

3. A method of detecting a predisposition in a human subject for developing cancer, comprising:

a) collecting a biological sample from the subject;

b) genotyping the sample at polymorphic nucleotide positions; and

c) determining whether an ASE-associated haplotype is present in the sample, the haplotype comprising polymorphic nucleotide positions wherein the presence of the haplotype indicates a genetic predisposition for developing cancer in the subject.

4. The method of claim 3, wherein the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, breast cancer, and non-small-cell lung cancer.

5. A method of detecting a predisposition to cancer, comprising steps of

a) Designing and synthesizing oligonucleotide primers capable of amplifying parts of human TFGBR1 gene and its genomic region,

b) Amplifying genomic DNA of CRC patients and normal control individuals using the primers of step (a);

c) Sequencing the amplified genomic DNA and identifying sequence variations (polymorphisms) of the amplified genomic DNA by comparing it with an existing sequence of human TGFBR1 gene;

d) Screening normal control individuals and cancer patients for said polymorphisms identified in step (c) by sequencing or genotyping of the amplified genomic DNA of the individuals using the said primers of step (a);

e) Computing risk haplotypes for CRC using said polymorphisms in the human TGFRB1 gene and its genomic region based on their frequency distribution in normal individuals and cancer patients; and

f) Predicting the risk or susceptibility to cancer based on the haplotype present at the polymorphic sites in the individuals tested.

6. The method of claim 5, wherein the cancer is selected from the group consisting of colorectal cancer, pancreatic cancer, breast cancer, and non-small-cell lung cancer.

7. A method of diagnosis and identification of susceptibility to cancer in an individual, the method comprising the steps of:

(a) obtaining a sample of the patient'"'"'s tissue;

(b) determining the expression level of TGFBR1;

(c) obtaining a reference expression level for TGFBR1 for a normal control;

(d) comparing the expression data for TGFBR1 of step (b) with the reference expression for TGFBR1 of step (c), wherein a ratio of the sample expression TGFBR1 to the reference expression of the TGFBR1 indicating altered expression of TGFBR1 in the sample indicates altered susceptibility to cancer in the individual.

8. The method of claim 7, wherein the altered expression of TGFBR1 is lowered expression, wherein the altered susceptibility to cancer is increased susceptibility, and the cancer is selected from the group consisting of colorectal cancer, breast cancer, and non-small cell lung cancer.

9. The method of claim 7, wherein the altered expression of TGFBR1 is lowered expression, wherein the altered susceptibility to cancer is decreased susceptibility, and the cancer is pancreatic cancer.

10. A method of identifying a candidate compound for modifying TGFBR1 expression, the method comprising:

contacting a test compound with a cell expressing TGFBR1;

monitoring expression level of TGFBR1; and

selecting the test compound as a candidate compound for modifying TGFBR1 expression if the test compound modifies the expression of TGFBR1, relative to the expression of TGRBR1 in a cell of the same cell type that is not contacted with the test compound.

11. The method of claim 10, wherein the expression level of TGFBR1 is increased.

12. The method of claim 10, wherein the expression level of TGFBR1 is decreased.

13. The method of claim 10, wherein the cell is a cultured cell from a tumor selected from the group consisting of a colorectal tumor, a breast tumor, a non-small cell lung cancer tumor, and a pancreatic tumor.