Toma, H. | bioRxiv Science

bioRxiv2020

CDKN2C homozygous loss identifies a distinct subtype of TP53/RB1-wildtype leiomyosarcoma with frequent CIC genomic alterations and 1p/19q-codeletion

PurposeLeiomyosarcomas (LMS) harbor frequent inactivation of TP53 and RB1, and extensive DNA copy number alterations. Here, we describe a distinct recurrent genomic signature in TP53/RB1-wildtype uterine LMS. MethodsTissues from 276,645 unique advanced cancers, including 2,570 uterine and soft tissue LMS were sequenced by hybrid-capture-based next-generation DNA and RNA sequencing/comprehensive genomic profiling of up to 406 genes. We characterized clinicopathologic features of relevant cases. ResultsWe identified 77 LMS with homozygous copy loss of CDKN2C at chromosome 1p32.3 (3.0% of LMS). Genomic alterations (GAs) in TP53, RB1, and ATRX were rare in comparison with the remainder of the LMS cohort (11.7% vs 73.4%, 0% vs 54.5%, 2.6% vs 24.5%, all p<0.0001). CDKN2C-null LMS cases were significantly enriched for GAs in CIC (40.3% vs 1.4%) at 19q13.2, CDKN2A (46.8% vs 7.0%), and RAD51B (16.9% vs 1.7%; all p<0.0001). Chromosome arm-level aneuploidy analysis of available LMS cases (n=1,251) found that 85% (n=33/39) of CDKN2C-null LMS cases exhibited 1p/19q-codeletion, with significant enrichment in comparison to the remainder of the evaluated LMS cohort (85% vs. 5.1%, p<0.0001). 99% of CDKN2C-null cases were in females; median age was 61 years at surgery (range, 36-81 years). 55 cases were of uterine primary, 4 cases non-uterine, and the remaining 18 of uncertain primary site. 6 patients had a prior history of leiomyomatosis or uterine smooth muscle tumor of uncertain malignant potential. 60% of cases showed at least focal epithelioid variant histology. Most cases were of known advanced stage, with 62% of confirmed uterine primary cases at FIGO stage IVB. ConclusionThe identification of this novel genomic subset may have prognostic and/or therapeutic clinical relevance, including use of specific cyclin-dependent kinase inhibitors.

cancer biology↗

bioRxiv2019

Natural infection and vertical transmission of two flaviviruses (Yellow fever and Zika) in mosquitoes in primary forests in the Brazilian state of Rio de Janeiro (Diptera: Culicidae)

BackgroundZika virus (ZIKV) was recently introduced in the American continent, probably transmitted by Aedes aegypti and possibly by Ae. albopictus and Culex quinquefasciatus in urban environments. ZIKV represents a known public health problem as it has been involved in newborn cases of congenital microcephaly in South America since 2005. The transmission of this virus in forested areas of other countries and its relative ubiquity in relation to its vectors and reservoirs raises suspicions of its adaptation to non-human modified environments (i.e., natural forests reserve) or on this continent, similar to those seen for Yellow fever virus (YFV). The objective of this work was to have an epidemiological monitoring tool mapping insects as well as circulating arboviruses in wild areas with low human interference. This study was based on the history of the insect flavivirus spreading cycle.\n\nMethods/Principal FindingsUsing a previously described sensitive PCR-based assay to assess the conserved NS5 region of the Flavivirus genus, both YFV partial genome and ZIKV were found in pools of Aedes albopictus, a sylvatic mosquito adapted to human-modified environments, and in Haemagogus leucocelaenus, a sylvatic mosquito.\n\nConclusionsThis is the first report of natural infection by ZIKV in mosquitoes in a sylvatic environment on the American continent. The wide distribution of these mosquitoes is probably important in the transmission of ZIKV. Vertical transmission indicates a higher efficiency for the maintenance and transmission of the virus in nature as well as the presence of the ZIKV in permanent character in the forest areas as it occurs with the YFV thus making more difficult the prevention of new cases of Zika in humans.\n\nAuthor SummaryArboviruses are diseases transmitted by arthropod vectors, hence the origin of the term ARthropod BOrne VIRUS, which is adopted since 1942. This work had as objective to survey the circulating insects as well as to detect the presence of viruses in them. Arboviruses circulate between insects and vertebrate hosts, having importance for promoting diseases in humans and animals. The diseases most known at the time, due to the recent cases reported by South America, are Dengue, Zika, Yellow Fever and Chikungunya. For this study, we used appropriate traps to collect the insects and their eggs in wild areas where there is little human interference. After collection, mosquitoes and / or eggs were identified and separated as to the source and species. The eggs were kept in laboratory conditions for the hatching of new insects. All the insects obtained were separated into pools to be macerated and thus extract the RNA from the viruses to be studied. Using molecular biology techniques, in our case the RT-PCR (Reverse Transcriptase Polymerase Chain Reaction), we amplified the RNA and in sequentially, we performed the sequencing reaction. With sequencing, it is possible to identify which virus material is present since each virus has a characteristic arrangement. For the identification of the sequences, we need to use some computational programs that guarantee us the correct result.

molecular biology↗