NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer.

PURPOSE: The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS: We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non-EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS: NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup (P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION: NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

Neotropical Clavulina: Two new species from Mexico and a re-evaluation of Clavulina floridana.

Clavulina comprises ca. 90 described species distributed worldwide in both tropical and temperate regions. However, only one species (C. floridana) has been described so far from tropical North America. We used morphological and molecular data from three DNA loci (nuc rDNA internal transcribed spacer region ITS1-5.8S-ITS2 [ITS], a portion of nuc 28S rDNA [28S], and a fragment of DNA-directed RNA polymerase II second largest subunit [RPB2]) from basidiomata and ectomycorrhizas collected in tropical ecosystems from three biogeographic provinces of Mexico and one tropical province in the USA to investigate the phylogenetic and taxonomic diversity of Clavulina in the region. Nine new species-level clades were discovered, two of which are proposed as new species (C. arboreiparva and C. tuxtlasana). Specimens of C. floridana recently collected in Florida were included in our analyses, for which a modern description is provided. In addition, C. floridana is a new record for Mexico. The diversity of Clavulina in tropical North America is comparable to that found in lowland tropical South America. However, some of the species found in tropical deciduous forests produce small, rare, and inconspicuous basidiomata, which easily go unnoticed, and therefore are poorly represented in collections. Many species remain undescribed in tropical regions of North America.

Expansion of the genus Imleria in North America to include Imleria floridana, sp. nov., and Imleria pallida, comb. nov.

Imleria is a small genus of Boletaceae found primarily in the Northern Hemisphere characterized by the light to dark brown hymenophore that stains blue. In Florida, specimens of Imleria were collected that resembled I. badia, a species known primarily from northeastern North America and Europe. Five nuclear loci of these Florida specimens were sequenced and phylogenetically analyzed. A nuc rDNA internal transcribed spacer ITS1-5.8S-ITS2 (ITS) phylogeny of Imleria was generated using primarily uncultured environmental sequences to confirm ectomycorrhizal associations. Based on morphological and molecular data, we describe a new species, Imleria floridana. Results from these analyses also support the new combination Imleria pallida. A lectotype of I. pallida is also established from Charles H. Peck's original material. We discuss the distinguishing characters and species of Imleria found in North America and provide a key to the known worldwide species of Imleria.