The Use of Three-Dimensional DNA Fluorescent In Situ Hybridization (3D DNA FISH) for the Detection of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer (NSCLC) Circulating Tumor Cells
Arutha Kulasinghe,Yenkai Lim,Yenkai Lim,Joanna Kapeleris,Joanna Kapeleris,Majid Ebrahimi Warkiani,Kenneth J. O'Byrne,Kenneth J. O'Byrne,Kenneth J. O'Byrne,Chamindie Punyadeera,Chamindie Punyadeera +10 more
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TL;DR: This study provides proof-of-principle for the use of 3D DNA FISH in the determination of CTC ALK translocations in NSCLC and captures a well-defined separation of 3′ and 5′ signals indicative of ALK Translation.
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Abstract: Tumor tissue biopsy is often limited for non-small cell lung cancer (NSCLC) patients and alternative sources of tumoral information are desirable to determine molecular alterations such as anaplastic lymphoma kinase (ALK) rearrangements. Circulating tumor cells (CTCs) are an appealing component of liquid biopsies, which can be sampled serially over the course of treatment. In this study, we enrolled a cohort of ALK-positive (n = 8) and ALK-negative (n = 12) NSCLC patients, enriched for CTCs using spiral microfluidic technology and performed DNA fluorescent in situ hybridization (FISH) for ALK. CTCs were identified in 12/20 NSCLC patients ranging from 1 to 26 CTCs/7.5 mL blood. Our study revealed that 3D imaging of CTCs for ALK translocations captured a well-defined separation of 3' and 5' signals indicative of ALK translocations and overlapping 3'/5' signal was easily resolved by imaging through the nuclear volume. This study provides proof-of-principle for the use of 3D DNA FISH in the determination of CTC ALK translocations in NSCLC.
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Citations
Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC).
Connor O’Leary,Connor O’Leary,Connor O’Leary,Harry Gasper,Katherine B. Sahin,Katherine B. Sahin,Ming Tang,Ming Tang,Arutha Kulasinghe,Arutha Kulasinghe,Mark N. Adams,Mark N. Adams,Derek J. Richard,Derek J. Richard,Kenneth J. O'Byrne,Kenneth J. O'Byrne,Kenneth J. O'Byrne +16 more
TL;DR: Data are emerging to suggest that this technique may be capable of identifying early resistance mechanisms and consequential disease progression on the basis of the analysis of blood-based circulating tumor cells, which could lead to improved patient outcomes when used as a monotherapy over traditional cytotoxic systemic therapy.
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High-plex and high-throughput digital spatial profiling of non-small-cell lung cancer (NSCLC)
James Monkman,James Monkman,Touraj Taheri,Majid Ebrahimi Warkiani,Connor O’Leary,Rahul Ladwa,Rahul Ladwa,Derek J. Richard,Derek J. Richard,Kenneth J. O'Byrne,Arutha Kulasinghe +10 more
TL;DR: This study reveals that the DSP methodology can be a powerful tool for determining the expression of a large number of protein markers from a single tissue slide, and implements both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy samples.
A fully automated assay to detect the expression of pan-cytokeratins and of EML4-ALK fusion protein in circulating tumour cells (CTCs) predicts outcome of non-small cell lung cancer (NSCLC) patients
Elisabetta Rossi,Michele Aieta,Alfredo Tartarone,Aldo Pezzuto,Antonella Facchinetti,Daniele Santini,Paola Ulivi,Vienna Ludovini,Luciana Possidente,Pasquale Fiduccia,Nadia Minicuci,Rita Zamarchi +11 more
TL;DR: In this paper, the authors combined the classical standard assay (SA) with an expanded cytokeratins profile (EA) and quantified the expression of EML4-ALK fusion protein in CTCs.
The Pandora's box of novel technologies that may revolutionize lung cancer.
Habib Sadeghi Rad,Hamid Sadeghi Rad,Yavar Shiravand,Payar Radfar,David Arpon,Majid Ebrahimi Warkiani,Kenneth J. O'Byrne,Arutha Kulasinghe +7 more
TL;DR: In this article, the authors reviewed the recent advancements in spatial profiling technologies for the analysis of NSCLC tissue samples to gain new insights and therapeutic options for non-small cell lung cancer (NSCLC) patients.
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Heterogeneous Tumor-Immune Microenvironments between Primary and Metastatic Tumors in a Patient with ALK Rearrangement-Positive Large Cell Neuroendocrine Carcinoma.
Takahiro Tashiro,Kosuke Imamura,Yusuke Tomita,Daisuke Tamanoi,Akira Takaki,Kazuaki Sugahara,Ryo Sato,Koichi Saruwatari,Shinya Sakata,Megumi Inaba,Sunao Ushijima,Naomi Hirata,Takuro Sakagami +12 more
TL;DR: In this paper, a 32-year-old female patient with ALK-rearrangement-positive large cell neuroendocrine carcinoma (LCNEC) or anaplastic lymphoma kinase (ALK) rearrangement positive lung cancer was presented.
