DIAGNOSIS AND TREATMENT OF CANCERS WITH MicroRNA LOCATED IN OR NEAR CANCER-ASSOCIATED CHROMOSOMAL FEATURES

Abstract

MicroRNA genes are highly associated with chromosomal features involved in the etiology of different cancers. The perturbations in the genomic structure or chromosomal architecture of a cell caused by these cancer-associated chromosomal features can affect the expression of the miR gene(s) located in close proximity to that chromosomal feature. Evaluation of miR gene expression can therefore be used to indicate the presence of a cancer-causing chromosomal lesion in a subject. As the change in miR gene expression level caused by a cancer-associated chromosomal feature may also contribute to cancerigenesis, a given cancer can be treated by restoring the level of miR gene expression to normal. microRNA expression profiling can be used to diagnose cancer and predict whether a particular cancer is associated with an adverse prognosis. The identification of specific mutations associated with genomic regions that harbor miR genes in CLL patients provides a means for diagnosing CLL and possibly other cancers.

1 . A method of determining increased risk of a human subject developing a cancer, or increased likelihood of the presence of a cancer in a human subject, comprising the steps of:
 (i) measuring in a sample from the subject the level of at least one miR-155(BIC) gene product; and   (ii) comparing the level of the at least one miR-155(BIC) gene product in the sample to a control level of the miR-155(BIC) gene product,   wherein an increase in the level of the miR-155(BIC) gene product in the sample relative to the control level of miR-155(BIC) gene product is indicative of the subject either having increased risk of developing the cancer or increased likelihood of the presence of the cancer.   
     
     
         2 . The method of  claim 1 , wherein the at least one miR-155(BIC) gene product comprises SEQ ID NO:183. 
     
     
         3 . The method of  claim 1 , wherein the at least one miR-155(BIC) gene product comprises nucleotides 4-25 of SEQ ID NO:183. 
     
     
         4 . The method of  claim 1 , wherein the cancer is selected from the group consisting of: bladder cancer; esophageal cancer; lung cancer; stomach cancer; kidney cancer; cervical cancer; ovarian cancer; breast cancer; lymphoma; Ewing sarcoma; hematopoietic tumors; solid tumors; gastric cancer; colorectal cancer; brain cancer; epithelial cancer; nasopharyngeal cancer; uterine cancer; hepatic cancer; head-and-neck cancer; renal cancer; male germ cell tumors; malignant mesothelioma; myelodysplastic syndrome; pancreatic or biliary cancer; prostate cancer; thyroid cancer; urothelial cancer; renal cancer; Wilm's tumor; small cell lung cancer; melanoma; skin cancer; osteosarcoma; neuroblastoma; leukemia (acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia); glioblastoma multiforme; medulloblastoma; lymphoplasmacytoid lymphoma; and rhabdomyosarcoma. 
     
     
         5 . The method of  claim 4 , wherein the cancer is breast cancer. 
     
     
         6 . The method of  claim 4 , wherein the cancer is lung cancer. 
     
     
         7 . The method of  claim 6 , wherein the lung cancer is small cell lung cancer. 
     
     
         8 . The method of  claim 4 , wherein the cancer is colorectal cancer. 
     
     
         9 . The method of  claim 1 , wherein the level of the at least one miR-155(BIC) gene product in the sample is measured using an assay selected from the group consisting of northern blot analysis, in situ hybridization and quantitative reverse transcriptase polymerase chain reaction. 
     
     
         10 . The method of  claim 1 , wherein the sample is a tissue sample. 
     
     
         11 . The method of  claim 10 , wherein the tissue sample is a biopsy. 
     
     
         12 . The method of  claim 1 , wherein the sample is a blood sample. 
     
     
         13 . A method of determining increased risk of a human subject developing a cancer, or increased likelihood of the presence of a cancer in a human subject, comprising the steps of:
 (1) reverse transcribing at least one miR-155(BIC) RNA from a sample from the subject to provide at least one miR-155(BIC) target oligodeoxynucleotide;   (2) hybridizing the at least one miR-155(BIC) target oligodeoxynucleotide to a microarray comprising miRNA-specific probe oligonucleotides that include at least one miR-155(BIC) RNA-specific probe oligonucleotide to provide a hybridization profile for the sample, wherein the hybridization profile includes a hybridization signal for the at least one miR-155(BIC) RNA; and   (3) comparing the sample hybridization profile to a control hybridization profile, wherein the control hybridization profile includes a control hybridization signal for the at least one miR-155(BIC) RNA,   wherein a hybridization signal for the at least one miR-155(BIC) RNA in the sample hybridization profile that is greater than the control hybridization signal for the at least one miR-155(BIC) RNA indicates the subject has increased risk of developing the cancer or increased likelihood of the presence of the cancer.   
     
     
         14 . The method of  claim 13 , wherein the at least one miR-155(BIC) gene product comprises SEQ ID NO:183. 
     
     
         15 . The method of  claim 13 , wherein the at least one miR-155(BIC) gene product comprises nucleotides 4-25 of SEQ ID NO:183. 
     
     
         16 . The method of  claim 13 , wherein the cancer is selected from the group consisting of: bladder cancer; esophageal cancer; lung cancer; stomach cancer; kidney cancer; cervical cancer; ovarian cancer; breast cancer; lymphoma; Ewing sarcoma; hematopoietic tumors; solid tumors; gastric cancer; colorectal cancer; brain cancer; epithelial cancer; nasopharyngeal cancer; uterine cancer; hepatic cancer; head-and-neck cancer; renal cancer; male germ cell tumors; malignant mesothelioma; myelodysplastic syndrome; pancreatic or biliary cancer; prostate cancer; thyroid cancer; urothelial cancer; renal cancer; Wilm's tumor; small cell lung cancer; melanoma; skin cancer; osteosarcoma; neuroblastoma; leukemia (acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia); glioblastoma multiforme; medulloblastoma; lymphoplasmacytoid lymphoma; and rhabdomyosarcoma. 
     
     
         17 . The method of  claim 16 , wherein the cancer is selected from the group consisting of: breast cancer; lung cancer; and colorectal cancer. 
     
     
         18 . The method of  claim 13 , wherein the sample is a tissue sample. 
     
     
         19 . The method of  claim 13 , wherein the sample is a blood sample. 
     
     
         20 . The method of  claim 13 , wherein the microarray comprises miRNA-specific probes oligonucleotides for a substantial portion of the human miRNome.