Molecular cytogenetic delineation of deletions and translocations involving chromosome band 7q22 in myeloid leukemias

Loss of chromosome 7 (-7) or deletion of its long arm (7q-) are recurring chromosome abnormalities in myeloid disorders, especially in therapy-related myelodysplastic syndrome (t-MDS) and acute myeloid leukemia (t-AML). The association of -7/7q- with myeloid leukemia suggests that these regions contain a novel tumor suppressor gene(s) whose loss of function contributes to leukemic transformation or tumor progression. Based on chromosome banding analysis, two critical regions have been identified: one in band 7q22 and a second in bands 7q32-q35. We analyzed bone marrow and blood samples from 21 patients with myeloid leukemia (chronic myeloid leukemia, n = 2; de novo MDS, n = 4; de novo AML, n = 13: t-AML, n = 2) that on chromosome banding analysis exhibited deletions (n = 19) or reciprocal translocations (n = 2) of band 7q22 using fluorescence in situ hybridization. As probes, we used Alu-polymerase chain reaction products from 22 yeast artificial chromosome (YAC) clones that span chromosome bends 7q21.1-q32, including representative clones from a panel of YACs recognizing a contiguous genomic DNA fragment of 5 to 6 Mb in band 7q22. In the 19 cases with deletions, we identified two distinct commonly deleted regions: one region within band 7q22 was defined by the two CML cases; the second region encompassed a distal part of band 7q22 and the entire band 7q31 and was defined by the MDS/AML cases. The breakpoint of one of the reciprocal translocations was mapped to 7q21.3, which is centromeric to both of the commonly deleted regions. The breakpoint of the second translocation, which was present in unstimulated bone marrow and phytohemagglutinin-stimulated blood of an MDS patient, was localized to a 400-kb genomic segment in 7q22 within the deletion cluster of the MDS/AML cases. In conclusion, our data show marked heterogeneity of 7q22 deletion and translocation breakpoints in myeloid leukemias, suggesting the existence of more than one pathogenetically relevant gene.link_to_OA_fulltex

Molecular cytogenetic characterization of a critical region in bands 7q35-q36 commonly deleted in malignant myeloid disorders

Loss of chromosome 7 (-7) or deletion of the long arm (7q-) are recurring chromosome abnormalities in myeloid leukemias. The association of - 7/7q- with myeloid leukemia suggests that these regions contain novel tumor suppressor gene(s), whose loss of function contribute to leukemic transformation or tumor progression. Based on chromosome banding analysis, two critical regions have been identified, one in band q22 and another in bands q32-q35. Presently there are no data available on the molecular delineation of the distal critical region. In this study we analyzed bone marrow and blood samples from 13 patients with myeloid leukemia (de novo myelodysplastic syndrome [MDS], n=3; de novo acute myeloid leukemia [AML], n=9; therapy-related (t-) AML, n=1) which, on chromosome banding analysis, exhibited deletions (n=12) or in one case a balanced translocation involving bands 7q31-qter using fluorescence in situ hybridization (FISH). As probes we used representative clones from a contig map of yeast artificial chromosome (YAC) clones that spans chromosome bands 7q31.1-qter. In the 12 cases with loss of 7q material, we identified a commonly deleted region of approximately 4 to 5 megabasepairs in size encompassing the distal part of 7q35 and the proximal part of 7q36. Furthermore, the breakpoint of the reciprocal translocation from the patient with t-AML was localized to a 1,300-kb sized YAC clone that maps to the proximal boundary of the commonly deleted region. Interestingly, in this case both homologs of chromosome 7 were affected: one was lost (-7) and the second exhibited the t(7q35). The identification and delineation of translocation and deletion breakpoints provides the first step toward the identification of the gene(s) involved in the pathogenesis of 7q35-q36 aberrations in myeloid disorders.link_to_OA_fulltex

The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K

Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation1. Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets2. They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines3-5, we identify CR8-a cyclin-dependent kinase (CDK) inhibitor6-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues

Long-read sequencing of diagnosis and post-therapy medulloblastoma reveals complex rearrangement patterns and epigenetic signatures

Cancer genomes harbor a broad spectrum of structural variants (SVs) driving tumorigenesis, a relevant subset of which escape discovery using short-read sequencing. We employed Oxford Nanopore Technologies (ONT) long-read sequencing in a paired diagnostic and post-therapy medulloblastoma to unravel the haplotype-resolved somatic genetic and epigenetic landscape. We assembled complex rearrangements, including a 1.55-Mbp chromothripsis event, and we uncover a complex SV pattern termed templated insertion (TI) thread, characterized by short (mostly <1 kb) insertions showing prevalent self-concatenation into highly amplified structures of up to 50 kbp in size. TI threads occur in 3% of cancers, with a prevalence up to 74% in liposarcoma, and frequent colocalization with chromothripsis. We also perform long-read-based methylome profiling and discover allele-specific methylation (ASM) effects, complex rearrangements exhibiting differential methylation, and differential promoter methylation in cancer-driver genes. Our study shows the advantage of long-read sequencing in the discovery and characterization of complex somatic rearrangements

