Research Papers:

Copy number profiles of paired primary and metastatic colorectal cancers

Futoshi Kawamata, Ann-Marie Patch, Katia Nones, Catherine Bond, Diane McKeone, Sally-Ann Pearson, Shigenori Homma, Cheng Liu, Lochlan Fennell, Troy Dumenil, Gunter Hartel, Nozomi Kobayasi, Hideki Yokoo, Moto Fukai, Hiroshi Nishihara, Toshiya Kamiyama, Matthew E. Burge, Christos S. Karapetis, Akinobu Taketomi, Barbara Leggett, Nicola Waddell and Vicki Whitehall _

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Oncotarget. 2018; 9:3394-3405. https://doi.org/10.18632/oncotarget.23277

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Futoshi Kawamata1,2,*, Ann-Marie Patch3,*, Katia Nones3, Catherine Bond1, Diane McKeone1, Sally-Ann Pearson1, Shigenori Homma2, Cheng Liu1,5, Lochlan Fennell1, Troy Dumenil1, Gunter Hartel4, Nozomi Kobayasi2, Hideki Yokoo2, Moto Fukai2, Hiroshi Nishihara2, Toshiya Kamiyama2, Matthew E. Burge6, Christos S. Karapetis7, Akinobu Taketomi2, Barbara Leggett1,5,6, Nicola Waddell3,5,# and Vicki Whitehall1,5,8,#

1Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia

2Hokkaido University Graduate School of Medicine, Sapporo, Japan

3Medical Genomics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia

4Statistics Group, QIMR Berghofer Medical Research Institute, Brisbane, Australia

5The University of Queensland, Brisbane, Australia

6Royal Brisbane and Women’s Hospital, Brisbane, Australia

7Flinders University, Adelaide, Australia

8Pathology Queensland, Brisbane, Australia

*Co-first authors

#These authors contributed equally to this work

Correspondence to:

Vicki Whitehall, email: [email protected]

Keywords: colorectal cancer; liver metastasis; loss of heterozygosity; copy number alterations; chemotherapy

Received: July 14, 2017     Accepted: November 20, 2017     Published: December 15, 2017


Liver metastasis is the major cause of death following a diagnosis of colorectal cancer (CRC). In this study, we compared the copy number profiles of paired primary and liver metastatic CRC to better understand how the genomic structure of primary CRC differs from the metastasis. Paired primary and metastatic tumors from 16 patients and their adjacent normal tissue samples were analyzed using single nucleotide polymorphism arrays. Genome-wide chromosomal copy number alterations were assessed, with particular attention to 188 genes known to be somatically altered in CRC and 24 genes that are clinically actionable in CRC. These data were analyzed with respect to the timing of primary and metastatic tissue resection and with exposure to chemotherapy. The genomic differences between the tumor and paired metastases revealed an average copy number discordance of 22.0%. The pairs of tumor samples collected prior to treatment revealed significantly higher copy number differences compared to post-therapy liver metastases (P = 0.014). Loss of heterozygosity acquired in liver metastases was significantly higher in previously treated liver metastasis samples compared to treatment naive liver metastasis samples (P = 0.003). Amplification of the clinically actionable genes ERBB2, FGFR1, PIK3CA or CDK8 was observed in the metastatic tissue of 4 patients but not in the paired primary CRC. These examples highlight the intra-patient genomic discrepancies that can occur between metastases and the primary tumors from which they arose. We propose that precision medicine strategies may therefore identify different actionable targets in metastatic tissue, compared to primary tumors, due to substantial genomic differences.

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