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

TY - JOUR

T1 - Validation of computational determination of microsatellite status using whole exome sequencing data from colorectal cancer patients

AU - Johansen, Amanda Frydendahl Boll

AU - Kassentoft, Christine Gaasdal

AU - Knudsen, Michael

AU - Laursen, Maria Bach

AU - Madsen, Anders Husted

AU - Iversen, Lene Hjerrild

AU - Sunesen, Kåre Gotschalck

AU - Rasmussen, Mads Heilskov

AU - Andersen, Claus Lindbjerg

PY - 2019/10/21

Y1 - 2019/10/21

N2 - 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.

AB - 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.

KW - Colorectal cancer

KW - DNA MISMATCH REPAIR

KW - DNA mismatch repair deficiency

KW - Exome sequencing

KW - IMMUNOTHERAPY

KW - INSTABILITY DETECTION

KW - LYNCH-SYNDROME

KW - MSI

KW - MSIsensor

KW - MSS

KW - MUTATIONAL PROCESSES

KW - Microsatellite instability

KW - PERFORMANCE

KW - POLE

KW - POLYMERASE-EPSILON

KW - PREDICTOR

KW - SIGNATURES

KW - TUMORS

UR - http://www.scopus.com/inward/record.url?scp=85073725074&partnerID=8YFLogxK

U2 - 10.1186/s12885-019-6227-7

DO - 10.1186/s12885-019-6227-7

M3 - Journal article

C2 - 31638937

SN - 1471-2407

VL - 19

JO - BMC Cancer

JF - BMC Cancer

IS - 1

M1 - 971

ER -