TY - JOUR
T1 - A Novel Next-Generation Sequencing Approach to Detecting Microsatellite Instability and Pan-Tumor Characterization of 1000 Microsatellite Instability–High Cases in 67,000 Patient Samples
AU - Trabucco, Sally E.
AU - Gowen, Kyle
AU - Maund, Sophia L.
AU - Sanford, Eric
AU - Fabrizio, David A.
AU - Hall, Michael J.
AU - Yakirevich, Evgeny
AU - Gregg, Jeffrey P.
AU - Stephens, Phil J.
AU - Frampton, Garrett M.
AU - Hegde, Priti S.
AU - Miller, Vincent A.
AU - Ross, Jeffrey S.
AU - Hartmaier, Ryan J.
AU - Huang, Shih Min A.
AU - Sun, James X.
N1 - Publisher Copyright:
© 2019 American Society for Investigative Pathology and the Association for Molecular Pathology
PY - 2019/11
Y1 - 2019/11
N2 - Microsatellite instability (MSI) is an important biomarker for predicting response to immune checkpoint inhibitor therapy, as emphasized by the recent checkpoint inhibitor approval for MSI-high (MSI-H) solid tumors. Herein, we describe and validate a novel method for determining MSI status from a next-generation sequencing comprehensive genomic profiling assay using formalin-fixed, paraffin-embedded samples. This method is 97% (65/67) concordant with current standards, PCR and immunohistochemistry. We further apply this method to >67,000 patient tumor samples to identify genes and pathways that are enriched in MSI-stable or MSI-H tumor groups. Data show that although rare in tumors other than colorectal and endometrial carcinomas, MSI-H samples are present in many tumor types. Furthermore, the large sample set revealed that MSI-H tumors selectively share alterations in genes across multiple common pathways, including WNT, phosphatidylinositol 3-kinase, and NOTCH. Last, MSI is sufficient, but not necessary, for a tumor to have elevated tumor mutation burden. Therefore, MSI can be determined from comprehensive genomic profiling with high accuracy, allowing for efficient MSI-H detection across all tumor types, especially those in which routine use of immunohistochemistry or PCR-based assays would be impractical because of a rare incidence of MSI. MSI-H tumors are enriched in alterations in specific signaling pathways, providing a rationale for investigating directed immune checkpoint inhibitor therapies in combination with pathway-targeted therapies.
AB - Microsatellite instability (MSI) is an important biomarker for predicting response to immune checkpoint inhibitor therapy, as emphasized by the recent checkpoint inhibitor approval for MSI-high (MSI-H) solid tumors. Herein, we describe and validate a novel method for determining MSI status from a next-generation sequencing comprehensive genomic profiling assay using formalin-fixed, paraffin-embedded samples. This method is 97% (65/67) concordant with current standards, PCR and immunohistochemistry. We further apply this method to >67,000 patient tumor samples to identify genes and pathways that are enriched in MSI-stable or MSI-H tumor groups. Data show that although rare in tumors other than colorectal and endometrial carcinomas, MSI-H samples are present in many tumor types. Furthermore, the large sample set revealed that MSI-H tumors selectively share alterations in genes across multiple common pathways, including WNT, phosphatidylinositol 3-kinase, and NOTCH. Last, MSI is sufficient, but not necessary, for a tumor to have elevated tumor mutation burden. Therefore, MSI can be determined from comprehensive genomic profiling with high accuracy, allowing for efficient MSI-H detection across all tumor types, especially those in which routine use of immunohistochemistry or PCR-based assays would be impractical because of a rare incidence of MSI. MSI-H tumors are enriched in alterations in specific signaling pathways, providing a rationale for investigating directed immune checkpoint inhibitor therapies in combination with pathway-targeted therapies.
UR - http://www.scopus.com/inward/record.url?scp=85073350226&partnerID=8YFLogxK
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=purepublist2023&SrcAuth=WosAPI&KeyUT=WOS:000496996500013&DestLinkType=FullRecord&DestApp=WOS
U2 - 10.1016/j.jmoldx.2019.06.011
DO - 10.1016/j.jmoldx.2019.06.011
M3 - Article
C2 - 31445211
SN - 1525-1578
VL - 21
SP - 1053
EP - 1066
JO - Journal of Molecular Diagnostics
JF - Journal of Molecular Diagnostics
IS - 6
ER -