Journal article
RNA-Seq Reveals Differences in Expressed Tumor Mutation Burden in Colorectal and Endometrial Cancers with and without Defective DNA-Mismatch Repair
The Journal of molecular diagnostics : JMD, Vol.23(5), pp.555-564
05/2021
DOI: 10.1016/j.jmoldx.2021.01.008
PMID: 33549857
Abstract
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.
Details
- Title: Subtitle
- RNA-Seq Reveals Differences in Expressed Tumor Mutation Burden in Colorectal and Endometrial Cancers with and without Defective DNA-Mismatch Repair
- Creators
- Margaret A DiGuardo - Mayo ClinicJaime I Davila - St. Olaf CollegeRory A Jackson - Mayo ClinicAsha A Nair - Mayo ClinicNumrah Fadra - Mayo ClinicKay T Minn - Mayo ClinicMazen A Atiq - Mayo ClinicShabnam Zarei - Cleveland ClinicJoseph H Blommel - Mayo ClinicShannon M Knight - Mayo ClinicJin Jen - Mayo ClinicBruce W Eckloff - Mayo ClinicJesse S Voss - Mayo ClinicKandelaria M Rumilla - Mayo ClinicSarah E Kerr - Hospital Pathology Associates, Minneapolis, Minnesota.Dora M Lam-Himlin - Department of Laboratory Medicine and Pathology, Divisions of Laboratory Genetics and Experimental Pathology, and Health Sciences Research, Mayo Clinic, Phoenix, ArizonaAndrew M Bellizzi - University of IowaRondell P Graham - Mayo ClinicBenjamin R Kipp - Mayo ClinicRobert B Jenkins - Mayo ClinicKevin C Halling - Mayo Clinic
- Resource Type
- Journal article
- Publication Details
- The Journal of molecular diagnostics : JMD, Vol.23(5), pp.555-564
- DOI
- 10.1016/j.jmoldx.2021.01.008
- PMID
- 33549857
- NLM abbreviation
- J Mol Diagn
- ISSN
- 1525-1578
- eISSN
- 1943-7811
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 05/2021
- Academic Unit
- Pathology
- Record Identifier
- 9984185277502771
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