Abstract 4382: Genomic events associated with metastasis of colorectal cancer by whole-genome sequencing

Abstract

Abstract Background: The diversity of the genomic landscape in colorectal cancer (CRC) is under active investigation. Concordance in molecular events between primary CRC and metastatic tumors is a subject of debate. Understanding the genetic background of metastatic CRC facilitates personalized therapies that target specific molecular events associated with the tumor. Methods: We performed whole genome sequencing in matched primary, metastasis and normal tissues from 3 patients with RAS/NRAS/BRAF wild types and microsatellite stable CRC. We implemented an analysis pipeline that integrated the genetic lesions to characterize somatic single nucleotide variations (SNVs), short insertions and deletions (indels), structural variations including fusions and copy number alterations. Results: Both primary and metastatic tumors showed a predominant mutational signature of C: G →T: A transition. A total of 282 non-silent mutations were identified in 3 pairs of CRC (median 63 per tumor, range 42 to 98). There were 148 (52.5%) variants shared in matched primary and metastatic tumors, 63 (22.3%) were found unique to primary and 71 (25.2%) were unique to the metastases. Only common well known genes (APC and TP53) and TTN mutations were found to be recurrent in the 3 patients. A total of 609 (range 33-171 per tumor) structural variants were discovered with 44.1% concordance between primary and metastasis pairs. We also identified 6 novel candidate fusions shared in primary and metastases and 2 private to the primary tumors. Consistent with the result of previous studies, copy loss at chromosome 17p and 18, and gain at chromosome 5, 8 and 13 were the common events both in the primary and metastatic tumor. Discussion and conclusions: Our data demonstrated a considerable difference in mutational landscape between primary CRCs and their matching metastatic tumors. The result suggested that the metastasis might originate from a distinct subclone from a heterogeneous primary tumor, or additional gain or loss of function via mutation to permit tumor invasion and spreading is necessary to facilitate metastasis. Each of the two models is complicated by the possibility of tumor heterogeneity within the primary tumor. In conclusion, comprehensive analysis and assessment for the genomic events is a powerful approach to delve deeper into the internal relations and contradictions between primary and paired metastases, helping to identify novel genomic events associated with metastasis of CRC. Citation Format: Yi Pan, Joanna Tong, Johnny Kwan, Kwok Wai Lo, Anthony Chan, Ka Fai To. Genomic events associated with metastasis of colorectal cancer by whole-genome sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4382. doi:10.1158/1538-7445.AM2017-4382