Detection of chromosomal abnormalities associated with endometrial cancer

Abstract

The methods and compositions described herein address the need for diagnostic method that could be offered to women during yearly checkups to allow for early detection, diagnosis and classification, and treatment of endometrial cancer. In addition, these methods and compositons addresse the current need for improving diagnostic accuracy of biopsy procedures in symptomatic patients.

1 . A method of detecting the presence of endometrial carcinoma in a biological sample from a subject, the method comprising:
 contacting the sample with one or more probes for one or more chromosome regions selected from the group consisting of: 1q, 2p, 2q, 3p, 3q, 7p, 8p, 8q, 9p, 9q, the centromeric region of chromosome 10, 10q, 15q, 16q, 17p, the centromeric region of chromosome 18, 18q, 19p, 20q, and 22q;   incubating the one or more probes with the sample under conditions in which each probe binds selectively with a polynucleotide sequence on its target chromosome or chromosomal region to form a stable hybridization complex; and   detecting hybridization of the one or more probes, wherein a hybridization pattern showing at least one gain or loss or imbalance at a chromosomal region targeted by the probes is indicative of endometrial carcinoma.   
     
     
         2 . The method of  claim 1 , wherein a hybridization pattern showing a gain in one or more chromosome regions selected from the group consisting of: 1q, 2p, 3q, 8q, 10q, and 20q is indicative of endometrial carcinoma. 
     
     
         3 . The method of  claim 2 , wherein a hybridization pattern showing a gain in one or more chromosome regions selected from the group consisting of: 1q, 10p, and 10q is indicative of endometrioid carcinoma. 
     
     
         4 . The method of  claim 2 , wherein a hybridization pattern showing a gain in one or more chromosome regions selected from the group consisting of: 3q, 8q, 18q, and 20q is indicative of non-endometrioid carcinoma. 
     
     
         5 . The method of  claim 1 , wherein a hybridization pattern showing a gain in 1q31-qtel is indicative of endometrial carcinoma. 
     
     
         6 . The method of  claim 1 , wherein a hybridization pattern showing a loss in one or more chromosome regions selected from the group consisting of: 9p, 9q, 15q, 16q, 17p, 18q, 19p, and 22q is indicative of endometrial carcinoma. 
     
     
         7 . The method of  claim 1 , wherein a hybridization pattern showing a loss in one or more chromosome regions selected from the group consisting of: 15q11-q13, 18q21, and 19 ptel is indicative of endometrial carcinoma. 
     
     
         8 . The method of  claim 1 , wherein said one or more probes are for one or more chromosome subregions selected from the group consisting of: 1q25, 2p24, 2q26, 3p21, 3q27-q29, 7p21, 8p11, 8q24, 9q34, the centromeric region of chromosome 10, 10q23, 10q26, 15q11-q13, 16q24, the centromeric region of chromosome 18, 18q21, 20q12 and 20q13. 
     
     
         9 . The method of  claim 8 , wherein said one or more probes are for one or more chromosome subregions selected from the group consisting of: 1q25-q31, 2p24, 3p21.3, 3q27-q29, 7p21, 8p11.2-p11.1, 8q24, 9q34, 10q23.3, 10q26, 15q11-q13, 16q24.3, 18q21.3, 20q12, and 20q13.2. 
     
     
         10 . The method of  claim 8 , wherein said one or more probes are for one or more chromosome subregions selected from the group consisting of: 1q25, 10q23.3, 18q21.2, CEP10, CEP18, 8p11.2, 8q24, 2p24.3, 2q26.32, 10q26.13, and 20q13.2. 
     
     
         11 . The method of  claim 8 , wherein the sample is contacted with a combination of at least 3 probes for a set of chromosome subregions selected from the group consisting of:
 1q25, 8q24, 15q11-q13;   1q25, 10q26, 15q11-q13;   1q25, 2p24, 8q24   1q25, 8q24, 10q26;   1q25, 8p11, 15q11-q13;   1q25, 2p24, 8p11;   1q25, 8p11, 10q26;   1q25, 8p11, 8q24;   1q25, 2p24, 10q26;   1q25, 2p24, 15q11-q13;   8q24, 10q26, 15q11-q13;   1q25, 8p11, 20q13;   1q25, 8q24, 20q13;   1q25, 15q11-q13, 20q13;   1q25, 10q26, 20q13;   8p11, 10q26, 15q11-q13;   1q25, 2p24, 20q13;   2p24, 8p11, 10q26;   2p24, 8q24, 10q26;   2p24, 10q26, 15q11-q13;   2p24, 8q24, 15q11-q13;   10q26, 15q11-q13, 20q13;   1q25, 8p11, 18q21;   1q25, 8q24, 18q21;   1q25, 10q26, 18q21;   1q25, 15q11-q13, 18q21;   8p11, 8q24, 10q26;   8q24, 10q26, 20q13;   1q25, 2p24, 18q21;   2p24, 8p11, 8q24;   2p24, 8p11, 15q11-q13;   8p11, 8q24, 15q11-q13;   2p24, 10q26, 20q13;   8p11, 10q26, 20q13;   2p24, 8p11, 20q13;   2p24, 8q24, 20q13;   8q24, 15q11-q13, 20q13; and   8p11, 15q11-q13, 20q13.   
     
     
         12 . The method of  claim 11 , wherein the sample is contacted with a combination of at least 3 probes for a set of chromosome subregions selected from the group consisting of:
 1q25, 18q21, CEP18, 8q24;   2p24, 2q26, 10q26, 2q13; and   10q23, CEP10, and 8p11.   
     
