Culex quinquefasciatus (the Southern house mosquito) is an important mosquito vector of viruses such as West Nile virus and St. Louis encephalitis virus as well of nematodes that cause lymphatic filariasis. It is one species within the Culex pipiens species complex and enjoys a distribution throughout tropical and temperate climates of the world. The ability of C. quinquefasciatus to take blood meals from birds, livestock and humans contributes to its ability to vector pathogens between species. We describe the genomic sequence of C. quinquefasciatus, its repertoire of 18,883 protein-coding genes is 22% larger than Ae. aegypti and 52% larger than An. gambiae with multiple gene family expansions including olfactory and gustatory receptors, salivary gland genes, and genes associated with xenobiotic detoxification.

Mutations in non-coding DNA regions are increasingly recognized as cancer drivers. These mutations can modify gene expression in cis or by inducing high-order chormatin structure modifications with long-range effects. Previous analysis reported the detection of recurrent and functional noncoding DNA mutations in the chronic lymphocytic leukemia (CLL) genome, such as those in the 3′ untranslated region of NOTCH1 and in the PAX5 super-enhancer. In this report, we used whole genome sequencing data produced by the International Cancer Genome Consortium in order to analyze regions with previously reported regulatory activity. This approach enabled the identification of numerous recurrently mutated regions that were frequently positioned in the proximity of genes involved in immune and oncogenic pathways. By correlating these mutations with expression of their nearest genes, we detected significant transcriptional changes in genes such as PHF2 and S1PR2. More research is needed to clarify the function of these mutations in CLL, particularly those found in intergenic regions. A major part of mutations in the cancer genome occur in non-coding DNA regions, and their function is still beginning to be understood 1. Non-coding DNA comprises approximately 98% of the human genome, but recent research has proven that most of these regions are either part of regulatory motifs or actively transcribed to RNA 2,3. These mutations can induce functional genomic changes by altering the binding of transcription factors or by inducing high-order chromatin structural modifications 2,4. For example, mutations in 5′ and 3′ untranslated regions (UTRs) may disturb RNA structural conformation, modify microRNA binding sites or disrupt polyadenylation signals 2. In a similar fashion, mutations affecting non-protein coding genes such as microRNA and long intergenic RNA genes (lincRNAs) are known cancer driver events 2,5. Different studies have evidenced that the expression of genes such as BRCA1, CDH10, CCND1, MALAT1, PAX5, RB1, SDHD, TERT, TOX3, and TAL1 is influenced by non-coding DNA mutations in regulatory regions of the cancer genome 1,6,7. The Pancancer Analysis of Whole Genomes (PCAWG) project has revealed the existence of common and tumor-specific recurrently mutated functional elements near known cancer drivers 7. Some of these driver mutations can induce long-range changes in genome organization and trigger abnormal expression of distant oncogenes and tumor suppressors 8. Furthermore, the sequence distribution of these driver mutations is not random. Hornshøj et al. (2018) identified a significant enrichment in conserved CCCT-binding factor (CTCF) binding sites among recurrently mutated non-coding DNA regions with cancer specificity 6. Similarly, Line et al. (2019) identified 21 recurrently altered CTCF-rich insulator regions in the cancer genome, and elegantly demonstrated that some of these mutations drive tumor proliferation 9. Chronic Lymphocytic Leukemia (CLL) is among the most frequent lymphoproliferative disorders, and it is cha...

INTRODUCTION Follicular lymphoma (FL) may, over time, transform into an aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). Transformed follicular lymphomas (tFL) have a worse prognosis due to poorer response to treatment than primary DLBCL. The incidence of transformation is estimated in ~3% per year, although it varies largely between different studies (24%-70% overall). These differences are mainly due to different criteria to define tFL, to lack of evidence of tFL by biopsy, absence of clonality studies discarding secondary de novo NHL, studies performed in the pre-Rituximab era, or different follow-up times among studies. With all this pitfalls, the actual incidence of transformation remains an open question. The aim of the present study is to analyse the incidence and prognostic impact of transformation in patients with FL in a large retrospective series of the Spanish group of Lymphomas (GELTAMO). PATIENTS&METHODS A total of 1763 patients from 19 Spanish centres diagnosed of FL between 2000 and 2011 were recruited in the study. Data were obtained from the database of centres willing to participate in this study. True tFL (FL to DLBCL) were recorded. From the original cohort, FL IIIb, composite FL+DLBCL, discordant FL (FL in bone marrow and DLBCL in adenopathy or viceversa), and downgrading tFL (DLBCL at diagnosis and relapse of FL) were excluded. Patients with inadequate follow-up were not considered. Therefore, 1611 patients (grade I, II, and IIIa) were finally included. This study was approved by the Salamanca University Hospital Ethic Committee. RESULTS One hundred and ten patients (median follow up of 6 years) were transformed to DLBCL. Cumulative incidence of transformation at 5, 10, and 15 years was of 5%, 9%, and 14%, respectively. With a median follow up of 75.9 months (2 to 179), median time to transformation was 66 months, ranged 1-179. Considering survival from diagnosis of FL, tFL patients had a shorter OS than non-transformed (19% vs. 69%, p<0,0001). Most of the tFL patients (92%) have previously received treatment for FL, 63% of them with Rituximab. Median number of treatment lines before transformation was 2 (1-7). Factors influencing risk of tFL in the multivariate analysis included non-response to first line therapy (PR, p<0.001, HR:2,5 95% CI:1.5-4.2; others, p<0.0001, HR: 8,1 95% CI: 4.1-16.0), and FLIPI>2 (p=0.002, HR: 2,1 95% CI: 1.3-3.4). In the multivariate analysis, factors predicting decreased OS after transformation included non-achievement of CR after first line therapy (p<0,001, HR:4.3 95% CI:2-9.1), and elevated LDH at the moment of transformation (p=0,003, HR:3 95% CI:1.5-6.3). We analyzed separately the role of autologous stem cell transplantation (ASCT) in transformed FL patients. Patients that received ASCT were significantly younger (<70 years) p<0,001, had a better performance status (ECOG <2) (p=0,008) and had achieved a better response (CR) (p<0,001) than those who did not receive ASCT. All of them in our series were treated with rituximab based regimens at transformation. When we analyzed those patients that were eligible for ASCT (younger than 70), patients that received ASCT showed a better OS after transformation than those who did not (51% vs 26% at 5 years, p=0,004). Interestingly, patients who achieve CR to first line therapy at transformation did not beneficiate of ASCT (54% vs 66% at 5 years, p=0,8) while those who do not achieve CR did (50% vs 16% at 5 years, p=0,008). CONCLUSIONS In this series, one of the largest reported in the rituximab era, high risk FLIPI (>=2) and non-response to FL first line therapy were associated with a higher risk of transformation.Only non-response to transformed FL treatment therapy and a high LDH at transformation were associated with a worse OS after transformation in the multivariate analysis. Autologous transplantation in transformed patients could have a benefit in terms of OS after transformation, but after the introduction of immunochemotherapy strategies, perhaps patients responding to treatment after transformation do not beneficiate from this strategy. *Equal contribution; ‡Equal senior contribution Disclosures Sancho: CELLTRION, Inc.: Research Funding.