Method for determining the likelihood that a subject has or will develop cancer

Abstract

A method determines the likelihood that a subject has or will develop cancer. The method is based on identifying whether targeted somatic mutagenesis of a nucleic acid molecule by a mutagenic agent has occurred. The mutations are at one or more motifs recognized or targeted by the mutagenic agent such as AID, an APOBEC cytidine deaminase or aflatoxin, The nucleic acid molecule includes the whole exome. The cancer can be any of breast, prostate, liver, colon, pancreatic, skin, cervical, lymphoid, hematopoietic and ovarian cancer; and the biological sample comprises, respectively, breast, prostate, liver, colon, pancreatic, skin, cervical, lymphoid, hematopoietic or ovarian tissue or cells.

What is claimed is: 
     
         1 . A method for determining the likelihood that a subject has or will develop cancer, comprising:
 obtaining a nucleic acid molecule from a biological sample from a subject; detecting in the sequence of the nucleic acid molecule, for a plurality of mutations, the mutation type and the codon context of an individual mutation, wherein the codon context of an individual mutation is determined by determining at which of the three positions of a corresponding mutated codon the individual mutation occurs; detecting the occurrence of targeted somatic mutagenesis, wherein targeted somatic mutagenesis has occurred when there is a higher than expected percentage or number of mutations of a mutation type at one of three positions in a codon in a plurality of mutated codons; and   determining that the subject is likely to have or to develop cancer when targeted somatic mutagenesis has occurred; wherein:   the mutations are at one or more motifs recognized or targeted by a mutagenic agent selected from the group consisting of AID, an APOBEC cytidine deaminase and aflatoxin;   the nucleic acid molecule comprises the whole exome; and   the cancer is selected from the group consisting of breast, prostate, liver, colon, pancreatic, skin, cervical, lymphoid, hematopoietic and ovarian cancer; and the biological sample comprises, respectively, breast, prostate, liver, colon, pancreatic, skin, cervical, lymphoid, hematopoietic or ovarian tissue or cells.   
     
     
         2 . The method of  claim 1 , wherein the mutagenic agent is AID and the number or percentage of observed G>A mutations in GYW motifs at MC-2 sites, the number or percentage of observed A>G mutations in WA motifs at MC-2 sites, or C>T mutations in WRC motifs at MC-1 sites in the non-transcribed strand of the nucleic acid molecule is higher than expected. 
     
     
         3 . The method of  claim 1 , wherein the mutagenic agent is APOBEC3G if the number or percentage of observed G>A mutations in CG motifs at MC-2 sites, C>T mutations in CG motifs at MC-1 sites or the number or percentage of observed C>T mutations in CC motifs at MC-1 sites in the non-transcribed strand of the nucleic acid molecule is higher than expected. 
     
     
         4 . The method of  claim 1 , wherein the mutagenic agent is APOBEC1 if the number or percentage of observed C>T mutations in CA motifs at MC-1 sites or G>A mutations in TG motifs at MC-2 sites in the non-transcribed strand of the nucleic acid molecule is higher than expected. 
     
     
         5 . The method of  claim 1 , wherein the mutagenic agent is APOBEC3H if the number or percentage of observed G>A mutations in GA motifs at MC-1 sites in the non-transcribed strand of the nucleic acid molecule is higher than expected. 
     
     
         6 . The method of  claim 1 , wherein the mutagenic agent is aflatoxin if the number or percentage of observed G>T mutations in GG motifs at MC-3 sites in the non-transcribed strand of the nucleic acid molecule is higher than expected.