Defective DNA mismatch repair (dMMR) causes elevated tumour mutational burden (TMB) and microsatellite instability (MSI) in multiple cancer types. dMMR/MSI colorectal cancers (CRCs) have enhanced T... Show moreDefective DNA mismatch repair (dMMR) causes elevated tumour mutational burden (TMB) and microsatellite instability (MSI) in multiple cancer types. dMMR/MSI colorectal cancers (CRCs) have enhanced T-cell infiltrate and favourable outcome; however, this association has not been reliably detected in other tumour types, including endometrial cancer (EC). We sought to confirm this and explore the underpinning mechanisms. We first meta-analysed CRC and EC trials that have examined the prognostic value of dMMR/MSI and confirmed that dMMR/MSI predicts better prognosis in CRC, but not EC, with statistically significant variation between cancers (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.54-0.73 versus HR = 1.15, 95% CI = 0.72-1.58; P-INT = 0.02). Next, we studied intratumoural immune infiltrate in CRCs and ECs of defined MMR status and found that while dMMR was associated with increased density of tumour-infiltrating CD3(+) and CD8(+) T-cells in both cancer types, the increases were substantially greater in CRC and significant only in this group (P-INT = 4.3e-04 and 7.3e-03, respectively). Analysis of CRC and EC from the independent Cancer Genome Atlas (TCGA) series revealed similar variation and significant interactions in proportions of tumour-infiltrating lymphocytes, CD8(+), CD4(+), NK cells and immune checkpoint expression, confirming a more vigorous immune response to dMMR/MSI in CRC than EC. Agnostic analysis identified the IFN gamma pathway activity as strongly upregulated by dMMR/MSI in CRC, but downregulated in EC by frequent JAK1 mutations, the impact of which on IFN gamma response was confirmed by functional analyses. Collectively, our results confirm the discordant prognosis of dMMR/MSI in CRC and EC and suggest that this relates to differences in intratumoural immune infiltrate and tumour genome. Our study underscores the need for tissue-specific analysis of cancer biomarkers and may help inform immunotherapy use. (c) 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. Show less
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... Show moreIntroduction 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. Show less
Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy... Show moreIndividuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals. Show less
