Clinical Targeted Next-Generation Sequencing Shows Increased Mutational Load in Endometrioid-type Endometrial Adenocarcinoma With Deficient DNA Mismatch Repair

International Journal of Gynecological Pathology : Official Journal of the International Society of Gynecological Pathologists
Paul J LeeIan S Hagemann

Abstract

A subset of endometrial adenocarcinomas (EACs) exhibit microsatellite instability and have deficient DNA mismatch repair (dMMR). The overall aim of the study was to compare the spectrum of mutations in endometrioid-type EAC with and without dMMR by using a clinically validated next-generation sequencing assay. We retrospectively identified 19 EACs with known mismatch repair status that had undergone targeted sequencing of a panel of cancer-related genes. The mismatch repair status was ascertained by immunohistochemistry against MLH1, PMS2, MSH2, and MSH6 mismatch proteins. Somatic mutations in EAC with dMMR were compared against those in cases with proficient MMR (pMMR). The dMMR EAC showed a normalized mean of 66.6 mutations/Mb per case compared with pMMR EAC with a mean of 26.2 (P<0.05). The most commonly mutated genes were PTEN (89% of dMMR, 50% of pMMR), PIK3CA (67% vs. 40%), ATM (89% vs. 40%), and FLT3 (67% vs. 50%). The transition/transversion ratio was 4.7 versus 2.8 for the dMMR and pMMR cohorts, respectively (P<0.05). Copy number variant analysis did not demonstrate significant differences between the dMMR and pMMR cohorts and was not correlated with histologic grade of EAC. In conclusion, tumorigenesis of EAC in the c...Continue Reading

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Citations

Feb 3, 2019·Virchows Archiv : an International Journal of Pathology·Dolors CuevasXavier Matias-Guiu

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Methods Mentioned

BETA
PCR
Illumina sequencing

Software Mentioned

pMMR
mSINGS
CopywriteR
Pindel
GATK
MSIsensor
Genome Analysis Tool Kit
VarScan 2
Graphpad
Prism

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