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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Veröffentlicht in:Nature cancer Jg. 1; H. 1; S. 59 - 74
Hauptverfasser: 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
Sprache:Englisch
Veröffentlicht: England Nature Publishing Group 01.01.2020
Schlagworte:
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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Zusammenfassung: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.
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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
ISSN:2662-1347
2662-1347
DOI:10.1038/s43018-019-0010-1