A method of extracting nucleic acid from a biological sample, comprising the steps of: (a) providing a biological sample obtained from a subject, wherein the sample comprises a heterogeneous collection of nucleic acid containing materials comprising cells or microvesicles, or both; (b) performing a sample pre-processing step on the biological sample to obtain a fraction comprising the heterogeneous collection of nucleic acid-containing materials, wherein the pre-processing step excludes protein, lipids, debris from dead cells and other potential contaminants and PCR inhibitors from the heterogeneous nucleic acid containing materials; (c) performing an affinity exclusion operation by contacting the heterogeneous collection of nucleic acid-containing materials with an affinity agent that binds a surface marker and removing nucleic acid-materials that bind to the affinity agent to deplete nucleic acid-containing materials originating from a specific donor type cell or a specific tumor cell type, followed by an extraction enhancement operation, wherein the surface marker is a tumor marker selected from the markers listed in Table 2, and wherein the extraction enhancement operation comprises use of an agent selected from the group consisting of an RNase inhibitor, a protease, a reducing agent, a decoy substrate, a soluble receptor, a small interfering RNA, an RNA binding molecule, a RNase denaturing substance, and any combination thereof, in combination with a processing step selected from the group consisting of washing of the nucleic acid-containing materials; size separation of RNases from the biological sample; denaturation of proteins in the biological sample; and combinations thereof; and (d) extracting nucleic acid from the resulting materials. (a) providing a biological sample obtained from a subject, wherein the sample comprises a heterogeneous collection of nucleic acid containing materials comprising cells or microvesicles, or both; (b) performing a sample pre-processing step on the biological sample to obtain a fraction comprising the heterogeneous collection of nucleic acid-containing materials, wherein the pre-processing step excludes protein, lipids, debris from dead cells and other potential contaminants and PCR inhibitors from the heterogeneous nucleic acid containing materials; (c) performing an affinity exclusion operation by contacting the heterogeneous collection of nucleic acid-containing materials with an affinity agent that binds a surface marker and removing nucleic acid-materials that bind to the affinity agent to deplete nucleic acid-containing materials originating from a specific donor type cell or a specific tumor cell type, followed by an extraction enhancement operation, wherein the surface marker is a tumor marker selected from the markers listed in Table 2, and wherein the extraction enhancement operation comprises use of an agent selected from the group consisting of an RNase inhibitor, a protease, a reducing agent, a decoy substrate, a soluble receptor, a small interfering RNA, an RNA binding molecule, a RNase denaturing substance, and any combination thereof, in combination with a processing step selected from the group consisting of washing of the nucleic acid-containing materials; size separation of RNases from the biological sample; denaturation of proteins in the biological sample; and combinations thereof; and (d) extracting nucleic acid from the resulting materials. <EOS>