Integrated Analyses of Breast and Colorectal Cancers

Abstract

Genome-wide analysis of copy number changes in breast and colorectal tumors used approaches that can reliably detect homozygous deletions and amplifications. The number of genes altered by major copy number changes—deletion of all copies or amplification of at least twelve copies per cell—averaged thirteen per tumor. These data were integrated with previous mutation analyses of the Reference Sequence genes in these same tumor types to identify genes and cellular pathways affected by both copy number changes and point alterations. Pathways enriched for genetic alterations include those controlling cell adhesion, intracellular signaling, DNA topological change, and cell cycle control. These analyses provide an integrated view of copy number and sequencing alterations on a genome-wide scale and identify genes and pathways that are useful for cancer diagnosis and therapy.

1 . A method of characterizing a breast or colon tumor in a human, comprising the steps of:
 determining a mutated pathway selected from those listed in Table 3 or SI Table 6 in a breast or colon tumor sample by determining at least one somatic mutation in a gene in the pathway in a test sample relative to a normal sample of the human;   assigning the breast or colon tumor to a first group of breast or colon tumors that have a somatic mutation in a gene in said pathway.   
     
     
         2 . The method of  claim 1  wherein the first group comprises tumors with mutations in a plurality of genes in said pathway. 
     
     
         3 . The method of  claim 1  wherein the first group consists of tumors with mutation in a gene in said pathway. 
     
     
         4 . The method of  claim 1  wherein a mutation is determined by DNA sequencing. 
     
     
         5 . The method of  claim 1  wherein a mutation is determined by DNA sequencing in which a polymerase or ligase enzyme is used to join together nucleotides and oligonucleotides complementary to the gene. 
     
     
         6 . The method of  claim 1  wherein a mutation is determined by DNA sequencing in which a single stranded DNA molecule obtained from the gene is hybridized to a single stranded DNA reagent. 
     
     
         7 . The method of  claim 1  wherein a mutation is determined by DNA sequencing in which DNA molecules are separated by length or mass. 
     
     
         8 . The method of  claim 1  wherein a mutation is determined by DNA sequencing employing a dideoxynucleotide inhibitor. 
     
     
         9 . The method of  claim 1  wherein a mutation is determined by DNA sequencing in an automated sequencing machine. 
     
     
         10 . The method of  claim 1  further comprising the steps of:
 administering a drug or drug candidate to the first group.   
     
     
         11 . The method of  claim 10  further comprising the steps of:
 administering a drug or drug candidate to a second group of breast or colon tumors that does not have a mutation is said pathway.   
     
     
         12 . The method of  claim 11  further comprising the steps of:
 comparing efficacy of the drug or drug candidate on the first group to efficacy on the second group;   identifying a pathway which correlates with increased or decreased efficacy of the drug or candidate drug in the first group relative to the second group.   
     
     
         13 . The method of  claim 1  further comprising the steps of:
 comparing efficacy of a candidate or known anti-cancer therapeutic on the first group to efficacy on a second group of breast or colon tumors that does not have a mutation is said pathway;   identifying a pathway which correlates with increased or decreased efficacy of the candidate or known anti-cancer therapeutic in the first group relative to other groups.   
     
     
         14 . The method of  claim 1  wherein the mutation is selected from the group consisting of a point mutation, a homozygous deletion, and a genomic amplification. 
     
     
         15 . A method of detecting or diagnosing a breast or colon tumor or minimal residual disease of a breast or colon tumor or molecular relapse of a breast or colon tumor in a human, comprising the steps of:
 determining in a test sample of a tumor or suspected tumor of the human, a genomic amplification of at least one genomic region, said genomic region selected from the group consisting of those listed in SI Table 4 or Table 1;   identifying the human as likely to have a breast or colon tumor, minimal residual disease, or molecular relapse of breast or colon tumor when the amplification is determined.   
     
     
         16 . The method of  claim 15  wherein genomic amplification is determined by generating fragments of genomic DNA from the test sample, ligating the fragments into a concatenate, and sequencing the concatenate. 
     
     
         17 . The method of  claim 15  wherein genomic amplification is determined by hybridizing genomic DNA from the test sample to an array of oligonucleotides. 
     
     
         18 . The method of  claim 15  wherein the genomic amplification is at least 6-fold increased relative to a normal sample of the human. 
     
     
         19 . A method of detecting or diagnosing a breast or colon tumor or minimal residual disease of a breast or colon tumor or molecular relapse of a breast or colon tumor in a human, comprising the steps of:
 determining in a test sample of a tumor or suspected tumor of the human, a genomic deletion of at least one genomic region, said genomic region selected from the group consisting of those listed in SI Table 5 or Table 2;   identifying the human as likely to have a breast or colon tumor, minimal residual disease, or molecular relapse of breast or colon tumor when the homozygous deletion is determined.   
     
     
         20 . The method of  claim 19  wherein genomic deletion is determined by generating fragments of genomic DNA from the test sample, ligating the fragments into a concatenate, and sequencing the concatenate. 
     
     
         21 . The method of  claim 19  wherein genomic deletion is determined by hybridizing genomic DNA from the test sample to an array of oligonucleotides. 
     
     
         22 . The method of  claim 19  wherein the genomic deletion is homozygous.