Oncotarget

Research Papers:

Molecular characterization of circulating colorectal tumor cells defines genetic signatures for individualized cancer care

Say Li Kong _, Xingliang Liu, Nur-Afidah Mohamed Suhaimi, Kenneth Jia Hao Koh, Min Hu, Daniel Yoke San Lee, Igor Cima, Wai Min Phyo, Esther Xing Wei Lee, Joyce A. Tai, Yu Miin Foong, Jess Honganh Vo, Poh Koon Koh, Tong Zhang, Jackie Y. Ying, Bing Lim, Min-Han Tan, Axel M. Hillmer

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Oncotarget. 2017; 8:68026-68037. https://doi.org/10.18632/oncotarget.19138

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Abstract

Say Li Kong1, Xingliang Liu1, Nur-Afidah Mohamed Suhaimi2, Kenneth Jia Hao Koh1, Min Hu2, Daniel Yoke San Lee2, Igor Cima2,3,4, Wai Min Phyo2,5, Esther Xing Wei Lee2, Joyce A. Tai1, Yu Miin Foong2, Jess Honganh Vo2,5, Poh Koon Koh2,6, Tong Zhang1, Jackie Y. Ying2, Bing Lim1, Min-Han Tan2,5,6 and Axel M. Hillmer1,7

1Genome Institute of Singapore, Singapore 138672, Singapore

2Institute of Bioengineering and Nanotechnology, Singapore 138669, Singapore

3German Cancer Consortium (DKTK), Essen/Düsseldorf, Heidelberg 69120, Germany

4German Cancer Research Center (DKFZ), Heidelberg 69120, Germany

5Lucence Diagnostics Pte Ltd, Singapore 159555, Singapore

6Concord Cancer Hospital Singapore, Singapore 289891, Singapore

7TRON-Translational Oncology at the University Medical Center of The Johannes Gutenberg University gGmbH, Mainz 55131, Germany

Correspondence to:

Say Li Kong, email: kongsl@gis.a-star.edu.sg

Axel M. Hillmer, email: hillmer@gis.a-star.edu.sg

Keywords: circulating tumor cells, colorectal cancer, targeted sequencing, druggable mutation, mutation signatures

Received: October 12, 2016    Accepted: June 02, 2017    Published: July 10, 2017

ABSTRACT

Studies on circulating tumor cells (CTCs) have largely focused on platform development and CTC enumeration rather than on the genomic characterization of CTCs. To address this, we performed targeted sequencing of CTCs of colorectal cancer patients and compared the mutations with the matched primary tumors. We collected preoperative blood and matched primary tumor samples from 48 colorectal cancer patients. CTCs were isolated using a label-free microfiltration device on a silicon microsieve. Upon whole genome amplification, we performed amplicon-based targeted sequencing on a panel of 39 druggable and frequently mutated genes on both CTCs and fresh-frozen tumor samples. We developed an analysis pipeline to minimize false-positive detection of somatic mutations in amplified DNA. In 60% of the CTC-enriched blood samples, we detected primary tumor matching mutations. We found a significant positive correlation between the allele frequencies of somatic mutations detected in CTCs and abnormal CEA serum level. Strikingly, we found driver mutations and amplifications in cancer and druggable genes such as APC, KRAS, TP53, ERBB3, FBXW7 and ERBB2. In addition, we found that CTCs carried mutation signatures that resembled the signatures of their primary tumors. Cumulatively, our study defined genetic signatures and somatic mutation frequency of colorectal CTCs. The identification of druggable mutations in CTCs of preoperative colorectal cancer patients could lead to more timely and focused therapeutic interventions.


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