ABSTRACT
PURPOSE: To comprehensively characterize tissue-specific and molecular subclasses of multiple PIK3CA (multi-PIK3CA) mutations and assess their impact on potential therapeutic outcomes. EXPERIMENTAL DESIGN: We profiled a pan-cancer cohort comprised of 352,392 samples across 66 tumor types using a targeted hybrid capture-based next-generation sequencing panel covering at least 324 cancer-related genes. Molecularly defined subgroups, allelic configuration, clonality, and mutational signatures were identified and tested for association with PI3K inhibitor therapeutic response. RESULTS: Multi-PIK3CA mutations are found in 11% of all PIK3CA-mutant tumors, including 9% of low tumor mutational burden (TMB) PIK3CA-mutant tumors, and are enriched in breast and gynecologic cancers. Multi-PIK3CA mutations are frequently clonal and in cis on the same allele and occur at characteristic positions across tumor types. These mutations tend to be mutually exclusive of mutations in other driver genes, and of genes in the PI3K pathway. Among PIK3CA-mutant tumors with a high TMB, 18% are multi-PIK3CA mutant and often harbor an apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational signature. Despite large differences in specific allele combinations comprising multi-PIK3CA mutant tumors, especially across cancer types, patients with different classes of multi-PIK3CA mutant estrogen receptor-positive, HER2-negative breast cancers respond similarly to PI3K inhibition. CONCLUSIONS: Our pan-tumor study provides biological insights into the genetic heterogeneity and tissue specificities of multi-PIK3CA mutations, with potential clinical utility to guide PI3K inhibition strategies.
Subject(s)
Breast Neoplasms , Phosphatidylinositol 3-Kinases , Humans , Female , Phosphatidylinositol 3-Kinases/genetics , Genetic Heterogeneity , Breast Neoplasms/pathology , Mutation , Class I Phosphatidylinositol 3-Kinases/geneticsABSTRACT
AIM: The aim and objective of this in vitro study was to evaluate the antimicrobial efficacy of root canal sealers (bioceramic [BC] sealer, Epiphany self-etch sealer, and AH-Plus sealer) on Staphylococcus aureus and Candida albicans. MATERIALS AND METHODS: An agar well diffusion assay method was used to determine the efficacy of the root canal sealer against S. aureus (ATCC 6538) and C. albicans (ATCC 10231). Root canal sealers were divided into three groups: BC sealer, Epiphany self-etch sealer, and AH-Plus sealer, and the standard antibiotic disc of amoxiclav and fluconazole was kept as a control against S. aureus and C. albicans. The diameters of the growth inhibition zones against S. aureus and C. albicans for each group were recorded and compared at 24 h. The differences between groups were analyzed by one-way ANOVA and Tukey's post hoc tests for intergroup analysis. RESULTS: AH-Plus sealer exhibited a larger zone of inhibition than the other two sealers against S. aureus and C. albicans at 24 h. The standard antibiotic disc of fluconazole, which was used as a control against C. albicans, exhibited a higher antimicrobial activity than the AH-Plus sealer at 24 h, whereas Epiphany self-etch sealer showed the least antimicrobial activity against S. aureus and C. albicans. CONCLUSION: The AH-plus root canal sealer exhibits a better antibacterial action against S. aureus and C. albicans at 24 h.