The Porto European Cancer Research Summit 2021

Key stakeholders from the cancer research continuum met in May 2021 at the European Cancer Research Summit in Porto to discuss priorities and specific action points required for the successful implementation of the European Cancer Mission and Europe's Beating Cancer Plan (EBCP). Speakers presented a unified view about the need to establish high-quality, networked infrastructures to decrease cancer incidence, increase the cure rate, improve patient's survival and quality of life, and deal with research and care inequalities across the European Union (EU). These infrastructures, featuring Comprehensive Cancer Centres (CCCs) as key components, will integrate care, prevention and research across the entire cancer continuum to support the development of personalized/precision cancer medicine in Europe. The three pillars of the recommended European infrastructures – namely translational research, clinical/prevention trials and outcomes research – were pondered at length. Speakers addressing the future needs of translational research focused on the prospects of multiomics assisted preclinical research, progress in Molecular and Digital Pathology, immunotherapy, liquid biopsy and science data. The clinical/prevention trial session presented the requirements for next-generation, multicentric trials entailing unified strategies for patient stratification, imaging, and biospecimen acquisition and storage. The third session highlighted the need for establishing outcomes research infrastructures to cover primary prevention, early detection, clinical effectiveness of innovations, health-related quality-of-life assessment, survivorship research and health economics. An important outcome of the Summit was the presentation of the Porto Declaration, which called for a collective and committed action throughout Europe to develop the cancer research infrastructures indispensable for fostering innovation and decreasing inequalities within and between member states. Moreover, the Summit guidelines will assist decision making in the context of a unique EU-wide cancer initiative that, if expertly implemented, will decrease the cancer death toll and improve the quality of life of those confronted with cancer, and this is carried out at an affordable cost.Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. JT reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, DaiichiSankyo, F. Hoffmann‐La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. And also educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). JT also declares institutional financial interest in form of financial support for clinical trials or contracted research for Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann‐La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen‐Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK. MB has received funding for his research projects and for educational grants to the University of Dresden by Bayer AG (2016‐2018), Merck KGaA (2014‐open) and Medipan GmbH (2014‐2018). He is on the supervisory board of HI‐STEM GmbH (Heidelberg) for the German Cancer Research Center (DKFZ, Heidelberg) and also member of the supervisory body of the Charité University Hospital, Berlin. As former chair of OncoRay (Dresden) and present CEO and Scientific Chair of the German Cancer Research Center (DKFZ, Heidelberg), he has been or is responsible for collaborations with a multitude of companies and institutions, worldwide. In this capacity, he has discussed potential projects and signed contracts for research funding and/or collaborations with industry and academia for his institute(s) and staff, including but not limited to pharmaceutical companies such as Bayer, Boehringer Ingelheim, Bosch, Roche and other companies such as Siemens, IBA, Varian, Elekta, Bruker, etc. In this role, he was/is also responsible for the commercial technology transfer activities of his institute(s), including the creation of start‐ups and licensing. This includes the DKFZ‐PSMA617 related patent portfolio [WO2015055318 (A1), ANTIGEN (PSMA)] and similar IP portfolios. MB confirms that, to the best of his knowledge, none of the above funding sources were involved in the preparation of this paper. BB has received research funding from 4D Pharma, Abbvie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi‐Sankyo, Eli Lilly, GSK, Inivata, Janssen, Onxeo, OSE immunotherapeutics, Pfizer, Roche‐Genentech, Sanofi, Takeda, Tolero Pharmaceuticals. FC declares consultancy role for: Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi‐Sankyo, Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics, Medscape, Merck‐Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre‐Fabre, prIME Oncology, Roche, Sanofi, Samsung Bioepis, Seagen, Teva. SF is a consulting or advisory board member at Bayer, Illumina, Roche; has received honoraria from Amgen, Eli Lilly, PharmaMar, Roche; has received research funding from AstraZeneca, Pfizer, PharmaMar, Roche; has received sponsorship of travel or accommodation expenses by Amgen, Eli Lilly, Illumina, PharmaMar, Roche. SG owns AstraZeneca stock and is a full‐time employee of AstraZeneca. PN has had an advisory role at Bayer, MSD Oncology, has received honoraria from Bayer, Novartis and MSD Oncology, and has had travel expenses paid by Novartis. JO has been an advisory board member at Roche, Novartis, Bayer, Merck, Eisai, Astrazeneca, Pierre Fabre Medicament and Bristol‐Myers Squibb. He has also received research funding by IPO Porto, Astrazeneca, Fundação para a Ciencia e a Tecnologia (FCT) and Liga Portuguesa Contra o Cancro (LPCC). AR is an employee of European Federation of Pharmaceutical Industries and Associations, Brussels, MSD International Business GmbH, Kriens, Switzerland[CvG1], and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA, who may own stock and/or hold stock options in the Company.RS serves as principal investigator of the ASCO TAPUR study. ASCO receives research grants from the following companies in support of the study: Astra‐Zeneca, Bayer, Boehringer‐Ingelheim, Bristol Myers Squibb, Genentech, Lilly, Merck, Pfizer, Seattle Genetics. Dr. Schilsky serves as a member of the managing board of Clariifi and as a consultant to Bryologyx, Cellworks Group, EQRx, and Scandion Oncology. The Netherlands Cancer Institute receives research support via EV from Roche, Astrazeneca, Eisai, Novartis, GSK, Clovis, BMS, MSD, Pfizer, Amgen, Bayer, Lilly, Janssen and Seagen. LZ is founder of everImmune, member of the board of directors of Transgene, member of the scientific advisory board of Transgene, EpiVax, Lytix Biopharma. LZ has also had research contracts with: Merus, Roche, Tusk, Kaleido, GSK, BMS, Incyte, Pileje, Innovate Pharma, and Transgene and has received honoraria by Transgene. All other authors have no conflicts of interest to declare. Regarding the design of innovative and adaptive clinical trials, two examples were illustrated: the first European multimodular, two‐part academic CCE‐endorsed Basket of Baskets (BoB) study, and the recently launched CCE Building Data Rich Clinical Trials (DART) Consortium, which is supported by EU’s Horizon 2020 research and innovation programme (Box 13 ). We are grateful for the support by Carolina Espina, International Agency for Research on Cancer; Christina von Gertten, European Academy of Cancer Sciences; Ana Augusta Silva, Portuguese Oncology Institute of Porto; and Teresa Tavares, Ministry of Science, Technology and Higher Education, Portugal for their excellent cooperation. Carmen Jeronimo, Portuguese Oncology Institute of Porto, collaborated in the presentation of Porto Comprehensive Cancer Center by Raquel Seruca

