New therapeutic targets for pulmonary sarcomatoid carcinomas based on their genomic and phylogenetic profiles

Abstract

ObjectivesPulmonary sarcomatoid carcinomas are rare and generally aggressive tumors composed of carcinomatous and sarcomatous components; however, the evolution of sarcomatoid cancer has not been elucidated. Here, we aimed to evaluate the mutational profiles and phylogeny of sarcomatoid carcinomas using next generation sequencing and in-silico analysis to facilitate the development of novel therapies.MethodsFour patients who underwent surgery for sarcomatoid cancer were enrolled. Cancer cells were collected from carcinomatous and sarcomatous components in each tumor by laser capture microdissection. Next-generation sequencing was performed in each component, and the mutation profiles were compared. For further inference of phylogenies, phylogenetic and PyClone analyses were performed. Mismatch repair disturbance and programmed death ligand-1 (PD-L1) expression were also evaluated.ResultsComparative genetic analysis of different histological areas revealed that the separate components shared several common mutations, which showed relatively high cellular prevalence in the PyClone statistical inference. Phylogenetic analysis showed that the sarcomatous component had ramified from the carcinomatous component in the early phase of the evolution process and accumulated a number of mutations that were different from those of the carcinomatous component. Moreover, microsatellite instability was detected in a case of sarcomatoid cancer and PD-L1 was strongly positive (≥ 50%) in all sarcomatoid cancers.ConclusionsOur data suggest that sarcomatoid carcinoma evolves from a common ancestral clone, and its phylogenetic features may reflect high-grade malignancy in pulmonary sarcomatoid carcinoma. High tumor mutation burden and strong PD-L1 staining may provide a rationale for the use of targeted immunotherapies in pulmonary sarcomatoid carcinomas.

Dendrimer size effects on the selective brain tumor targeting in orthotopic tumor models upon systemic administration

“…Clinically, patients with gliosarcoma face poorer prognoses 64 . Sarcomatous elements in tumors have been shown to correlate with increased PD‐L1 expression by tumor cells and suppression of the cytotoxic T‐cells 67 . This suppression creates an anti‐inflammatory immune environment that polarizes macrophages into TAMs, which exhibit efficient phagocytosis and endocytosis 68‐70 .…”

ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach

“…The literature search identified globally 158 unduplicated articles, 126 of which were excluded after reviewing their title/abstract, which left 32 articles eligible for full text review. After applying our inclusion and exclusion criteria, 18 articles (for 17 cohorts) were selected for this systematic review [7,[59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75] (supplementary Figure S1, available at Annals of Oncology online).…”

“…The vast majority of the cohorts reported data on patients from the USA, followed by Asian and European subjects. The majority of the manuscripts (59%) investigated original cohorts of patients [7,61,[63][64][65][66][67][68][69][70]75], whereas data derived from external (public or private) databases were used in some papers [59,62,[71][72][73][74].…”

“…TMB was assessed using whole-exome sequencing in 5 (29%) studies [7,59,60,69,70], and using multigene cancer panels in the remaining 12 (71%), where TMB-high is variably defined as tumours showing at least 17 or 20 mutations/Mb upon sequencing of at least 1.2-1.5 Mb [61][62][63][64][65][66][67][71][72][73][74][75]. To assess MSI status, an approach based on both IHC to assess MMR status and/or molecular assessment of microsatellites by MSI-PCR and NGS was applied in most studies (82%) [7, 59-61, 64, 66, 68-75].…”

“…Genomic analyses have shown that particular mutational signatures can contribute to high TMB independently from MSI status. These include BRCA1/2 (breast cancer genes 1 and 2) and APOBEC deficiency, neoantigen load, ultraviolet rays exposure and mutations affecting TP53 and polymerase e (POLE) (supplementary Figure S2, available at Annals of Oncology online) [7,59,70,[90][91][92][93][94][95].…”