bims-myxlip 2021-05-02 papers

Issue of 2021–05–02
five papers selected by
Laura Mannarino, Humanitas Research

Cancer Cell. 2021 Apr 28. pii: S1535-6108(21)00208-7. [Epub ahead of print]

STAG2 mutations alter CTCF-anchored loop extrusion, reduce cis-regulatory interactions and EWSR1-FLI1 activity in Ewing sarcoma.

Didier Surdez, Sakina Zaidi, Sandrine Grossetête, Karine Laud-Duval, Anna Sole Ferre, Lieke Mous, Thomas Vourc'h, Franck Tirode, Gaelle Pierron, Virginie Raynal, Sylvain Baulande, Erika Brunet, Véronique Hill, Olivier Delattre.

STAG2, a cohesin family gene, is among the most recurrently mutated genes in cancer. STAG2 loss of function (LOF) is associated with aggressive behavior in Ewing sarcoma, a childhood cancer driven by aberrant transcription induced by the EWSR1-FLI1 fusion oncogene. Here, using isogenic Ewing cells, we show that, while STAG2 LOF profoundly changes the transcriptome, it does not significantly impact EWSR1-FLI1, CTCF/cohesin, or acetylated H3K27 DNA binding patterns. In contrast, it strongly alters the anchored dynamic loop extrusion process at boundary CTCF sites and dramatically decreases promoter-enhancer interactions, particularly affecting the expression of genes regulated by EWSR1-FLI1 at GGAA microsatellite neo-enhancers. Down-modulation of cis-mediated EWSR1-FLI1 activity, observed in STAG2-LOF conditions, is associated with enhanced migration and invasion properties of Ewing cells previously observed in EWSR1-FLI1low cells. Our study illuminates a process whereby STAG2-LOF fine-tunes the activity of an oncogenic transcription factor through altered CTCF-anchored loop extrusion and cis-mediated enhancer mechanisms.

Keywords: CTCF; Ewing sarcoma; STAG1; STAG2; anchorage; chromatin extrusion; cohesin; enhancer; loop; migration

DOI: https://doi.org/10.1016/j.ccell.2021.04.001

Cancers (Basel). 2021 Apr 20. pii: 1983. [Epub ahead of print]13(8):

Fourteen-Day Gemcitabine-Docetaxel Chemotherapy Is Effective and Safer Compared to 21-Day Regimen in Patients with Advanced Soft Tissue and Bone Sarcoma.

Minggui Pan, Maily K Trieu, Manpreet Sidhu, Jeanette Yu, Tiffany Seto, Kristen Ganjoo.

Gemcitabine-docetaxel (G-D) combination is an effective chemotherapy for patients with advanced soft tissue and bone sarcoma, first developed with G administered on days 1 and 8, and D on day 8 every 21 days and later modified to be administered every 14 days in 2012. The 14-day regimen has become increasingly adopted. However, its efficacy and toxicities have not been compared. We identified 161 patients with metastatic or locally advanced soft tissue and bone sarcoma treated with either a 14-day or 21-day regimen within Northern California Kaiser Permanente from 1 January 2017 to 30 July 2020 and compared the outcomes and toxicity profiles of patients treated with the either regimen. Seventy-nine (49%) and 82 (51%) patients received the 14-day and the 21-day regimen, respectively, with similar response rate (22.8% and 15.8%, p = 0.26), median progression-free survival (PFS, 4.0 and 3.2 months, p = 0.15), and median overall survival (OS, 12.6 and 14.7 months, p = 0.55). Subset analysis of the untreated patients (approximately 60% of the entire cohort) as well as the patients with leiomyosarcoma only (approximately 50% of the entire cohort) showed that OS was not significantly different between the two regimens. Febrile neutropenia requiring hospitalization occurred in 10 and one patients (p = 0.006) and intolerance leading to discontinuation of chemotherapy occurred in 12 and two patients (p = 0.006) treated with the 21-day and the 14-day regimens, respectively. CDKN2A deletion/mutation or CDK4 amplification was associated with worse median OS (p = 0.06), while a RB1 deletion/mutation was associated with better median PFS (p = 0.05), and these two genomic alterations were mutually exclusive. Our data demonstrate that, compared to the traditional 21-day G-D regimen, the 14-day G-D regimen is equally effective but safer. In addition, CDKN2A and RB1 pathways play significant role on the outcomes of the patients.