Human papillomavirus-mediated carcinogenesis and HPV-associated oral and oropharyngeal squamous cell carcinoma. Part 1: Human papillomavirus-mediated carcinogenesis

High-risk human papillomavirus (HPV) E6 and E7 oncoproteins are essential factors for HPV-induced carcinogenesis, and for the maintenance of the consequent neoplastic growth. Cellular transformation is achieved by complex interaction of these oncogenes with several cellular factors of cell cycle regulation including p53, Rb, cyclin-CDK complexes, p21 and p27. Both persistent infection with high-risk HPV genotypes and immune dysregulation are associated with increased risk of HPV-induced squamous cell carcinoma

Immunotherapeutic maintenance treatment with toll-like receptor 9 agonist lefitolimod in patients with extensive-stage small-cell lung cancer: Results from the exploratory, controlled, randomized, international phase 2 IMPULSE study

Background: The immune surveillance reactivator lefitolimod (MGN1703), a DNA-based TLR9 agonist, might foster innate and adaptive immune response and thus improve immune-mediated control of residual cancer disease. The IMPULSE phase 2 study evaluated the efficacy and safety of lefitolimod as maintenance treatment in extensive-stage small-cell lung cancer (ES-SCLC) after objective response to first-line chemotherapy, an indication with a high unmet medical need and stagnant treatment improvement in the last decades. Patients and methods: 103 patients with ES-SCLC and objective tumor response (as per RECIST 1.1) following 4 cycles of platinum-based first-line induction therapy were randomized to receive either lefitolimod maintenance therapy or local standard of care at a ratio of 3:2 until progression or unacceptable toxicity. Results: From 103 patients enrolled, 62 were randomized to lefitolimod, 41 to the control arm. Patient demographics and response patterns to first-line therapy were balanced. Lefitolimod exhibited a favorable safety profile and pharmacodynamic assessment confirmed the mode-of-action showing a clear activation of monocytes and production of interferon-gamma-induced protein 10 (IP-10). While in the ITT population no relevant effect of lefitolimod on progression-free and overall survival (OS) could be observed, two pre-defined patient subgroups indicated promising results, favoring lefitolimod with respect to OS: in patients with a low frequency of activated CD86+ B cells (hazard ratio, HR 0.53, 95%CI 0.26-1.08; n = 38 of 88 analyzed) and in patients with reported chronic obstructive pulmonary disease (COPD) (HR 0.48, 95%CI 0.20-1.17, n = 25 of 103). Conclusions: The IMPULSE study showed no relevant effect of lefitolimod on the main efficacy endpoint OS in the ITT, but (1) the expected pharmacodynamic response to lefitolimod, (2) positive OS efficacy signals in two pre-defined subgroups and (3) a favorable safety profile. These data support further exploration of lefitolimod in SCLC