A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma

Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion-sampled metastatic pancreatic cancers, finding that squamous fea...

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Published in:	Nature cancer Vol. 1; no. 1; pp. 59 - 74
Main Authors:	Hayashi, Akimasa, Fan, Jun, Chen, Ruoyao, Ho, Yu-jui, Makohon-Moore, Alvin P., Lecomte, Nicolas, Zhong, Yi, Hong, Jungeui, Huang, Jinlong, Sakamoto, Hitomi, Attiyeh, Marc A., Kohutek, Zachary A., Zhang, Lance, Boumiza, Aida, Kappagantula, Rajya, Baez, Priscilla, Bai, Jessica, Lisi, Marta, Chadalavada, Kalyani, Melchor, Jerry P., Wong, Winston, Nanjangud, Gouri J., Basturk, Olca, O’Reilly, Eileen M., Klimstra, David S., Hruban, Ralph H., Wood, Laura D., Overholtzer, Michael, Iacobuzio-Donahue, Christine A.
Format:	Journal Article
Language:	English
Published:	England Nature Publishing Group 01.01.2020
Subjects:	Autopsies Carcinoma, Pancreatic Ductal - genetics Carcinoma, Squamous Cell - genetics Chromatin Evolution & development Genomes Humans Labeling Medical prognosis Metastasis Morphology Pancreatic cancer Pancreatic Neoplasms Pancreatic Neoplasms - genetics Patients Phylogeny Taxonomy
ISSN:	2662-1347, 2662-1347
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Abstract	Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion-sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq-defined basal-like subtype. In patients with coexisting basal and squamous and classical and glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical and glandular tumor. Cancers with squamous features were significantly more likely to have clonal mutations in chromatin modifiers, intercellular heterogeneity for amplification and entosis. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology and somatic mutations in chromatin modifier genes in the context of clonal evolution of pancreatic cancer.
AbstractList	Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion-sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq-defined basal-like subtype. In patients with coexisting basal and squamous and classical and glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical and glandular tumor. Cancers with squamous features were significantly more likely to have clonal mutations in chromatin modifiers, intercellular heterogeneity for MYC amplification and entosis. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology and somatic mutations in chromatin modifier genes in the context of clonal evolution of pancreatic cancer. Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion-sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq-defined basal-like subtype. In patients with coexisting basal and squamous and classical and glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical and glandular tumor. Cancers with squamous features were significantly more likely to have clonal mutations in chromatin modifiers, intercellular heterogeneity for amplification and entosis. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology and somatic mutations in chromatin modifier genes in the context of clonal evolution of pancreatic cancer. Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion-sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq-defined basal-like subtype. In patients with coexisting basal and squamous and classical and glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical and glandular tumor. Cancers with squamous features were significantly more likely to have clonal mutations in chromatin modifiers, intercellular heterogeneity for MYC amplification and entosis. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology and somatic mutations in chromatin modifier genes in the context of clonal evolution of pancreatic cancer.Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion-sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq-defined basal-like subtype. In patients with coexisting basal and squamous and classical and glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical and glandular tumor. Cancers with squamous features were significantly more likely to have clonal mutations in chromatin modifiers, intercellular heterogeneity for MYC amplification and entosis. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology and somatic mutations in chromatin modifier genes in the context of clonal evolution of pancreatic cancer. Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion-sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq-defined basal-like subtype. In patients with coexisting basal and squamous and classical and glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical and glandular tumor. Cancers with squamous features were significantly more likely to have clonal mutations in chromatin modifiers, intercellular heterogeneity for MYC amplification and entosis. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology and somatic mutations in chromatin modifier genes in the context of clonal evolution of pancreatic cancer.Iacobuzio-Donahue and colleagues use integrated transcriptomic, histologic and mutational data to analyze squamous features of pancreatic ductal adenocarcinoma (PDAC), further refining the understanding of heterogeneity and evolution in PDAC.
Author	Wong, Winston Melchor, Jerry P. Klimstra, David S. Iacobuzio-Donahue, Christine A. Chen, Ruoyao Kohutek, Zachary A. Boumiza, Aida Hong, Jungeui Hruban, Ralph H. Huang, Jinlong Baez, Priscilla Sakamoto, Hitomi Lisi, Marta Chadalavada, Kalyani Wood, Laura D. O’Reilly, Eileen M. Overholtzer, Michael Hayashi, Akimasa Nanjangud, Gouri J. Basturk, Olca Kappagantula, Rajya Zhang, Lance Fan, Jun Bai, Jessica Makohon-Moore, Alvin P. Zhong, Yi Attiyeh, Marc A. Ho, Yu-jui Lecomte, Nicolas
AuthorAffiliation	7 Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA 4 Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA 3 Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA 6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 1 The David M. Rubenstein Center for Pancreatic Cancer Research, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2 Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
AuthorAffiliation_xml	– name: 4 Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA – name: 5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA – name: 6 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA – name: 7 Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA – name: 1 The David M. Rubenstein Center for Pancreatic Cancer Research, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA – name: 2 Human Oncology and Pathogenesis Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA – name: 3 Cell Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 A.H. and C.A.I.-D. designed the study. A.H., J.F., A.P.M.-M., H.S., M.A.A., A.B., R.K., P.B., L.D.W., R.H.H. and C.A.I.-D. collected autopsy samples. A.H. and C.A.I.-D. reviewed the histology of autopsy samples and selected cases. O.B., D.S.K., A.H. and C.A.I.-D. reviewed the pathology of MSK Clinical IMPACT cases. A.H. and C.A.I.-D. reviewed the pathology of surgical cases in TCGA cohort A.H., R.C., M.O., K.C., M.L., G.J.N. and C.A.I.-D. reviewed the entosis of Immuno-FISH slides. A.H. and J.F. prepared RNA samples. A.P.M.-M., J.Hong, H.S., Z.A.K. and A.H. prepared the DNA samples. A.H., Y.Z. and C.A.I.-D. performed RNA sequencing. Y.H., A.H., L.Z. and J.Huang analyzed RNA sequencing results. A.P.M.-M., J. Ho., Z.A.K., H.S. M.A.A., A.H., and C.A.I.-D. performed DNA sequencing. M.A.A., A.P.M.-M., J.Hong, A.H. and C.A.I.-D. analyzed DNA sequencing results and derived the phylogenies. A.P.M.-M., J.Hong, A.H., J.P.M. and C.A.I.-D. managed the sequencing data. W.W. and E.M.O. collected samples and clinical information for MSK Clinical IMPACT. M.L., K.C. and G.J.N. performed immuno-FISH. J.B. and N.L. performed organoid experiments. A.H., R.C., Y.H., M.O., N.L. and C.A.I.-D. wrote the manuscript. All authors reviewed and edited the final manuscript. Author contributions
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Snippet	Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown....
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SubjectTerms	Autopsies Carcinoma, Pancreatic Ductal - genetics Carcinoma, Squamous Cell - genetics Chromatin Evolution & development Genomes Humans Labeling Medical prognosis Metastasis Morphology Pancreatic cancer Pancreatic Neoplasms Pancreatic Neoplasms - genetics Patients Phylogeny Taxonomy
Title	A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma
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