Mitochondrial genome sequencing of marine leukaemias reveals cancer contagion between clam species in the Seas of Southern Europe

Clonally transmissible cancers are tumour lineages that are transmitted between individuals via the transfer of living cancer cells. In marine bivalves, leukaemia-like transmissible cancers, called hemic neoplasia (HN), have demonstrated the ability to infect individuals from different species. We performed whole-genome sequencing in eight warty venus clams that were diagnosed with HN, from two sampling points located more than 1000 nautical miles away in the Atlantic Ocean and the Mediterranean Sea Coasts of Spain. Mitochondrial genome sequencing analysis from neoplastic animals revealed the coexistence of haplotypes from two different clam species. Phylogenies estimated from mitochondrial and nuclear markers confirmed this leukaemia originated in striped venus clams and later transmitted to clams of the species warty venus, in which it survives as a contagious cancer. The analysis of mitochondrial and nuclear gene sequences supports all studied tumours belong to a single neoplastic lineage that spreads in the Seas of Southern Europe.Postprin

Heterogeneity of genomic evolution and mutational profiles in multiple myeloma

Multiple myeloma is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Here we use whole-exome sequencing, copy-number profiling and cytogenetics to analyse 84 myeloma samples. Most cases have a complex subclonal structure and show clusters of subclonal variants, including subclonal driver mutations. Serial sampling reveals diverse patterns of clonal evolution, including linear evolution, differential clonal response and branching evolution. Diverse processes contribute to the mutational repertoire, including kataegis and somatic hypermutation, and their relative contribution changes over time. We find heterogeneity of mutational spectrum across samples, with few recurrent genes. We identify new candidate genes, including truncations of SP140, LTB, ROBO1 and clustered missense mutations in EGR1. The myeloma genome is heterogeneous across the cohort, and exhibits diversity in clonal admixture and in dynamics of evolution, which may impact prognostic stratification, therapeutic approaches and assessment of disease response to treatment

Spread of a SARS-CoV-2 variant through Europe in the summer of 2020.

Following its emergence in late 2019, the spread of SARS-CoV-21,2 has been tracked by phylogenetic analysis of viral genome sequences in unprecedented detail3–5. Although the virus spread globally in early 2020 before borders closed, intercontinental travel has since been greatly reduced. However, travel within Europe resumed in the summer of 2020. Here we report on a SARS-CoV-2 variant, 20E (EU1), that was identified in Spain in early summer 2020 and subsequently spread across Europe. We find no evidence that this variant has increased transmissibility, but instead demonstrate how rising incidence in Spain, resumption of travel, and lack of effective screening and containment may explain the variant’s success. Despite travel restrictions, we estimate that 20E (EU1) was introduced hundreds of times to European countries by summertime travellers, which is likely to have undermined local efforts to minimize infection with SARS-CoV-2. Our results illustrate how a variant can rapidly become dominant even in the absence of a substantial transmission advantage in favourable epidemiological settings. Genomic surveillance is critical for understanding how travel can affect transmission of SARS-CoV-2, and thus for informing future containment strategies as travel resumes. © 2021, The Author(s), under exclusive licence to Springer Nature Limited

An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance

Whole Genome Sequencing Reveals Recurrent Structural Driver Events in Peripheral T-Cell Lymphomas Not Otherwise Specified

