BRM Expression and Related Diagnostics
The present invention relates to isolated polynucleotides comprising a polymorphism in a promoter region of a BRM gene, and methods and compounds for causing BRM re-expression in cells, such as cancer cells, that have lost BRM expression. The present invention also relates to screening methods for identifying BRM expression-promoting compounds, and to methods of accessing cancer risk through the identification of polymorphisms in the BRM promoter.
1 . An isolated polynucleotide comprising a polymorphism in a promoter region of a BRM gene or a complementary nucleic acid thereof.
2 . The isolated polynucleotide of claim 1 , wherein the polymorphism is an insertion polymorphism, 5′ of the transcriptional start site of the BRM gene.
3 . The isolated polynucleotide of claim 2 , wherein the insertion polymorphism comprises an insertion mutation at position −741 by relative to the transcriptional start site of the BRM gene.
4 . The isolated polynucleotide of claim 2 , wherein the insertion polymorphism comprises an insertion mutation at position −1321 by relative to the transcriptional start site of the BRM gene.
5 . The isolated polynucleotide of claim 2 , wherein the insertion polymorphism comprises an insertion mutation at position −741 and −1321 by relative to the transcriptional start site of the BRM gene.
6 . The isolated polynucleotide of claim 1 , wherein the isolated polynucleotide comprises a nucleotide sequence of any one of SEQ ID NOs: 42-185 or a complementary sequence thereof.
7 . The isolated polynucleotide of claim 1 , wherein the isolated polynucleotide consists of a nucleotide sequence of any one of SEQ ID NOs: 42-185 or a complementary sequence thereof.
8 . The isolated polynucleotide of claim 6 , wherein the isolated polynucleotide comprises the nucleotide sequence of SEQ ID NO:42.
9 . The isolated polynucleotide of claim 6 , wherein the isolated polynucleotide comprises the nucleotide sequence of SEQ ID NO:43
10 . A composition comprising an isolated polynucleotide according to claim 1 .
11 . A vector comprising a polynucleotide according to claim 1 .
12 . A host cell comprising a vector according to claim 11 .
13 . An array of BRM polymophism oligonucleotides immobilized on a solid support surface, wherein the oligonucleotides are each from about 10 to 200 nucleotides in length, comprise a polymorphism in a promoter region of a BRM gene.
14 . The array according to claim 13 , wherein the polymorphism comprises an insertion mutation at position −741 by of the transcriptional start site of the BRM gene.
15 . The array according to claim 13 , wherein the polymorphism comprises an insertion mutation at position by of the transcriptional start site of the BRM gene.
16 . The array according to claim 13 , wherein the array comprises a mixture of oligonucleotides, the oligonucleotides having a polymorphism insertion mutation at position −741 or −1321 by of the transcriptional start site of the BRM gene.
17 . The array according to claim 13 , wherein the oligonucleotides are immobilized to the substrate by at least one of: covalent attachment, non-covalent attachment or coupled to the substrate through a linker.
18 . The array according to claim 13 , wherein said polymorphisms in said BRM promoter are associated with cancer.
19 . A method for detecting a propensity of a subject to develop a cancer, the method comprising: analyzing a polynucleotide sample derived from the subject for the presence of a polymorphism in a promoter region of a BRM gene, wherein the polymorphism is associated with an increased risk for developing cancer.
20 . The method according to claim 19 , wherein the cancer is selected from the group consisting of: bladder, breast, cervical, cholangiocarcinoma, colorectal, endometrial, esophageal, gastric, head and neck, kidney, liver, lung, nasopharyngeal, ovarian, pancreas/gall bladder, prostate, thyroid, osteosarcoma, rhabdomyosarcoma, synovial sarcoma, Kaposi's sarcoma, leiomyosarcoma, MFH/fibrosarcoma, adult T-Cell leukemia, lymphomas, multiple myeloma, glioblastomas, (glioblastoma multiforme), melanoma, mesothelioma and Wilms tumor cancer.
21 . The method according to claim 19 , wherein the presence or absence of the polymorphism in subject's polynucleotide sample is determined by contacting the polynucleotide sample with an oligonucleotide having a polymorphism in a promoter region of a BRM gene or a complement thereof, under conditions suitable for selective hybridization of the polynucleotide sample to the oligonucleotide; and determining whether hybridization has occurred, thereby indicating the presence of the polymorphism in the subject's polynucleotide.
22 . The method according to claim 19 , wherein the polymorphism is at least one insertion mutation at position −741 by or −1321 upstream of the transcriptional start site of the BRM gene.
23 . The method according to claim 19 , wherein the insertion polymorphism comprises an insertion mutation at position −741 by of the transcriptional start site of the BRM gene.
24 . The method according to claim 19 , wherein the insertion polymorphism comprises an insertion mutation at position −1321 by of the transcriptional start site of the BRM gene.
25 . The method according to claim 19 , wherein the cancer is lung cancer.