Mismatch repair deficiency is rare in bone and soft tissue tumors

Abstract

Introduction: There has been an increased demand for mismatch repair (MMR) status testing in sarcoma patients after the success of immune checkpoint inhibition (ICI) in MMR deficient tumors. However, data on MMR deficiency in bone and soft tissue tumors is sparse, rendering it unclear if routine screening should be applied. Hence, we aimed to study the frequency of MMR deficiency in bone and soft tissue tumors after we were prompted by two (potential) Lynch syndrome patients developing sarcomas. Methods: Immunohistochemical expression of MLH1, PMS2, MSH2 and MSH6 was assessed on tissue micro arrays (TMAs), and included 353 bone and 539 soft tissue tumors. Molecular data was either retrieved from reports or microsatellite instability (MSI) analysis was performed. In MLH1 negative cases, additional MLH1 promoter hypermethylation analysis followed. Furthermore, a systematic literature review on MMR deficiency in bone and soft tissue tumors was conducted. Results: Eight MMR deficient tumors were identified (1%), which included four leiomyosarcoma, two rhabdomyosarcoma, one malignant peripheral nerve sheath tumor and one radiation-associated sarcoma. Three patients were suspected for Lynch syndrome. Literature review revealed 30 MMR deficient sarcomas, of which 33% were undifferentiated/unclassifiable sarcomas. 57% of the patients were genetically predisposed. Conclusion: MMR deficiency is rare in bone and soft tissue tumors. Screening focusing on tumors with myogenic differentiation, undifferentiated/unclassifiable sarcomas and in patients with a genetic predisposition / co-occurrence of other malignancies can be helpful in identifying patients potentially eligible for ICI.

Soft Tissue Leiomyosarcoma With Microsatellite Instability, High Tumor Mutational Burden, and Programmed Death Ligand-1 Expression Showing Pathologic Complete Response to Pembrolizumab: A Case Report

“…The studies that report a higher incidence of MSI-H/MMRd status tend to be older studies with smaller sample sizes, whereas more recent contemporary studies or studies with larger sample sizes tend to report an incidence of around 1%-2%, which is likely more reflective of the true incidence. 7 , 13 - 15 Most MSI-H/MMRd sarcomas contain mutations in MSH2 or MLH1 , whereas MSH6 mutations (which was seen in our case) and PMS2 mutations form the minority, with an incidence of 11.6% and 2.3% of cases, respectively, in one study. 16…”

Histopathological and Molecular Profiling of Clear Cell Sarcoma and Correlation with Response to Crizotinib: An Exploratory Study Related to EORTC 90101 “CREATE” Trial

“…It is not surprising that some of these pathways have already been related to CCSA, such as transcriptional regulation and RTK signaling [ 8 , 10 ]. Furthermore, MMR-related protein MSH6 has previously been tested and was found to be absent in two out of 9 (22%) CCSA cases (one of which showed microsatellite instability) [ 56 , 57 ]. In our cohort, MMR dysregulation was observed in 6 of 24 (25%), which is in-line with the literature and indicates a potential contribution of MMR in a subset of CCSA cases.…”

Linking Immunity with Genomics in Sarcomas: Is Genomic Complexity an Immunogenic Trigger?

“…Thus, many clinical trials with T cell checkpoint blockade have enrolled sarcoma patients using these markers for selection, of which an all-encompassing overview is presented in the recent review article by Chew and colleagues [88]. In general, sarcomas have a relatively low mutational burden, infrequently express PD-L1, and less than 2% display defects in the DNA mismatch repair system [89][90][91]. Despite the absence of these predictive biomarkers, a considerable fraction of sarcoma patients respond to checkpoint blockade which supports the pursue of immunotherapy in sarcoma.…”

“…Moreover, alveolar soft-part sarcomas do not harbor many mutations aside from their characteristic TFE3-ASPCR1 fusion. Interestingly, it was suggested that few cases of alveolar-soft part sarcomas that responded well to checkpoint blockade exhibited MMRd [92,93], although the alleged prevalence of MMRd in alveolar soft-part sarcomas could not be confirmed in a larger cohort [91]. As opposed to tumors with well-known immunogenic features, such as a high mutation burden, it is speculated that the specific fusion found in alveolar soft-part sarcomas influences immune-related pathways underlying response to anti-PD-1 treatment.…”

“…In line with these findings, half of the sporadic cases of sarcomas with MMRd lack PD-L1 expression. However, MMRd sarcomas are still considered eligible for immune checkpoint inhibition as they often harbor a high mutational burden [91,96]. Some interesting and illustrative examples of the importance of TMB for response to checkpoint blockade are UV-induced angiosarcomas and occasional cases of myxofibrosarcomas and (UV-induced) undifferentiated soft tissue sarcomas [6,75,76,[97][98][99].…”