Methods of diagnosing and treating cancer targeting extrachromosomal DNA
Provided herein are, inter alia, methods and compositions to detect, monitor and treat cancer, wherein the cancer includes amplified extrachromosomal oncogenes. The methods are useful for personalized treatment and exploit differential expression of amplified extrachromosomal oncogenes in cancer cells versus healthy cells.
1. A method of detecting an amplified extrachromosomal oncogene in a human subject in need thereof, said method comprising:
(i) obtaining a biological sample from a human subject;
(ii) sequencing the genome of said human subject from said biological sample;
(iii) detecting whether an amplified extrachromosomal oncogene is present in said biological sample; and,
(iv) determining the number of circular extrachromosomal DNA (ecDNA) particles per cancer cell.
2. The method of claim 1 , wherein said amplified extrachromosomal oncogene forms part of a circular extrachromosomal DNA.
3. The method of claim 1 , wherein said detecting comprises:
(1) detecting an intracellular location of said amplified extrachromosomal oncogene relative to a standard control;
(2) mapping said circular extrachromosomal DNA; and
(3) detecting genetic heterogeneity of said circular extrachromosomal DNA relative to a standard control.
4. A method of detecting an amplified extrachromosomal oncogene in a cancer subject undergoing treatment for cancer, said method comprising:
(i) obtaining a first biological sample from said cancer subject undergoing treatment for cancer; and
(ii) sequencing the genome of said human subject from said biological sample;
(iii) detecting in said first biological sample a first level of an amplified extrachromosomal oncogene; and,
(iv) determining the number of circular extrachromosomal DNA (ecDNA) particles per cancer cell.
5. The method of claim 4 comprising after step (ii)-(iv):
(v) obtaining a second biological sample from said subject;
(vi) detecting in said second biological sample a second level of said amplified extrachromosomal oncogene;
(vii) determining the number of circular extrachromosomal DNA (ecDNA) particles per cell in said second biological sample; and,
(viii) comparing said first level to said second level.
6. The method of claim 4 , wherein said amplified extrachromosomal oncogene forms part of a circular extrachromosomal DNA.
7. The method of claim 5 , wherein said detecting comprises:
(1) detecting an intracellular location of said amplified extrachromosomal oncogene relative to a standard control;
(2) detecting a level of said circular extrachromosomal DNA relative to a standard control;
(3) mapping said circular extrachromosomal DNA; and
(4) detecting genetic heterogeneity of said circular extrachromosomal DNA.
8. The method of claim 1 , wherein said biological sample is a blood-derived biological sample, a urine-derived biological sample, a tumor sample, or a tumor fluid sample.
9. The method of claim 1 , wherein said determining the number of circular extrachromosomal DNA (ecDNA) particles per cell comprises preparing metaphase spreads of cells from said biological sample.
10. The method of claim 1 , wherein said amplified extrachromosomal oncogene is EGFR, c-Myc, N-Myc, cyclin D1, ErbB2, CDK4, CDK6, BRAF, MDM2, or MDM4.