RNA-Seq Reveals Differences in Expressed Tumor Mutation Burden in Colorectal and Endometrial Cancers with and without Defective DNA-Mismatch Repair.

Autor:	DiGuardo MA; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Davila JI; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota; Department of Mathematics, Statistics, and Computer Science, St. Olaf College, Northfield, Minnesota., Jackson RA; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Nair AA; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota., Fadra N; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota., Minn KT; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Atiq MA; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Zarei S; Robert J Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio., Blommel JH; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Knight SM; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Jen J; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Eckloff BW; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Voss JS; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Rumilla KM; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Kerr SE; Hospital Pathology Associates, Minneapolis, Minnesota., Lam-Himlin DM; Department of Laboratory Medicine and Pathology, Divisions of Laboratory Genetics and Experimental Pathology, and Health Sciences Research, Mayo Clinic, Phoenix, Arizona., Bellizzi AM; Holden Comprehensive Cancer Center, Department of Pathology, University of Iowa, Iowa City, Iowa., Graham RP; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Kipp BR; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Jenkins RB; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Halling KC; Division of Laboratory Genetics and Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address: halling.kevin@mayo.edu.
Jazyk:	angličtina
Zdroj:	The Journal of molecular diagnostics : JMD [J Mol Diagn] 2021 May; Vol. 23 (5), pp. 555-564. Date of Electronic Publication: 2021 Feb 04.
DOI:	10.1016/j.jmoldx.2021.01.008
Abstrakt:	Tumor mutation burden (TMB) is an emerging biomarker of immunotherapy response. RNA sequencing in FFPE tissue samples was used for determining TMB in microsatellite-stable (MSS) and microsatellite instability-high (MSI-H) tumors in patients with colorectal or endometrial cancer. Tissue from tumors and paired normal tissue from 46 MSI-H and 12 MSS cases were included. Of the MSI-H tumors, 29 had defective DNA mismatch-repair mutations, and 17 had MLH1 promoter hypermethylation. TMB was measured using the expressed somatic nucleotide variants (eTMB). A method of accurate measurement of eTMB was developed that removes FFPE-derived artifacts by leveraging mutation signatures. There was a significant difference in the median eTMB values observed between MSI-H and MSS cases: 27.3 versus 6.7 mutations/megabase (mut/Mb) (P = 3.5 × 10 -9 ). Among tumors with defective DNA-mismatch repair, those with mismatch-repair mutations had a significantly higher median eTMB than those with hypermethylation: 28.1 versus 17.5 mut/Mb (P = 0.037). Multivariate analysis showed that MSI status, tumor type (endometrial or colorectal), and age were significantly associated with eTMB. Additionally, using whole-exome sequencing in a subset of these patients, it was determined that DNA TMB correlated well with eTMB (Spearman correlation coefficient, 0.83). These results demonstrate that RNA sequencing can be used for measuring eTMB in FFPE tumor specimens. (Copyright © 2021 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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