References
Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution
Christopher Abbosh,Nicolai Juul Birkbak,Nicolai Juul Birkbak,Gareth A. Wilson,Gareth A. Wilson,Mariam Jamal-Hanjani,Tudor Constantin,Raheleh Salari,John Le Quesne,David A. Moore,Selvaraju Veeriah,Rachel Rosenthal,Teresa Marafioti,Eser Kirkizlar,Thomas B.K. Watkins,Thomas B.K. Watkins,Nicholas McGranahan,Nicholas McGranahan,Sophia Ward,Sophia Ward,Luke Martinson,Joan Riley,Francesco Fraioli,Maise Al Bakir,Eva Grönroos,Francisco Zambrana,Raymondo Endozo,Wenya Linda Bi,Wenya Linda Bi,Fiona M. Fennessy,Fiona M. Fennessy,Nicole Sponer,Diana Johnson,Joanne Laycock,Seema Shafi,Justyna Czyzewska-Khan,Andrew Rowan,Tim Chambers,Nik Matthews,Nik Matthews,Samra Turajlic,Samra Turajlic,Crispin T. Hiley,Crispin T. Hiley,Siow Ming Lee,Martin Forster,Tanya Ahmad,Mary Falzon,Elaine Borg,David Lawrence,Martin Hayward,Shyam Kolvekar,Nikolaos Panagiotopoulos,Sam M. Janes,Ricky Thakrar,Asia Ahmed,Fiona H Blackhall,Yvonne Summers,Dina Hafez,Ashwini Naik,Apratim Ganguly,Stephanie Kareht,Rajesh Shah,Leena Dennis Joseph,Anne Marie Quinn,Phil Crosbie,Babu Naidu,Gary Middleton,Gerald Langman,Simon Trotter,Marianne Nicolson,Hardy Remmen,Keith M. Kerr,Mahendran Chetty,Lesley Gomersall,Dean A. Fennell,Apostolos Nakas,Sridhar Rathinam,Girija Anand,Sajid Khan,Peter Russell,Veni Ezhil,Babikir Ismail,Melanie Irvin-Sellers,Vineet Prakash,Jason F. Lester,Malgorzata Kornaszewska,Richard Attanoos,Haydn Adams,Helen E. Davies,Dahmane Oukrif,Ayse U. Akarca,John A. Hartley,Helen Lowe,Sara Lock,Natasha Iles,Harriet Bell,Yenting Ngai,Greg Elgar,Zoltan Szallasi,Zoltan Szallasi,Zoltan Szallasi,Roland F. Schwarz,Javier Herrero,Aengus Stewart,Sergio A. Quezada,Karl S. Peggs,Peter Van Loo,Peter Van Loo,Caroline Dive,Caroline Dive,C. Jimmy Lin,Matthew Rabinowitz,Hugo J.W.L. Aerts,Hugo J.W.L. Aerts,Allan Hackshaw,Jacqui Shaw,Bernhard Zimmermann,Charles Swanton,Charles Swanton +119 more
TL;DR: It is shown that phylogenetic ct DNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies.
EML4-ALK Mutations in Lung Cancer That Confer Resistance to ALK Inhibitors
Young Lim Choi,Manabu Soda,Yoshihiro Yamashita,Toshihide Ueno,Junpei Takashima,Takahiro Nakajima,Yasushi Yatabe,Kengo Takeuchi,Toru Hamada,Hidenori Haruta,Yuichi Ishikawa,Hideki Kimura,Tetsuya Mitsudomi,Yoshiro Tanio,Hiroyuki Mano +14 more
TL;DR: The discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor are reported.
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Ultra-fast, label-free isolation of circulating tumor cells from blood using spiral microfluidics
Majid Ebrahimi Warkiani,Majid Ebrahimi Warkiani,Bee Luan Khoo,Bee Luan Khoo,Lidan Wu,Andy Tay,Andy Tay,Ali Asgar S. Bhagat,Jongyoon Han,Jongyoon Han,Chwee Teck Lim,Chwee Teck Lim +11 more
TL;DR: This protocol describes detailed procedures for the production and use of a label-free spiral microfluidic device to allow size-based isolation of viable CTCs using hydrodynamic forces that are present in curvilinear microchannels.
519
Detection of Circulating Tumor Cells Harboring a Unique ALK Rearrangement in ALK-Positive Non–Small-Cell Lung Cancer
Emma Pailler,Julien Adam,Amélie Barthelemy,Marianne Oulhen,Nathalie Auger,Alexander Valent,Isabelle Borget,David Planchard,Melissa Taylor,Fabrice Andre,Jean-Charles Soria,Philippe Vielh,Benjamin Besse,Françoise Farace +13 more
TL;DR: The results suggest that CTCs harboring a unique ALK rearrangement and mesenchymal phenotype may arise from clonal selection of tumor cells that have acquired the potential to drive metastatic progression of ALK-positive NSCLC.
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Clinical Validation of an Ultra High-Throughput Spiral Microfluidics for the Detection and Enrichment of Viable Circulating Tumor Cells
Bee Luan Khoo,Majid Ebrahimi Warkiani,Daniel Shao-Weng Tan,Ali Asgar S. Bhagat,Darryl Irwin,Dawn Pingxi Lau,Alvin Soon Tiong Lim,Kiat Hon Lim,Sai Sakktee Krisna,Wan-Teck Lim,Yoon Sim Yap,Soo Chin Lee,Ross A. Soo,Jongyoon Han,Chwee Teck Lim +14 more
TL;DR: An ultra-sensitive mass spectrometry based system is used to highlight the presence of an EGFR-activating mutation in both isolated CTCs and plasma cell-free DNA (cf-DNA), and demonstrate concordance with the original tumor-biopsy samples.
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