Validation of computational determination of microsatellite status using whole exome sequencing data from colorectal cancer patients

Autor: Anders Husted Madsen, Maria Bach Laursen, Claus L. Andersen, Michael Knudsen, Kåre Gotschalck Sunesen, Amanda Frydendahl Boll Johansen, Mads Rasmussen, Lene Hjerrild Iversen, Christine Gaasdal Kassentoft
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Oncology
Exome sequencing
Male
PREDICTOR
Cancer Research
Colorectal cancer
MSIsensor
INSTABILITY DETECTION
DNA Mismatch Repair
Polymerase Chain Reaction
0302 clinical medicine
Surgical oncology
MUTATIONAL PROCESSES
Exome
DNA mismatch repair deficiency
Aged
80 and over
Predictive marker
High-Throughput Nucleotide Sequencing
DNA MISMATCH REPAIR
Middle Aged
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Prognosis
TUMORS
Immunohistochemistry
030220 oncology & carcinogenesis
POLE
Microsatellite
DNA mismatch repair
Female
Fluorouracil
Immunotherapy
Colorectal Neoplasms
Research Article
Adult
medicine.medical_specialty
Antimetabolites
Antineoplastic
POLYMERASE-EPSILON
lcsh:RC254-282
LYNCH-SYNDROME
03 medical and health sciences
Internal medicine
Genetics
medicine
Biomarkers
Tumor
Humans
IMMUNOTHERAPY
neoplasms
SIGNATURES
MSI
Aged
MSS
business.industry
Microsatellite instability
Computational Biology
PERFORMANCE
medicine.disease
digestive system diseases
030104 developmental biology
Mutation
business
Microsatellite Repeats
Zdroj: BMC Cancer
Johansen, A F B, Kassentoft, C G, Knudsen, M, Laursen, M B, Madsen, A H, Iversen, L H, Sunesen, K G, Rasmussen, M H & Andersen, C L 2019, ' Validation of computational determination of microsatellite status using whole exome sequencing data from colorectal cancer patients ', BMC Cancer, vol. 19, no. 1, 971 . https://doi.org/10.1186/s12885-019-6227-7
BMC Cancer, Vol 19, Iss 1, Pp 1-8 (2019)
ISSN: 1471-2407
DOI: 10.1186/s12885-019-6227-7
Popis: Background Microsatellite instability (MSI), resulting from a defective mismatch repair system, occurs in approximately 15% of sporadic colorectal cancers (CRC). Since MSI is associated with a poor response to 5-fluorouracile based chemotherapy and is a positive predictive marker of immunotherapy, it is routine practice to evaluate the MSI status of resected tumors in CRC patients. MSIsensor is a novel computational tool for determining MSI status using Next Generation Sequencing. However, it is not widely used in the clinic and has not been independently validated in exome data from CRC. To facilitate clinical implementation of computational determination of MSI status, we compared MSIsensor to current gold standard methods for MSI testing. Methods MSI status was determined for 130 CRC patients (UICC stage I-IV) using immunohistochemistry, PCR based microsatellite stability testing and by applying MSIsensor to exome sequenced tumors and paired germline DNA. Furthermore, we investigated correlation between MSI status, mutational load and mutational signatures. Results Eighteen out of 130 (13.8%) patients were microsatellite instable. We found a 100% agreement between MSIsensor and gold standard methods for MSI testing. All MSI tumors were hypermutated. In addition, two microsatellite stable (MSS) tumors were hypermutated, which was explained by a dominant POLE signature and pathogenic POLE mutations (p.Pro286Arg and p.Ser459Phe). Conclusion MSIsensor is a robust tool, which can be used to determine MSI status of tumor samples from exome sequenced CRC patients.
Databáze: OpenAIRE
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