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Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine
Open accessPublished version of a preprint
Abstract
Clinically relevant subtypes exist for pancreatic ductal adenocarcinoma (PDAC), but molecular characterization is not yet standard in clinical care. We implemented a biopsy protocol to perform time-sensitive whole-exome sequencing and RNA sequencing for patients with advanced PDAC. Therapeutically relevant genomic alterations were identified in 48% (34/71) and pathogenic/likely pathogenic germline alterations in 18% (13/71) of patients. Overall, 30% (21/71) of enrolled patients experienced a change in clinical management as a result of genomic data. Twenty-six patients had germline and/or somatic alterations in DNA-damage repair genes, and 5 additional patients had mutational signatures of homologous recombination deficiency but no identified causal genomic alteration. Two patients had oncogenic in-frame BRAF deletions, and we report the first clinical evidence that this alteration confers sensitivity to MAPK pathway inhibition. Moreover, we identified tumor/stroma gene expression signatures with clinical relevance. Collectively, these data demonstrate the feasibility and value of real-time genomic characterization of advanced PDAC. Significance: Molecular analyses of metastatic PDAC tumors are challenging due to the heterogeneous cellular composition of biopsy specimens and rapid progression of the disease. Using an integrated multidisciplinary biopsy program, we demonstrate that real-time genomic characterization of advanced PDAC can identify clinically relevant alterations that inform management of this difficult disease. Cancer Discov; 8(9); 1096–111. ©2018 AACR. See related commentary by Collisson, p. 1062. This article is highlighted in the In This Issue feature, p. 1047
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“there are also so-called “alternative drivers” found in the 8–10% of cases that are KRAS wild type104,105.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [105]
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Metadata
- Authors
- Aguirre, A. J., Nowak, J. A., Camarda, N. D., Moffitt, R. A., Ghazani, A. A., Hazar-Rethinam, M., Raghavan, S., Kim, J., Brais, L. K., Ragon, D., Welch, M. W., Reilly, E., McCabe, D., Marini, L., Anderka, K., Helvie, K., Oliver, N., Babic, A., Da Silva, A., Nadres, B., Van Seventer, E. E., Shahzade, H. A., St. Pierre, J. P., Burke, K. P., Clancy, T., Cleary, J. M., Doyle, L. A., Jajoo, K., McCleary, N. J., Meyerhardt, J. A., Murphy, J. E., Ng, K., Patel, A. K., Perez, K., Rosenthal, M. H., Rubinson, D. A., Ryou, M., Shapiro, G. I., Sicinska, E., Silverman, S. G., Nagy, R. J., Lanman, R. B., Knoerzer, D., Welsch, D. J., Yurgelun, M. B., Fuchs, C. S., Garraway, L. A., Getz, G., Hornick, J. L., Johnson, B. E., Kulke, M. H., Mayer, R. J., Miller, J. W., Shyn, P. B., Tuveson, D. A., Wagle, N., Yeh, J. J., Hahn, W. C., Corcoran, R. B., Carter, S. L., & Wolpin, B. M.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Stony Brook University (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- 1Dana-Farber Cancer Institute, Boston, Massachusetts.
- 9Massachusetts General Hospital Cancer Center, Boston, Massachusetts.
- Guardant (United States) (US)
- 14BioMed Valley Discoveries, Kansas City, Missouri.
- Harvard University (US)
- Cold Spring Harbor Laboratory (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Aguirre, Andrew J.
- Carter, Scott L.
- Wolpin, Brian M.
- ORCID
- Aguirre, Andrew J.
- Nowak, Jonathan A.
- Camarda, Nicholas D.
- Moffitt, Richard A.
- Ghazani, Arezou A.
- Hazar-Rethinam, Mehlika
- Raghavan, Srivatsan
- Kim, Jaegil
- Brais, Lauren K.
- Reilly, Emma
- McCabe, Devin
- Helvie, Karla
- Nadres, Brandon
- Burke, Kelly P.
- Clancy, Thomas
- Cleary, James M.
- Doyle, Leona A.
- McCleary, Nadine J.
- Meyerhardt, Jeffrey A.
- Ng, Kimmie
- Patel, Anuj K.
- Perez, Kimberly
- Rosenthal, Michael H.
- Rubinson, Douglas A.
- Ryou, Marvin
- Shapiro, Geoffrey I.
- Silverman, Stuart G.
- Nagy, Rebecca J.
- Lanman, Richard B.
- Knoerzer, Deborah
- Yurgelun, Matthew B.
- Fuchs, Charles S.
- Garraway, Levi A.
- Getz, Gad
- Hornick, Jason L.
- Johnson, Bruce E.
- Kulke, Matthew H.
- Mayer, Robert J.
- Miller, Jeffrey W.
- Shyn, Paul B.
- Tuveson, David A.
- Wagle, Nikhil
- Yeh, Jen Jen
- Hahn, William C.
- Corcoran, Ryan B.
- Carter, Scott L.
- Wolpin, Brian M.
- Venue
- Cancer Discovery
- Published
- 2018-09-01
- Volume
- 8
- Issue
- 9
- Pages
- 1096-1111
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6192263
- OpenAlex
- W2808191072
- Cited by
- 367
- References
- 55
- Citations by year
- 2026: 17 · 2025: 38 · 2024: 38 · 2023: 48 · 2022: 58 · 2021: 70 · 2020: 52 · 2019: 34 · 2018: 10
- FWCI
- 15.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Lustgarten Foundation
- Noble Effort Fund
- Peter R. Leavitt Family Fund
- Wexler Family Fund
- Promises for Purple
- HHS | NIH | National Cancer Institute (NCI) (P50CA127003, U01CA224146, U01CA210171, R01CA199064, K08CA2118420-01)
- Pancreatic Cancer Action Network (PanCAN)
- Hale Center for Pancreatic Cancer Research, Dana-Farber Cancer Institute
- Hope Funds for Cancer Research
- Doris Duke Charitable Foundation (DDCF)
- Conquer Cancer Foundation (CCF)
- Broman Fund for Pancreatic Cancer Research
- Harvard Clinical and Translational Sciences Center (UL1 TR001102)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- pancreatic ductal adenocarcinoma, advanced pancreatic cancer, precision medicine, exome sequencing, RNA sequencing, germline alterations, somatic alterations, DNA repair genes, homologous recombination deficiency, mutational signatures, MAPK inhibition, biopsy protocol, metastatic cancer
- MeSH terms
- Exome Sequencing, Adult, Aged, Aged, 80 and over, DNA Repair, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms, Genetic Variation, Gene Expression Regulation, Neoplastic, Sequence Analysis, RNA, Germ-Line Mutation, Gene Expression Profiling, MAP Kinase Signaling System, Carcinoma, Pancreatic Ductal, Genomics, Gene Regulatory Networks, Precision Medicine, Homologous Recombination
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