title: Molecular heterogeneity of non-small cell lung carcinoma patient-derived xenografts closely reflect their primary tumors.
abstract: Availability of lung cancer models that closely mimic human tumors remains a significant gap in cancer research, as tumor cell lines and mouse models may not recapitulate the spectrum of lung cancer heterogeneity seen in patients. We aimed to establish a patient-derived tumor xenograft (PDX) resource from surgically resected non-small cell lung cancer (NSCLC). Fresh tumor tissue from surgical resection was implanted and grown in the subcutaneous pocket of non-obese severe combined immune deficient (NOD SCID) gamma mice. Subsequent passages were in NOD SCID mice. A subset of matched patient and PDX tumors and non-neoplastic lung tissues were profiled by whole exome sequencing, single nucleotide polymorphism (SNP) and methylation arrays, and phosphotyrosine (pY)-proteome by mass spectrometry. The data were compared to published NSCLC datasets of NSCLC primary and cell lines. 127 stable PDXs were established from 441 lung carcinomas representing all major histological subtypes: 52 adenocarcinomas, 62 squamous cell carcinomas, one adeno-squamous carcinoma, five sarcomatoid carcinomas, five large cell neuroendocrine carcinomas, and two small cell lung cancers. Somatic mutations, gene copy number and expression profiles, and pY-proteome landscape of 36 PDXs showed greater similarity with patient tumors than with established cell lines. Novel somatic mutations on cancer associated genes were identified but only in PDXs, likely due to selective clonal growth in the PDXs that allows detection of these low allelic frequency mutations. The results provide the strongest evidence yet that PDXs established from lung cancers closely mimic the characteristics of patient primary tumors.
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Sheffield Institute of Translational Neuroscience, University of Sheffield, Sheffield, UK, S1O 2HQ.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wang
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Nhu-An
authors.initials: NA
authors.lastname: Pham
authors.affiliation: Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Jiefei
authors.initials: J
authors.lastname: Tong
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Shingo
authors.initials: S
authors.lastname: Sakashita
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Ghassan
authors.initials: G
authors.lastname: Allo
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Lucia
authors.initials: L
authors.lastname: Kim
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yanagawa
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Vibha
authors.initials: V
authors.lastname: Raghavan
authors.affiliation: Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: To
authors.affiliation: Ontario Institute of Cancer Research, Toronto, ON, Canada.
authors.forename: Quang M
authors.initials: QM
authors.lastname: Trinh
authors.affiliation: Ontario Institute of Cancer Research, Toronto, ON, Canada.
authors.forename: Maud H W
authors.initials: MH
authors.lastname: Starmans
authors.affiliation: Ontario Institute of Cancer Research, Toronto, ON, Canada.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Chan-Seng-Yue
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Dianne
authors.initials: D
authors.lastname: Chadwick
authors.affiliation: Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Chang-Qi
authors.initials: CQ
authors.lastname: Zhu
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Ni
authors.initials: N
authors.lastname: Liu
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Sharon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ignatchenko
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Dan
authors.initials: D
authors.lastname: Strumpf
authors.affiliation: Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Taylor
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Moghal
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.|Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kislinger
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.|Department of Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Medicine, University of Toronto, Toronto, ON, Canada.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: McPherson
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Muthuswamy
authors.affiliation: Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, ON, Canada.|Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Moran
authors.affiliation: Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts / Q000473:pathology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D023041:Xenograft Model Antitumor Assays / Q000379:methods
keywords: DNA methylation; copy number aberration; mass spectrometry; non-small cell lung cancer; phosphotyrosine-proteomics; transcriptome; whole exome next generation sequencing; xenograft