Methods and compositions for detection of Cowden Syndrome (CS) and CS-like syndrome

Abstract

In one aspect, the invention is directed to a method of detecting Cowden syndrome (CS) or CS-like syndrome in an individual comprising detecting the presence of a mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof in the individual, wherein detection of a mutated SDHB, SDHD or a combination thereof indicates that the individual is positive for CS or CS-like syndrome. In another aspect, the invention is directed to a method of determining whether an individual is at risk for developing Cowden syndrome (CS) or CS-like syndrome comprising detecting the presence of a mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof in the individual, wherein detection of a mutated SDHB, SDHD or a combination thereof indicates that the individual is at risk for developing for CS or CS-like syndrome. In yet another aspect, the invention is directed to an article of manufacture for detecting Cowden syndrome (CS) or Cowden-like syndrome in an individual, comprising one or more agents that detects mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof in the individual, and instructions for use.

1 . A method of detecting Cowden syndrome (CS) or CS-like syndrome in an individual comprising detecting the presence of a mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof in the individual, wherein detection of a mutated SDHB, SDHD or a combination thereof indicates that the individual is positive for CS or CS-like syndrome. 
     
     
         2 . The method of  claim 1  wherein the mutated SDHB is an Ala3Gly mutation, a Ser163Pro mutation or a combination thereof. 
     
     
         3 . The method of  claim 1  wherein the mutated SDHD is a Gly12Ser mutation, a His50Arg mutation, a His145Asn mutation or a combination thereof. 
     
     
         4 . The method of  claim 1  wherein the individual is negative for a mutated phosphatase and tensin homolog deleted on chromsome ten (PTEN). 
     
     
         5 . The method of  claim 4  wherein the individual has elevated expression levels of maganese superoxide dismutase. 
     
     
         6 . The method of  claim 1  wherein the individual has a carcinoma of the breast, thyroid, kidney or a combination thereof. 
     
     
         7 . The method of  claim 6  wherein the thyroid carcinoma is a papillary thyroid carcinoma. 
     
     
         8 . The method of  claim 6  wherein the kidney carcinoma is a renal cell carcinoma. 
     
     
         9 . The method of  claim 1  wherein the presence of a mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof is detected in the individual by determining:
 the sequence of the SDHB, SDHD or combination thereof,   the function of the SDHB, SDHD or combination thereof,   or the sequence and the function.   
     
     
         10 . The method of  claim 9  wherein the sequence of the SDHB, SDHD or combination thereof is determined using polymerase chain reaction amplification and direct sequencing. 
     
     
         11 . The method of  claim 9  wherein the function of the SDHB, SDHD or combination thereof is determined by measuring the production of reactive oxygen species (ROS) wherein an increase in the production of ROS indicates the presence of a mutated SDHB, SDHD or a combination thereof. 
     
     
         12 . The method of  claim 11  wherein the production of ROS is measured using carboxy-H2DCFDA and confocal microscopy. 
     
     
         13 . The method of  claim 9  wherein the function of SDHB, SDHD or a combination thereof is determined by detecting activation of an antiapoptotic/proproliferative AKT (protein kinase B) pathway, a mitogen-activated kinase (MAPK) pathway or a combination thereof. 
     
     
         14 . The method of  claim 13  wherein phosphorylated AKT, phosphorylated MAPK or a combination thereof is measured. 
     
     
         15 . The method of  claim 14  wherein the phosphorylated AKT or phosphorylated MAPK is measured using one or more antibodies having binding specificity for the phosphorylated AKT or the phosphorylated MAPK. 
     
     
         16 . The method of  claim 1  further comprising comparing the presence of a mutated SDHB, SDHD or combination thereof in the individual to a control. 
     
     
         17 . The method of  claim 16  wherein the control is SDHB or SDHD of a normal individual. 
     
     
         18 . The method of  claim 1  further comprising obtaining a sample from the individual. 
     
     
         19 . The method of  claim 18  wherein the sample is a blood sample. 
     
     
         20 . The method of  claim 1  wherein the individual is a human. 
     
     
         21 . A method of determining whether an individual is at risk for developing Cowden syndrome (CS) or CS-like syndrome comprising detecting the presence of a mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof in the individual, wherein detection of a mutated SDHB, SDHD or a combination thereof indicates that the individual is at risk for developing for CS or CS-like syndrome. 
     
