Gokce Toruner, MD, PhD is a laboratory geneticist specialized in clinical cytogenetics and clinical molecular genetics. He is currently an Associate Professor in the Department of Hematopathology at the MD Anderson Cancer Center. Dr. Toruner received his medical degree from Hacettepe University, Turkey and earned his Ph.D. from Bilkent University, Turkey. Following his research post-doctoral training at the Rutgers-New Jersey Medical School, he completed a clinical laboratory fellowship in clinical molecular genomics and cytogenomics in the same institution. His clinical expertise is on cancer cytogenomics, NGS based solid tumor testing. and liquid biopsy. His current academic activities focus on structural and copy number aberration in neoplasia and incidental constitutional genetic findings detected during somatic genetic testing.
Gokce Toruner, Hui Chen, Sinchita Roy-Chowdhuri, Asif Rashid, Keyur Patel, Raja Luthra, L. Jeffrey Medeiros, Richard Yang
The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Background: Deficiency of DNA mismatch repair function can be assessed by immunohistochemical (IHC) analysis for loss of expression of the mismatch repair (MMR) proteins MLH1, MSH2, MSH6 and PMS2 or microsatellite instability (MSI) analysis. In some cases, however, there is a discrepancy between IHC and MSI analysis. Our aim was to explain with molecular mutation analysis these discordant cases between IHC and MSI results.
Methods: We reviewed 706 neoplasms accessioned between 2015-2021 (345 gastrointestinal, 142 genitourinary, 192 gynecologic, 27 miscellaneous). All neoplasms were assessed by IHC testing, MSI analysis and tumor-normal paired next generation sequencing (NGS) analysis, and 80% of cases with MLH1 loss had concurrent MLH1 methylation analysis.
Results: Fifty-eight (8.2%) of neoplasms had deficient MMR. Forty-four (76%) of these patients had both dMMR and MSI-high status. Ten of 14 discordant cases had a major discordance between IHC and MSI analysis: [MSI-High/intact MMR expression (n=3), microsatellite stable (MSS)/loss of MLH1&PMS2 (n=1), MSS/loss of MSH2&MSH6 (n=3), MSS/loss of MSH6 (n=3), MSS/loss of MSH1 &MSH2 (n=1)]. Remaining 4 neoplasms are either MSI-low or with equivocal IHC results. Methylation and NGS analysis revealed a molecular etiology in 3 of 10 (30%) neoplasms with major discordance, whereas in neoplasms without major discordance, this figure was 77%. (p=0.007)
Conclusion: For most neoplasms, IHC and MSI testing are concordant, and a molecular etiology that explains dMMR or MSI-High results can be identified. For neoplasms with major discordance, the addition and integration of NGS results and MLH1 methylation analysis can be beneficial for resolving borderline cases.