ObjectiveAlthough Polymerase-epsilon (POLE)-mutated and mismatch repair (MMR)-deficient endometrial cancers (ECs) are considered as promising candidates for anti-PD-1/PD-L1 therapy, selecting only these patients may exclude other patients who could potentially respond to this treatment strategy, highlighting the need of additional biomarkers for better patient selection. This study aims to evaluate potential predictive biomarkers for anti-PD-1/PD-L1 therapy in addition to POLE mutation (POLEm) and MMR deficiency (MMRd).MethodsWe performed next generation sequencing for POLE from 202 ECs, and immunohistochemistry for MLH1, MSH2, MSH6, PMS2, CD3, CD8, PD-1 and PD-L1 on full-section slides from these ECs. We assessed the association of POLEm and MMRd with clinicopathologic features, expression of check point proteins, and density of tumor-infiltrating lymphocytes (TILs). Prognostic impact of these immune markers was also evaluated.ResultsPOLEm, MMRd and high-grade tumors exhibited elevated level of TILs. Increased expression of PD-1 and PD-L1 was observed in MMRd and high-grade ECs. A subgroup of MMR proficient ECs also harbored increased density of TILs, and positive expression of PD-1 and PD-L1. In addition, negative expression of checkpoint proteins and high density of TILs in combination was associated with good prognosis.ConclusionsCandidates for PD-1 blockade may extend beyond POLEm and MMRd ECs, additional factors such as tumor grade, and combination of TILs levels and expression of checkpoint proteins may need to be considered for better patient selection.

Background Microcystic adnexal carcinoma (MAC) is a skin cancer with challenges in diagnosis and management. This study was aimed to detect molecular alterations of MAC and guide its pathologic diagnosis and treatment. Methods We performed transcriptome analysis on 5 MAC and 5 normal skin tissues, identified the differentially expressed genes, and verified them by immunohistochemistry. Results Three hundred four differentially expressed genes (DEGs) in MAC were identified by next-generation transcriptome sequencing, among which 225 genes were upregulated and 79 genes were downregulated. Four genes of the calcium signaling pathway, including calcium voltage-gated channel subunit alpha 1 S (CACNA1S), ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1 (ATP2A1), ryanodine receptor 1 (RYR1), and myosin light chain kinase 3 (MYLK3), were upregulated and then been verified by immunohistochemistry. The expression of CACNA1S, ATP2A1, RYR1, and MYLK3 was upregulated in MAC compared with normal sweat glands and syringoma tumor cells and was generally negative in trichoepithelioma and infundibulocystic type basal cell carcinoma. Conclusions The four genes of the calcium signaling pathway were upregulated in MAC at both RNA and protein levels. CACNA1S, ATP2A1, RYR1, and MYLK3 may be new diagnostic molecular markers and therapeutic targets for MAC.

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