Consensus Coding Sequences of Human Breast and Colorectal Cancers

Abstract

Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ˜90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.

1 . A method of treating a breast cancer in a human, comprising the steps of:
 determining in a test sample relative to a normal sample of the human, a somatic mutation in a gene or its encoded cDNA or protein, said gene selected from the group consisting of those listed in  FIG. 13  (Table S 5 );   identifying the sample as breast cancer when the somatic mutation is determined; and   administering a medical intervention to the human when the human is identified as having the somatic mutation in the test sample.   
     
     
         2 . The method of  claim 1  wherein the mutation is selected from those shown in  FIG. 12  (Table S 4 ). 
     
     
         3 . The method of  claim 1  wherein the gene is selected from the group consisting of: gelsolin GSN, cadherin genes CDH10 and CDH20, actin and SMAD binding protein filamin B FLNB, and autocrine motility factor receptor AMFR. 
     
     
         4 . The method of  claim 1  wherein the gene is selected from the group consisting of: ATP-dependent transporter ATP8B1, intrinsic factor-cobalamin receptor CUBN, actin binding protein DBN1, and tectorin alpha TECTA. 
     
     
         5 . The method of  claim 1  wherein the test sample is a breast tissue sample or a suspected breast cancer metastasis. 
     
     
         6 . The method of  claim 1  wherein the normal sample is a breast tissue sample. 
     
     
         7 - 12 . (canceled) 
     
     
         13 . A method for testing a candidate or known anti-cancer therapeutic, comprising the steps of:
 determining a CAN-gene mutational signature for a breast cancer by determining at least one somatic mutation in a test sample relative to a normal sample of a human, wherein the at least one somatic mutation is in one or more genes selected from the group consisting of  FIG. 13  (Table S 5 );   forming a first group of breast cancers that have the CAN-gene mutational signature;   comparing efficacy of the candidate or known anti-cancer therapeutic on the first group to efficacy on a second group of breast cancers that has a different CAN-gene mutational signature;   identifying a CAN gene mutational signature which correlates with increased or decreased efficacy of the candidate or known anti-cancer therapeutic relative to other groups.   
     
     
         14 . The method of  claim 13  wherein the at least one mutation is selected from those shown in  FIG. 12  (Table S 4 ). 
     
     
         15 . The method of  claim 13  wherein the at least one mutation is in one or more genes selected from the group consisting of: gelsolin GSN, cadherin genes CDH10 and CDH20, actin and SMAD binding protein filamin B FLNB, and autocrine motility factor receptor AMFR. 
     
     
         16 . The method of  claim 13  wherein the at least one mutation is in one or more genes selected from the group consisting of: ATP-dependent transporter ATP8B1, intrinsic factor-cobalamin receptor CUBN, actin binding protein DBN1, and tectorin alpha TECTA. 
     
     
         17 . The method of  claim 13  wherein the test sample is a breast tissue sample. 
     
     
         18 . The method of  claim 13  wherein the normal sample is a breast tissue sample. 
     
     
         19 . The method of  claim 13  wherein the CAN-gene mutational signature comprises at least 2 genes selected from  FIG. 13  (Table S 5 ) 
     
     
         20 . The method of  claim 13  wherein the CAN-gene mutational signature comprises at least 3 genes selected from  FIG. 13  (Table S 5 ). 
     
     
         21 . The method of  claim 13  wherein the CAN-gene mutational signature comprises at least 4 genes selected from  FIG. 13  (Table S 5 ). 
     
     
         22 . The method of  claim 13  wherein the CAN-gene mutational signature comprises at least 5 genes selected from  FIG. 13  (Table S 5 ). 
     
     
         23 . The method of  claim 13  wherein the CAN-gene mutational signature comprises at least 6 genes selected from  FIG. 13  (Table S 5 ). 
     
     
         24 . The method of  claim 13  wherein the CAN-gene mutational signature comprises at least 7 genes selected from  FIG. 13  (Table S 5 ). 
     
     
         25 - 48 . (canceled)