     
         22 . The method of  claim 21  wherein the mutated SDHB is an Ala3Gly mutation, a Ser163Pro mutation or a combination thereof. 
     
     
         23 . The method of  claim 21  wherein the mutated SDHD is a Gly12Ser mutation, a His50Arg mutation, a His145Asn mutation or a combination thereof. 
     
     
         24 . The method of  claim 21  wherein the individual is negative for a mutated phosphatase and tensin homolog deleted on chromsome ten (PTEN). 
     
     
         25 . The method of  claim 24  wherein the individual has elevated expression levels of maganese superoxide dismutase. 
     
     
         26 . The method of  claim 21  wherein the individual has a carcinoma of the breast, thyroid, kidney or a combination thereof 
     
     
         27 . The method of  claim 26  wherein the thyroid carcinoma is a papillary thyroid carcinoma. 
     
     
         28 . The method of  claim 26  wherein the kidney carcinoma is a renal cell carcinoma. 
     
     
         29 . The method of  claim 21  wherein the presence of a mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof is detected in the individual by determining
 the sequence of the SDHB, SDHD or combination thereof,   the function of the SDHB, SDHD or combination thereof,   or both the sequence and the function.   
     
     
         30 . The method of  claim 29  wherein the sequence of the SDHB, SDHD or combination thereof is determined using polymerase chain reaction amplification and direct sequencing. 
     
     
         31 . The method of  claim 29  wherein the function of the SDHB, SDHD or combination thereof is determined by measuring the production of reactive oxygen species (ROS) wherein an increase in the production of ROS indicates the presence of a mutated SDHB, SDHD or a combination thereof. 
     
     
         32 . The method of  claim 31  wherein the production of ROS is measured using carboxy-H2DCFDA and confocal microscopy. 
     
     
         33 . The method of  claim 29  wherein the function of SDHB, SDHD or a combination thereof is determined by detecting activation of an antiapoptotic/proproliferative AKT (protein kinase B) pathway, a mitogen-activated kinase (MAPK) pathway or a combination thereof. 
     
     
         34 . The method of  claim 33  wherein phosphorylated AKT, phosphorylated MAPK or a combination thereof is measured. 
     
     
         35 . The method of  claim 34  wherein the phosphorylated AKT or phosphorylated MAPK is measured using one or more antibodies having binding specificity for the phosphorylated AKT or the phosphorylated MAPK. 
     
     
         36 . The method of  claim 21  further comprising comparing the presence of a mutated SDHB, SDHD or combination thereof in the individual to a control. 
     
     
         37 . The method of  claim 36  wherein the control is one or more samples from a normal individual. 
     
     
         38 . The method of  claim 21  further comprising obtaining a sample from the individual. 
     
     
         39 . The method of  claim 38  wherein the sample is a blood sample. 
     
     
         40 . The method of  claim 21  wherein the individual is a human. 
     
     
         41 . An article of manufacture for detecting Cowden syndrome (CS) or Cowden-like syndrome in an individual, comprising one or more agents that detects mutated succinate dehydrogenase B (SDHB), mutated succinate dehydrogenase D (SDHD) or combination thereof in the individual, and instructions for use. 
     
     
         42 . The article of manufacture of  claim 41  wherein the mutated SDHB is an Ala3Gly mutation, a Ser63Pro mutation or a combination thereof. 
     
     
         43 . The article of manufacture of  claim 41  wherein the mutated SDHD is a Gly12Ser mutation, a His50Arg mutation, a His145Asn mutation or a combination thereof. 
     
     
         44 . The article of manufacture of  claim 41  wherein the agent detects the sequence of the SDHB, SDHD or combination thereof. 
     
     
         45 . The article of manufacture of  claim 41  wherein the agent detects the production of reactive oxygen species (ROS). 
     
     
         46 . The article of manufacture of  claim 41  wherein the agent detects phosphorylated AKT, phosphorylated MAPK or a combination thereof. 
     
     
         47 . The article of manufacture of  claim 46  wherein the agent is one or more antibodies having binding specificity for the phosphorylated AKT, the phosphorylated MAPK or a combination thereof.