Islands of genomic stability in the face of genetically unstable metastatic cancer Journal Article
| Authors: | Bowland, K.; Lai, J.; Skaist, A.; Zhang, Y.; Teh, S. S. K.; Roberts, N. J.; Thompson, E.; Wheelan, S. J.; Hruban, R. H.; Karchin, R.; Bailey, M. H.; Iacobuzio-Donahue, C. A.; Eshleman, J. R. |
| Article Title: | Islands of genomic stability in the face of genetically unstable metastatic cancer |
| Abstract: | Introduction Metastatic cancer affects millions of people worldwide annually and is the leading cause of cancer-related deaths. Most patients with metastatic disease are not eligible for surgical resection, and current therapeutic regimens have varying success rates, some with 5-year survival rates below 5%. Here, we test the hypothesis that metastatic cancer can be genetically targeted by exploiting single base substitution mutations unique to individual cells that occur as part of normal aging prior to transformation. These mutations are targetable because ~10% of them form novel tumor-specific “NGG” protospacer adjacent motif (PAM) sites targetable by CRISPR-Cas9. Methods Whole genome sequencing was performed on five rapid autopsy cases of patient-matched primary tumor, normal and metastatic tissue from pancreatic ductal adenocarcinoma decedents. CRISPR-Cas9 PAM targets were determined by bioinformatic tumor-normal subtraction for each patient and verified in metastatic samples by high-depth capture-based sequencing. Results We found that 90% of PAM targets were maintained between primary carcinomas and metastases overall. We identified rules that predict PAM loss or retention, where PAMs located in heterozygous regions in the primary tumor can be lost in metastases (private LOH), but PAMs occurring in regions of loss of heterozygosity (LOH) in the primary tumor were universally conserved in metastases. Conclusions Regions of truncal LOH are strongly retained in the presence of genetic instability and, therefore, represent genetic vulnerabilities in pancreatic adenocarcinomas. A CRISPR-based gene therapy approach targeting these regions may be a novel way to genetically target metastatic cancer. © 2024 Bowland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| Keywords: | controlled study; human tissue; human cell; genetics; mutation; pancreatic neoplasms; quality control; metastasis; carcinoma, pancreatic ductal; gene frequency; pathology; genomic instability; heterozygosity; pancreas tumor; neoplasm metastasis; gene therapy; pancreas adenocarcinoma; heterozygosity loss; autopsy; dna extraction; copy number variation; chromosome arm; pancreatic ductal carcinoma; high throughput sequencing; humans; human; male; female; article; whole genome sequencing; cancer cell line; crispr cas system; crispr-cas systems; crispr-cas9 system; substitution mutation; a38 cell line; genetically unstable metastatic cancer; genomic island |
| Journal Title: | PLoS ONE |
| Volume: | 19 |
| Issue: | 12 |
| ISSN: | 1932-6203 |
| Publisher: | Public Library of Science |
| Date Published: | 2024-12-19 |
| Start Page: | e0298490 |
| Language: | English |
| DOI: | 10.1371/journal.pone.0298490 |
| PUBMED: | 39700179 |
| PROVIDER: | scopus |
| PMCID: | PMC11658618 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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