Validation of CHIP-associated mutations in hematopoietic elements. (A-B) A lung adenocarcinoma (A) and a lung squamous cell carcinoma (SCC) (B) were synchronously diagnosed in patient 11. Both specimens had extensive lymphocyte infiltration. CGP revealed distinct genomic alterations in each tumor except for identical genomic alterations in TET2 and DNMT3A. (C) A lymph node biopsy without histologic evidence of tumor was macrodissected to confirm the presence of CHIP mutations. (A-C) hematoxylin and eosin stain; scale bars represent 200 μm. (D) The same TET2 and DNMT3A genomic alterations were detected at a VAF of 1.5% and 1.7%, respectively, confirming their presence in hematopoietic elements; 3D scatter plot shows genomic alterations in all 3 samples with their respective VAFs. (E) Peripheral blood samples were available for 13 patients with TET2 and DNMT3A genomic alterations at VAFs lower than expected from purity. In 10 patients, targeted deep sequencing detected the identical genomic alterations in blood that were present in the associated solid tumor. There was no statistical difference between the VAFs of alteration in peripheral blood and solid tumor specimen (rank-sum P = .38). For the other 3 patients, we detected the genomic alterations in the macrodissected tumor cells enriched from the original samples, while the genomic alterations were absent or at significantly lower level in enriched macrodissected lymphocytes (supplemental Figures 7-9). (F) In the peripheral blood of only 1 of 7 sequenced patients with clonal TET2 and/or DNMT3A mutations, a genomic alteration previously found in the original solid tumor was detected (supplemental Figure 10).