Methods and processes for non-invasive assessment of genetic variations

1. A method for enriching cancer nucleic acid from a biological sample comprising cancer cells from a subject, wherein the sample nucleic acid comprises a first histone-associated nucleic acid species and a second histone-associated nucleic acid species, the method comprising, wherein the second histone-associated nucleic acid species is cancer nucleic acid:

(a) contacting a cell-free circulating sample nucleic acid from a biological sample from a subject with an agent that specifically binds to a histone associated with normal nucleic acid species, wherein the histone is a H1 histone;

which sample nucleic acid comprises a normal nucleic acid species and a tumor-derived nucleic acid species, wherein the histone H1 is H1.0 or H1b, and

separating the histone associated normal nucleic acid species from the sample nucleic acid, thereby producing a separation product that is enriched for cancer nucleic acid in the sample nucleic acid; or

b) contacting the cell-free circulating sample nucleic acid with an agent that specifically binds to a histone associated with the cancer nucleic acid species, wherein the histone is H3, wherein the histone H3 is H3.1, H3.2 or H3t, thereby enriching the cancer nucleic acid.

2. The method of claim 1 , wherein the biological sample comprises cancer and non-cancer cells.

3. The method of claim 1 , comprising (c) performing an assay to analyze nucleic acid in the separation product.

4. The method of claim 1 , wherein the method step a) further comprises i) isolating cell free nucleic acids that are not bound to the agent that specifically binds to the H1 histone, and ii) contacting the isolated cell free nucleic acids from i) with an agent that specifically binds to H3.

5. The method of claim 1 , wherein the H3 histone is methylated, or the H1 histone is unmethylated.

6. The method of claim 1 , wherein the agent is an antibody.

7. The method of claim 1 , wherein the a) contacting the sample nucleic acid with the agent involves immunoprecipitation.

8. The method of claim 1 , wherein the biological sample comprises a blood sample, a serum sample, or a plasma sample.

9. The method of claim 1 , wherein obtaining the sample nucleic acid comprises subjecting the biological sample to an in vitro process that isolates the sample nucleic acid from other sample components.

10. The method of claim 1 , wherein the separation product comprises about 50% or greater second histone-associated nucleic acid species.

11. The method of claim 3 , wherein the assay for analyzing nucleic acid in the separation product comprises use of a sequencing process.

12. The method of claim 3 , wherein the assay detects the presence or absence of a genetic variation according to the assay performed in (c).

13. The method of claim 2 , wherein the cancer cells are from a cancer selected from the group consisting of a breast cancer, a colorectal cancer, a gastrointestinal cancer, a hepatocellular cancer, a lung cancer, melanoma, non-Hodgkin lymphoma, leukemia, multiple myeloma, a bladder cancer, hepatoma, a cervical cancer, an esophageal cancer, a pancreatic cancer, or a prostate cancer.

14. A method for enriching tumor-derived nucleic acid species from a biological sample comprising cancer cells from a subject,

(a) contacting a cell-free circulating sample nucleic acid from a biological sample from a subject with a first agent that specifically binds to a histone associated with the first histone-associated nucleic acid species,

wherein the histone is an H1 histone, wherein the histone H1 is H1.0 or H1b;

(b) separating the first histone-associated nucleic acid species that is bound to the agent away from the sample nucleic acid, thereby producing a separation product, wherein the separation product is enriched with second histone-associated nucleic acid species; and

(c) contacting the separation product with a second agent that specifically binds to a histone associated with the second histone-associated nucleic acid species, wherein the histone is an H3 histone, wherein the histone H3 is H3.1, H3.2, or H3t.