Historically, the differential diagnosis between different nodal peripheral T-cell lymphoma (PTCL) subtypes based on morphological and phenotypic grounds has posed great challenges. In the last few years, our knowledge of the molecular bases of different PTCLs has significantly expanded. However, peripheral T-cell lymphomas not otherwise specified (PTCL-NOSs) are still regarded to as a heterogeneous category encompassing PTCL cases not fitting other, more homogeneous, subtypes. In fact, PTCL-NOS is one of the few lymphoma subtypes where no recurrent driver mutations have been reported so far. In order to better characterized the PTCL-NOS genomic landscape, we decided to investigate 11 PTCL-NOS patients by a whole genome sequencing (WGS) approach (median coverage 27X). Ten out of eleven samples were collected from FFPE blocks and 2 were removed from analysis: one due to low cancer cell fraction (CCF) and the other based on cluster generation issues during sequencing likely caused by a hyper-fragmented DNA. Among the remaining 9 cases, we extracted 59,617 somatic base substitutions (range 2,471-10,756, median 6,358 per patient) and 20,531 small insertion-deletions (indels) (range 84-6,397, median 1,580). We were able to characterize the spectrum of FFPE-induced artefacts, mostly composed of point mutations and indels within LINE-1 (L1) elements, predominantly of the L1PA family. This is a crucial quality control step that could be applied to similar future studies from archive samples. Four samples were heavily involved by FFPE-related artefacts and were excluded for this reason. Using a non-negative matrix factorization (NNMF) algorithm we investigated for the first time the PTCL-NOS mutational signature landscape. We did not find novel processes in this entity, but rather known processes operative in other lymphoid malignancies. Among those: signatures 1 and 5, deriving from the age-related process of spontaneous deamination of methylated cytosines; signatures 2 and 13 deriving from aberrant activity of the APOBEC family of DNA deaminases; signatures 17 and 8, pertaining to two yet poorly characterized processes. The contribution of different processes to the mutational spectrum of each case was profoundly heterogeneous. Combining our data set with 64 previously published whole exome sequencing cases (23 ALCL, 15 AITLs, 9 PTCL-NOSs and 16 EATL-II), we confirmed the lack of recurrent driver mutations among PTCL-NOS. Taking advantage of WGS data, we therefore focused on structural variants (SVs: inversions, translocations, internal tandem duplications and deletions) and copy number alterations (CNAs). We found 372 SVs, with a stunning median of 73 per sample (range 56-86). Even more interesting, at least one complex event was observed in all but one patients, including one whole genome duplication (WGD) and five chromothripsis events in three patients, suggesting a critical role of SVs in shaping the PTCL-NOS genome. We found that known onco-drivers were recurrently disrupted by such events: the most frequent target was CDKN2A, deleted in 4 out of 5 patients, 2 of which carried homozygous deletions. Interestingly, PTEN loss was observed in 2 out of 4 CDKN2A-deleted patients. Given the high prevalence of these deletions, we extended our observation to an independent validation set of ALCLs (n=56), AITL (n=22) and PTCL-NOS (n=59) investigated by FISH (n=36), next generation sequencing (n=25) or SNP6 array series (n=76). Overall, CDKN2A was deleted in 22/59 (37%) PTCL-NOSs cases, and in 17/22 (77%) both alleles were lost. PTEN was deleted in 12/59 (20%) PTCL-NOS cases, all of which also carried a CDKN2A loss. Strikingly, the co-occurrence of CDKN2A and PTEN was found only among PTCL-NOS, and in none of the other entities. With the limitations of the small sample size, the presence of CDKN2A bi-allelic deletions was associated with inferior survival (25% [95% CI: 9-66%] 5-y OS for deleted cases vs 52% [95% CI: 28-96%] for wt/hemizygous cases, p=0.042) among patients treated with an autologous bone marrow transplant front line program for advance stage and high-risk disease (n=19). Our observations point at SVs as a main driver of PTCL-NOS, often involving known cancer genes and their downstream pathways. Furthermore, our data highlighted recurrent gene deletions that may be relevant for differential diagnosis within this category of lymphomas

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.J.M.C.T. is supported by European Research Council (ERC) Starting Grant 716290 ‘SCUBA CANCERS’, Ramon y Cajal grant RYC-2014-14999 and Spanish Ministry of Economy, Industry and Competitiveness (MINECO) grant SAF2015-66368-P. B.R.-M., E.G.A., M.S.G. and S.Z. are supported by PhD fellowships from Xunta de Galicia (Spain) ED481A-2016/151, ED481A-2017/299, ED481A-2017/306 and ED481A-2018/199, respectively. F.S. was supported by ERC Starting Grant 757700 ‘HYPER-INSIGHT’, MINECO grant BFU2017-89833-P ‘RegioMut’, and further acknowledges institutional funding from the MINECO Severo Ochoa award and from the CERCA Programme of the Catalan Government. Y.S.J. was supported by Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI16C2387). A.L.B. is supported by MINECO PhD fellowship BES-2016-078166. M.T. was supported by MINECO grant SAF2015-73916-JIN. R.B. received funding through the National Institutes of Health (U24CA210978 and R01CA188228). M.G.B. received funding through MINECO, AEI, Xunta de Galicia and FEDER (BFU2013-41554-P, BFU2016-78121-P, ED431F 2016/019). N.B. is supported by a My First AIRC grant from the Associazione Italiana Ricerca sul Cancro (number 17658). J.D. is a postdoctoral fellow of the Research Foundation Flanders (FWO) and the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement number 703594-DECODE). K.C. and Z.C. are supported by NIH R01 CA172652 and U41 HG007497. Z.C. is supported by an American Heart Association Institutional Data Fellowship Award (17IF33890015). P.A.W.E. is supported by Cancer Research UK. E.A.L. is supported by K01AG051791. I.M. is supported by Cancer Research UK (C57387/A21777). S.M.W. received funding through a SNSF Early Postdoc Mobility fellowship (P2ELP3_155365) and an EMBO Long-Term Fellowship (ALTF 755-2014). J.W. received funding from the Danish Medical Research Council (DFF-4183-00233). J.O.K. is supported by an ERC Starting Grant. This work is supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202) and the Wellcome Trust (FC001202). H.H.K. is supported by grants from the National Institute of General Medical Sciences (P50GM107632 and 1R01GM099875). K.H.B. is supported by P50GM107632, R01CA163705 and R01GM124531. This work was supported by the TransTumVar project PN013600.. This work was supported by the Wellcome Trust grant 0980

Haplotype-resolved diverse human genomes and integrated analysis of structural variation

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average contig N50: 26 Mbp) integrate all forms of genetic variation even across complex loci. We identify 107,590 structural variants (SVs), of which 68% are not discovered by short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterize 130 of the most active mobile element source elements and find that 63% of all SVs arise by homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1,526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population

Genomic insights into the Ixodes scapularis tick vector of Lyme disease

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent