Open AccessJournal Article
Consistent Chromosome Abnormalities in Adenocarcinoma of the Pancreas
Constance A. Griffin,Ralph H. Hruban,Laura Morsberger,T. Ellingham,Patricia P. Long,Elizabeth M. Jaffee,Karen M. Hauda,Stefan K. Bohlander,Charles J. Yeo +8 more
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In this paper, the authors studied 62 primary pancreatic adenocarcinomas obtained from surgical resections using classical cytogenetics and fluorescent in situ hybridization methods and found that the most frequent whole chromosomal gains were chromosomes 20 (eight tumors) and 7 (seven tumors).Abstract:
Little is known about the somatic genetic changes which characterize pancreatic adenocarcinoma. The identification of acquired genomic alterations would further our understanding of the biology of this neoplasm. We have studied 62 primary pancreatic adenocarcinomas obtained from surgical resections using classical cytogenetics and fluorescent in situ hybridization methods. Clonally abnormal karyotypes were observed in 44 neoplasms. Karyotypes were generally complex (greater than three abnormalities) and included both numerical and structural chromosome abnormalities. Many tumors contained at least one marker chromosome. The most frequent whole chromosomal gains were chromosomes 20 (eight tumors) and 7 (seven tumors). Losses were much more frequent: chromosome 18 was lost in 22 tumors followed in frequency by chromosomes 13 (16 tumors), 12 (13 tumors), 17 (13 tumors), and 6 (12 tumors). Structural abnormalities were frequent. Two hundred nine chromosome breakpoints were identified. Excluding Robertsonian translocations, the chromosomal arms most frequently involved were 1p (12); 6q (11); 7q and 17p (9 each); and 1q, 3p, 11p, and 19q (8 each). Portions of the long arm of chromosome 6 appeared to be lost in nine tumors. To determine whether the apparent losses of portions of 6q are real, four tumors with 6q deletions were hybridized with a biotin-labeled microdissection probe from 6q24-ter. Loss of one copy of this region was verified in three of four tumors. In addition, double minute chromosomes were identified in eight cases. To our knowledge, these represent the first primary specimens of pancreatic adenocarcinoma with cytogenetic evidence of gene amplification.read more
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Whole genomes redefine the mutational landscape of pancreatic cancer.
Nicola Waddell,Marina Pajic,Ann-Marie Patch,David K. Chang,Karin S. Kassahn,Peter Bailey,Amber L. Johns,David Miller,Katia Nones,Kelly Quek,Michael C.J. Quinn,Alan J. Robertson,Muhammad Zaki Hidayatullah Fadlullah,Timothy J. C. Bruxner,Angelika N. Christ,Ivon Harliwong,Senel Idrisoglu,Suzanne Manning,Craig Nourse,Ehsan Nourbakhsh,Shivangi Wani,Peter J. Wilson,Emma Markham,Nicole Cloonan,Matthew J. Anderson,J. Lynn Fink,Oliver Holmes,Stephen H. Kazakoff,Conrad Leonard,Felicity Newell,Barsha Poudel,Sarah Song,Darrin Taylor,Nick Waddell,Scott Wood,Qinying Xu,Jianmin Wu,Mark Pinese,Mark J. Cowley,Hong C. Lee,Marc D. Jones,Adnan Nagrial,Jeremy L. Humphris,Lorraine A. Chantrill,Venessa T. Chin,Angela Steinmann,Amanda Mawson,Emily S. Humphrey,Emily K. Colvin,Angela Chou,Christopher J. Scarlett,Andreia V. Pinho,Marc Giry-Laterriere,Ilse Rooman,Jaswinder S. Samra,James G. Kench,Jessica A. Pettitt,Neil D. Merrett,Christopher W. Toon,Krishna Epari,Nam Q. Nguyen,Andrew Barbour,Nikolajs Zeps,Nigel B. Jamieson,Janet Graham,Simone P. Niclou,Rolf Bjerkvig,Robert Grützmann,Daniela Aust,Ralph H. Hruban,Anirban Maitra,Christine A. Iacobuzio-Donahue,Christopher L. Wolfgang,Richard A. Morgan,Rita T. Lawlor,Vincenzo Corbo,Claudio Bassi,Massimo Falconi,Giuseppe Zamboni,Giampaolo Tortora,Margaret A. Tempero,Anthony J. Gill,James R. Eshleman,Christian Pilarsky,Aldo Scarpa,Elizabeth A. Musgrove,John V. Pearson,Andrew V. Biankin,Sean M. Grimmond +88 more
TL;DR: Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency, and 4 of 5 individuals with these measures of defective DNA maintenance responded to platinum therapy.
Journal ArticleDOI
Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas
Reuben Moncada,Dalia Barkley,Florian Wagner,Marta Chiodin,Joseph C. Devlin,Maayan Baron,Cristina H. Hajdu,Diane M. Simeone,Itai Yanai +8 more
TL;DR: Applying multimodal intersection analysis to primary pancreatic tumors, it is found that subpopulations of ductal cells, macrophages, dendritic cells and cancer cells have spatially restricted enrichments, as well as distinct coenrichments with other cell types.
Journal ArticleDOI
Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity
David Gisselsson,Louise Pettersson,Mattias Höglund,Markus Heidenblad,Ludmila Gorunova,Joop Wiegant,Fredrik Mertens,Paola Dal Cin,Felix Mitelman,Nils Mandahl +9 more
TL;DR: Tumors with BFB events showed a decreased elimination rate of unstable chromosome aberrations after irradiation compared with normal cells and other tumor cells, suggesting that a combination of mitotically unstable chromosomes and an elevated tolerance to chromosomal damage leads to constant genomic reorganization in many malignancies, thereby providing a flexible genetic system for clonal evolution and progression.
Journal ArticleDOI
Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia.
N. Tjarda van Heek,N. Tjarda van Heek,Alan K. Meeker,Scott E. Kern,Charles J. Yeo,Keith D. Lillemoe,John L. Cameron,G. Johan A. Offerhaus,Jessica Hicks,Robb E. Wilentz,Michael Goggins,Angelo M. De Marzo,Ralph H. Hruban,Anirban Maitra +13 more
TL;DR: Telomere shortening is by far the most common early genetic abnormality recognized to date in the progression model of pancreatic adenocarcinomas and may be an essential gatekeeper for maintaining chromosomal integrity, and thus, normal cellular physiology in pancreatic ductal epithelium.
Journal ArticleDOI
Immortal human pancreatic duct epithelial cell lines with near normal genotype and phenotype
Hong Ouyang,Lun-jun Mou,Catherine Luk,Ni Liu,Jana Karaskova,Jeremy A. Squire,Jeremy A. Squire,Ming-Sound Tsao,Ming-Sound Tsao +8 more
TL;DR: Results indicate that except for the loss of p53 functional pathway, the two clones of HPDE6-E6E7 cells demonstrated a near normal genotype and phenotype of pancreatic duct epithelial cells, which will be useful for future studies on the molecular basis of pancreas cancerogenesis and islet cell differentiation.
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