Combinatorial DNA screening
The present disclosure relates to methods for detecting unique genetic signatures derived from markers such as, for example, mutations, somatic or germ-line, in nucleic acids obtained from biological samples. The sensitivity of the methods provides for detection of mutations associated with a disease, e.g., cancer mutations, or with inherited disease, e.g., an autosomal recessive disease, in a noninvasive manner at ultra-low proportions of sequences carrying mutations to sequences carrying normal, e.g., non-cancer sequences, or a reference sequence, e.g., a human reference genome.
1. A method for treating a patient with a tumor therapy, the method comprising
determining a tumor fraction associated with a solid tumor of the patient, wherein determining the tumor fraction comprises
(a) screening genomic DNA from the solid tumor to identify a set of somatic mutations;
(b) identifying a subset of the somatic mutations to create a signature panel of mutations specific to the solid tumor, wherein the identification of the subset of the somatic mutations is based on a comparison of the screened genomic DNA from the solid tumor to genomic DNA from non-tumorigenic tissue; and
(c) screening a fluid sample of the patient for the signature panel of mutations, wherein the screening comprises sequencing DNA from the fluid sample, the fluid sample comprising cell free DNA, and wherein sequence reads obtained from the sequencing are used to ascertain the proportion of circulating tumor DNA in the fluid sample comprising cell free DNA from the patient, thereby determining the tumor fraction in the patient;
determining, based on the tumor fraction, a presence of the solid tumor in the patient; and,
in response to determining the presence of the solid tumor in the patient, administering a tumor therapy to the patient.
2. The method of claim 1 , wherein step (a) comprises screening matched tumor and non-tumor tissue from the patient.
3. The method of claim 1 , wherein identifying the set of somatic mutations and the subset of somatic mutations comprises whole genome sequencing or targeted sequencing.
4. The method of claim 3 , wherein the targeted sequencing is to introns, exons or a combination thereof.
5. The method of claim 1 , wherein screening the fluid sample for the signature panel of mutations comprises targeted sequencing of the subset of somatic mutations.
6. The method of claim 1 , further comprising screening a second fluid sample of the patient for the signature panel of mutations at one or more times during treatment to determine efficacy of the treatment.
7. The method of claim 1 , further comprising screening a second fluid sample of the patient for the signature panel of mutations at one or more times following completion of treatment to determine recurrence of the solid tumor.
8. The method of claim 1 , wherein the mutations in the signature panel of mutations comprise one or more mutations selected from SNPs, insertions, deletions, and translocations.
9. The method of claim 1 , wherein the cell free DNA is obtained from a blood sample of the patient.
10. The method of claim 9 , wherein the cell free DNA is obtained from blood plasma.
11. The method of claims 1 , wherein the tumor therapy comprises chemotherapy, radiation therapy, or a combination thereof.