Person: Lohr, Jens
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Publication Whole exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer
(2014) Lohr, Jens; Adalsteinsson, Viktor A.; Cibulskis, Kristian; Choudhury, Atish; Rosenberg, Mara; Cruz-Gordillo, Peter; Francis, Joshua; Zhang, Cheng-Zhong; Shalek, Alex K.; Satija, Rahul; Trombetta, John T.; Lu, Diana; Tallapragada, Naren; Tahirova, Narmin; Kim, Sora; Blumenstiel, Brendan; Sougnez, Carrie; Lowe, Alarice; Wong, Bang; Auclair, Daniel; Van Allen, Eliezer; Nakabayashi, Mari; Lis, Rosina T.; Lee, Gwo-Shu M.; Li, Tiantian; Chabot, Matthew S.; Ly, Amy; Taplin, Mary-Ellen; Clancy, Thomas; Loda, Massimo; Regev, Aviv; Meyerson, Matthew; Hahn, William; Kantoff, Philip; Golub, Todd; Getz, Gad; Boehm, Jesse S.; Love, J. ChristopherComprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic.
Publication Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors
(Nature Publishing Group UK, 2017) Adalsteinsson, Viktor A.; Ha, Gavin; Freeman, Sam; Choudhury, Atish D.; Stover, Daniel G.; Parsons, Heather; Gydush, Gregory; Reed, Sarah C.; Rotem, Denisse; Rhoades, Justin; Loginov, Denis; Livitz, Dimitri; Rosebrock, Daniel; Leshchiner, Ignaty; Kim, Jaegil; Stewart, Chip; Rosenberg, Mara; Francis, Joshua M.; Zhang, Cheng-Zhong; Cohen, Ofir; Oh, Coyin; Ding, Huiming; Polak, Paz; Lloyd, Max; Mahmud, Sairah; Helvie, Karla; Merrill, Margaret S.; Santiago, Rebecca A.; O’Connor, Edward P.; Jeong, Seong H.; Leeson, Rachel; Barry, Rachel M.; Kramkowski, Joseph F.; Zhang, Zhenwei; Polacek, Laura; Lohr, Jens; Schleicher, Molly; Lipscomb, Emily; Saltzman, Andrea; Oliver, Nelly M.; Marini, Lori; Waks, Adrienne; Harshman, Lauren C.; Tolaney, Sara M.; Van Allen, Eliezer; Winer, Eric P.; Lin, Nancy U.; Nakabayashi, Mari; Taplin, Mary-Ellen; Johannessen, Cory M.; Garraway, Levi; Golub, Todd; Boehm, Jesse S.; Wagle, Nikhil; Getz, Gad; Love, J. Christopher; Meyerson, MatthewWhole-exome sequencing of cell-free DNA (cfDNA) could enable comprehensive profiling of tumors from blood but the genome-wide concordance between cfDNA and tumor biopsies is uncertain. Here we report ichorCNA, software that quantifies tumor content in cfDNA from 0.1× coverage whole-genome sequencing data without prior knowledge of tumor mutations. We apply ichorCNA to 1439 blood samples from 520 patients with metastatic prostate or breast cancers. In the earliest tested sample for each patient, 34% of patients have ≥10% tumor-derived cfDNA, sufficient for standard coverage whole-exome sequencing. Using whole-exome sequencing, we validate the concordance of clonal somatic mutations (88%), copy number alterations (80%), mutational signatures, and neoantigens between cfDNA and matched tumor biopsies from 41 patients with ≥10% cfDNA tumor content. In summary, we provide methods to identify patients eligible for comprehensive cfDNA profiling, revealing its applicability to many patients, and demonstrate high concordance of cfDNA and metastatic tumor whole-exome sequencing.