Abstract
Brain metastases (BM) of colorectal cancer (CRC) are rare but lethal, and an understanding of their genomic landscape is lacking. We conduct an analysis of whole-exome sequencing (WES) and whole-genome sequencing (WGS) data on 19 trios of patient-matched BMs, primary CRC tumors, and adjacent normal tissue. Compared with primary CRC, BM exhibits elevated mutational signatures of homologous recombination deficiency (HRD) and mismatch repair deficiency (MMRD). Further analysis reveals two DNA damage response (DDR) signatures could emerge early and are enhanced in BM tissues but are eliminated eventually in matched primary CRC tissues. BM-specific mutations in DDR genes and elevated microsatellite instability (MSI) levels support the importance of DDR in the brain metastasis of CRC. We also identify BM-related genes (e.g., SCN7A, SCN5A, SCN2A, IKZF1, and PDZRN4) that carry frequent BM-specific mutations. These results provide a better understanding of the BM mutational landscape and insights into treatment.
Highlights
Brain metastases (BM) of colorectal cancer (CRC) are rare but lethal, and an understanding of their genomic landscape is lacking
31.3% (1416/4519, whole-exome sequencing (WES)) and 28.9% (45264/157377, whole-genome sequencing (WGS)) of the mutations in BMs were identified in primary CRC, indicating the evolution and selection of mutations during metastasis
The proportions of all six mutation groups were significantly different across BMs and matched primary tissues: C > T mutations were reduced in BM tissues compared with those in primary tissues, while the reverse was true of the other mutation types (Fig. 1a)
Summary
Brain metastases (BM) of colorectal cancer (CRC) are rare but lethal, and an understanding of their genomic landscape is lacking. A recent sequencing study on multiregion samples from 17 CRC patients reported that most local and distant metastases arise from independent subclones within the primary tumor[5], indicating genetic divergence and heterogeneity of metastatic diseases. A higher mutation rate of KRAS/NRAS and PIK3CA genes was reported in brain metastasis tissues[7,8] It remains largely unknown whether distinct genomic features exist in BM and primary CRC. We conduct WES and whole-genome sequencing (WGS) of biopsy samples from trios of patient-matched brain metastases, primary CRC tissues and adjacent normal samples (WES: 42 tissues from 11 patients; public WES: 13 tissues from 4 patients; WGS: 24 tissues from 8 patients) to (1) document genomic signatures during the evolution of CRC BM; (2) identify clinically actionable targets for the BM treatment; and (3) identify potential drivers in CRC BM
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
