Homozygous lack of was only detected in one LS patient, while single copy loss of occurred in 10% (3/29) of LS and 21% (4/19) of HS/CB patients

Homozygous lack of was only detected in one LS patient, while single copy loss of occurred in 10% (3/29) of LS and 21% (4/19) of HS/CB patients. remaining data, including de-identified clinical data, are available within the Article, Supplementary Information or Source Data file.?Source data are provided with this paper. Custom code for analysis and producing visualization of the paper can be accessed via the project github repository [https://github.com/pughlab/inspire-genomics]91. Abstract Serial circulating tumor DNA (ctDNA) monitoring is emerging as a noninvasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data Amiloride HCl exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (“type”:”clinical-trial”,”attrs”:”text”:”NCT02644369″,”term_id”:”NCT02644369″NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity Rabbit Polyclonal to UGDH and resistance. We identified the upregulated expression of is frequently altered in baseline tumors from pembrolizumab-treated patients with clinical benefit To uncover genomic alterations associated with pembrolizumab response, we identified genes that were more frequently altered by non-synonymous germline or somatic mutations in patients who experienced CB or high pembrolizumab sensitivity (HS/CB; was mutated in 5 HS/CB (26%) and none in LS of mixed cancer types (TNBC, Merkel cell carcinoma, HGSC, MM, sarcoma, and basal cell carcinoma) (Fig. ?(Fig.2A).2A). mutation frequency was 12.5% (9 of 72) in our data set and similarly distributed Amiloride HCl across cancer cohorts (HGSC: 0/19, TNBC: 1/21, HGSC 2/21, MM: 2/12, and Mixed: 4/28). Increased frequency of mutations was also identified from a similar Amiloride HCl analysis reported by Hugo et al.9 in a cohort of metastatic melanoma patients. Interestingly, mutations in were not enriched in either group (HS/CB?=?1/19, LS?=?3/27 (Fig. ?(Fig.2A).2A). No single gene was found to Amiloride HCl be significantly enriched for mutations in the LS group, possibly due to the large number of alternate and overlapping signaling transduction pathways that can manifest immune evasion and escape phenotypes. Open in a separate window Fig. 2 Somatic alterations in patients sensitive and resistant to pembrolizumab.A Co-mutation plot of mutation burden, mutation signatures, somatic, and germline mutations (purple, left) in selected DNA repair genes, known cancer and immune evasion related genes, and antigen presentation genes. Copy number alterations for selected immune evasion and antigen presentation genes are also shown (yellow, left). Samples are grouped as pembrolizumab-sensitive (in the HS/CB group) and resistant (in the LS group) and sorted in order of decreasing TMB within each group. Genes are grouped by curated categories and shown in order of decreasing frequency across both groups. (bold) had significantly higher mutation frequency in the ICB sensitive group. For the complete list of curated genes, refer to Supplementary Table?1. Only genes with alterations are shown. B Comparison of TMB between samples with or without mutations. C Comparison of PD-L1 expression by IHC staining between samples with or without mutations. For violin plots in B and C, the median for each group is marked by a horizontal black line in the center of a rectangle and data points are shown as open circles. The distance between the third-quartile (Q3) and first-quartile (Q1), known as the interquartile range (IQR), is marked around the median by a rectangle. Vertical lines extending from the top and bottom of the rectangle show the maximum (Q3?+?1.5-times IQR) and minimum(Q1?+?1.5-times IQR). Statistical significance was determined using two-sided Wilcoxon rank-sum tests. D Comparison of LOH frequency in pembrolizumab sensitivity groups. The number of samples with LOH within each sensitivity group is annotated.