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

Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers

“…Doublet-base substitution (DBS) signatures specific to MMRd tumors were also identified (DBS7 and DBS10 signatures) as well as small insertion and deletion (ID) signatures (ID1, ID2, ID7 signatures) [ 83 ]. Importantly, multiple distinct mutational signatures may result from different mutational processes, as shown for MMRd and Polymerase Epsilon ( POLE) /Polymerase Delta 1 ( POLD1) mutant tumors (SBS14 and SBS20) [ 83 , 84 , 85 ]. Overall, the identification of mutational signatures in cancer is pivotal to understanding the biological process behind a cancer type, thus ultimately informing clinical decision making.…”

The Challenge of Diagnosing Constitutional Mismatch Repair Deficiency Syndrome in Brain Malignancies from Young Individuals

“…Another possible option that would allow the identification of CMMRD in brain tumors would be sequencing to determine MSI, mutation burden and signatures, and other alterations characteristic of these tumors, such as POLE or POLD1 variants. In fact, a recent report has revealed novel signatures that are uniquely attributed to mismatch repair deficiency by using exome- and genome-wide microsatellite instability analysis [ 74 ]. In this study different microsatellite (MS)-mutated loci, lack of recurrently mutated MS-loci and lack of long MS-indels have been identified as the main differences between childhood and adult MMR-deficient cancers.…”

Upfront Adjuvant Immunotherapy of Replication Repair–Deficient Pediatric Glioblastoma With Chemoradiation-Sparing Approach

“…He underwent a repeat gross total resection, and pathology confirmed recurrent GBM. The specimen from this second resection was sent to the reference laboratory of the International Replication Repair Deficiency Consortium 10,11 for further analysis.…”