     
         13 . The method of  claim 11 , wherein the sample is contacted with a combination of at least 2 probes for a set of chromosome subregions selected from the group consisting of:
 18q21, 1q24, 8q24, CEP18;   1q24, 8q24, 10q26, CEP18;   18q21, 1q24, 10q26, CEP18;   1q24, 8q24, CEP18, 3q27-q29;   18q21, 1q24, 8q24, 10q26;   1q24, 2p24, 10q26, CEP18;   1q24, 10q26, CEP18, 3q27-q29;   1q24, 10q26, CEP18, 20q13;   1q24, CEP18, 3q27-q29, 20q13;   1q24, 2p24, CEP18, 3q27-q29;   18q21, 1q24, 10q26, 20q13;   1q24, 8q24, CEP18;   18q21, 1q24, CEP18; and   1q24, CEP18.   
     
     
         14 . The method of  claim 11 , wherein the sample is contacted with a combination of at least 4 probes for a set of chromosome subregions selected from the group consisting of:
 1q24, 8q24, CEP18, 20q13;   1q24, CEP18, 3q27-q29, 20q13;   1q24, CEP18, 20q13, 10q26;   CEP10, 8q24, CEP18, 1q24;   10q26, CEP10, 1q24, 8q24;   8q24, 1q24, 20q13, CEP18; 10q26;   20q13, CEP10, 1q24, 10q26.   wherein a hybridization pattern showing a gain in one or more of these chromosome subregions is indicative of endometrial carcinoma.   
     
     
         15 . The method of  claim 14 , wherein one or more of a gain at one of more of 1q24, 8q24, CEP18, and 20q13 are indicative of endometrial carcinoma. 
     
     
         16 . The method of  claim 14 , wherein one or more of a 20q13 gain, a 1q24 gain, a CEP10 imbalance, and a 10q26 gain are indicative of endometrial carcinoma. 
     
     
         17 . The method of  claim 1 , wherein the sample is contacted with a combination of at least 2 probes for a set of chromosome subregions selected from the group consisting of:
 18q21, 1q25, 8q24, CEP18;   1q25, 8q24, 10q26, CEP18;   18q21, 1q25, 10q26, CEP18;   1q25, 8q24, CEP18, 3q27-q29;   18q21, 1q25, 8q24, 10q26;   1q25, 2p24, 10q26, CEP18;   1q25, 10q26, CEP18, 3q27-q29;   1q25, 10q26, CEP18, 20q13;   1q25, CEP18, 3q27-q29, 20q13;   1q25, 2p24, CEP18, 3q27-q29;   18q21, 1q25, 10q26, 20q13;   1q25, 8q24, CEP18;   18q21, 1q25, CEP18; and   1q25, CEP18.   
     
     
         18 . The method of  claim 1 , wherein the sample is contacted with a combination of at least 4 probes for a set of chromosome subregions selected from the group consisting of:
 1q25, 8q24, CEP18, 20q13;   1q25, CEP18, 3q27-q29, 20q13;   1q25, CEP18, 20q13, 10q26;   CEP10, 8q24, CEP18, 1q25;   10q26, CEP10, 1q25, 8q24;   8q24, 1q25, 20q13, CEP18; 10q26;   20q13, CEP10, 1q25, 10q26.   wherein a hybridization pattern showing a gain in one or more of these chromosome subregions is indicative of endometrial carcinoma.   
     
     
         19 . The method of  claim 18 , wherein one or more of a gain at one of more of 1q25, 8q24, CEP18, and 20q13 are indicative of endometrial carcinoma. 
     
     
         20 . The method of  claim 18 , wherein one or more of a 20q13 gain, a 1q25 gain, a CEP10 imbalance, and a 10q26 gain are indicative of endometrial carcinoma. 
     
     
         21 . The method of  claim 1  wherein the probe combination distinguishes samples comprising endometrial carcinoma from samples that do not comprise endometrial carcinoma with a sensitivity of at least 93% and a specificity of at least 90%. 
     
     
         22 . The method of  claim 21 , wherein the sensitivity is at least 95% and the specificity is at least 90.4%. 
     
     
         23 . The method of  claim 22 , wherein the sensitivity is least 96% and the specificity is at least 91%. 
     
     
         24 . The method of  claim 1 , wherein the probe combination comprises between 2 and 10 probes. 
     
     
         25 . The method of  claim 1 , wherein the probe combination comprises between 3 and 8 probes. 
     
     
         26 . The method of  claim 1 , wherein the probe combination comprises 4 probes. 
     
     
         27 . The method of  claim 1 , wherein the method is carried out by array comparative genomic hybridization (aCGH) to probes immobilized on a substrate. 
     
     
         28 . The method of  claim 1 , wherein the method is carried out by fluorescence in situ hybridization, and each probe in the probe combination is labeled with a different fluorophore. 
     
     
         29 . The method of  claim 1 , wherein the sample comprises an endometrial brushing specimen or an endometrial biopsy specimen. 
     
     
         30 . The method of  claim 1 , wherein, when the results of the method indicate endometrial carcinoma, the method additionally comprises treating the subject for endometrial carcinoma. 
     
     
         31 . A combination of probes comprising between 2 and 10 probes selected from the groups set forth in  claim 1 , wherein the combination of probes has a sensitivity of at least 93% and a specificity of at least 90% for distinguishing samples comprising endometrial carcinoma from samples that do not comprise endometrial carcinoma. 
     
     
         32 - 35 . (canceled) 
     
     
         36 . A kit for diagnosing endometrial carcinoma, wherein the kit comprises a combination of probes comprising between 2 and 10 probes selected from the groups set forth in  claim 1 , wherein the combination of probes has a sensitivity of at least 93% and a specificity of at least 90% for distinguishing samples comprising endometrial carcinoma from samples that do not comprise endometrial carcinoma. 
     
     
         37 - 43 . (canceled)