Dataset Information

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

ABSTRACT: Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.

SUBMITTER: Chung J

PROVIDER: S-EPMC8223607 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Chung Jiil J Maruvka Yosef E YE Sudhaman Sumedha S Kelly Jacalyn J Haradhvala Nicholas J NJ Bianchi Vanessa V Edwards Melissa M Forster Victoria J VJ Nunes Nuno M NM Galati Melissa A MA Komosa Martin M Deshmukh Shriya S Cabric Vanja V Davidson Scott S Zatzman Matthew M Light Nicholas N Hayes Reid R Brunga Ledia L Anderson Nathaniel D ND Ho Ben B Hodel Karl P KP Siddaway Robert R Morrissy A Sorana AS Bowers Daniel C DC Larouche Valérie V Bronsema Annika A Osborn Michael M Cole Kristina A KA Opocher Enrico E Mason Gary G Thomas Gregory A GA George Ben B Ziegler David S DS Lindhorst Scott S Vanan Magimairajan M Yalon-Oren Michal M Reddy Alyssa T AT Massimino Maura M Tomboc Patrick P Van Damme An A Lossos Alexander A Durno Carol C Aronson Melyssa M Morgenstern Daniel A DA Bouffet Eric E Huang Annie A Taylor Michael D MD Villani Anita A Malkin David D Hawkins Cynthia E CE Pursell Zachary F ZF Shlien Adam A Kunkel Thomas A TA Getz Gad G Tabori Uri U

Cancer discovery 20201218 5

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indel ...[more]

PMID: 33355208

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Project description:BackgroundMismatch-repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity.MethodsSix hundred sixty-six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut-L homolog 1 (MLH1) methylation. Select samples underwent whole-transcriptome analysis and next-generation sequencing. MMR expression of metastatic/recurrent sites was evaluated.ResultsMSI testing identified 27.3% of cases as MSI-high (n = 182), MMR IHC identified 25.1% cases as MMR-deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut-S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6-associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR-deficient cases and 9% in MMR-proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial-mesenchymal transition.ConclusionsSubclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR-deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker-directed therapy.Plain language summaryEndometrial cancer is the most common gynecologic cancer, and 20%-40% of tumors have a defect in DNA proofreading known as mismatch-repair (MMR) deficiency. These results can be used to guide therapy. Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities. Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes. Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread. These MMR-deficient cells may drive tumor behavior and the risk of spreading cancer.

Dataset Information

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Publications

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

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