Keywords: docetaxel; gemcitabine; genomic alterations; sarcoma; survival

DOI: https://doi.org/10.3390/cancers13081983

Curr Opin Oncol. 2021 Apr 28.

Next-generation sequencing for the management of sarcomas with no known driver mutations.

Simon Vyse, Khin Thway, Paul H Huang, Robin L Jones.

PURPOSE OF REVIEW: Next-generation sequencing (NGS) has enabled fast, high-throughput nucleotide sequencing and has begun to be implemented into clinical practice for genomic-guided precision medicine in various cancer types. This review will discuss recent evidence that highlights opportunities for NGS to improve outcomes in sarcomas that have complex genomic profiles with no known driver mutations.
RECENT FINDINGS: Global genomic signatures detectable by NGS including tumour mutational burden and microsatellite instability have potential as biomarkers for response to immunotherapy in certain sarcoma subtypes including angiosarcomas. Identification of hallmarks associated with 'BRCAness' and homologous recombination repair defects in leiomyosarcomas and osteosarcomas may predict sensitivity to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. Lastly, the use of NGS for evaluating cancer predisposition in sarcomas may be useful for early detection, screening and surveillance.
SUMMARY: Currently, the implementation of NGS for every sarcoma patient is not practical or useful. However, adopting NGS as a complementary approach in sarcomas with complex genomics and those with limited treatment options has the potential to deliver precision medicine to a subgroup of patients, with novel therapies such as immune checkpoint and PARP inhibitors. Moving forward, molecular tumour boards incorporating multidisciplinary teams of pathologists, oncologists and genomic specialists to interpret NGS data will complement existing tools in diagnosis and treatment decision making in sarcoma patients.

DOI: https://doi.org/10.1097/CCO.0000000000000741

DNA Repair (Amst). 2021 Apr 20. pii: S1568-7864(21)00082-3. [Epub ahead of print]103 103126

Transcription-coupled nucleotide excision repair: New insights revealed by genomic approaches.

Mingrui Duan, Rachel M Speer, Jenna Ulibarri, Ke Jian Liu, Peng Mao.

Elongation of RNA polymerase II (Pol II) is affected by many factors including DNA damage. Bulky damage, such as lesions caused by ultraviolet (UV) radiation, arrests Pol II and inhibits gene transcription, and may lead to genome instability and cell death. Cells activate transcription-coupled nucleotide excision repair (TC-NER) to remove Pol II-impeding damage and allow transcription resumption. TC-NER initiation in humans is mediated by Cockayne syndrome group B (CSB) protein, which binds to the stalled Pol II and promotes assembly of the repair machinery. Given the complex nature of the TC-NER pathway and its unique function at the interface between transcription and repair, new approaches are required to gain in-depth understanding of the mechanism. Advances in genomic approaches provide an important opportunity to investigate how TC-NER is initiated upon damage-induced Pol II stalling and what factors are involved in this process. In this Review, we discuss new mechanisms of TC-NER revealed by genome-wide DNA damage mapping and new TC-NER factors identified by high-throughput screening. As TC-NER conducts strand-specific repair of mutagenic damage, we also discuss how this repair pathway causes mutational strand asymmetry in the cancer genome.

Keywords: CPD-seq; CSB; DNA damage; Mutagenesis; RNA Pol II

DOI: https://doi.org/10.1016/j.dnarep.2021.103126

Cancer. 2021 Apr 28.

Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities.

Silvia Stacchiotti, Anna Maria Frezza, Jean-Yves Blay, Elizabeth H Baldini, Sylvie Bonvalot, Judith V M G Bovée, Dario Callegaro, Paolo G Casali, RuRu Chun-Ju Chiang, George D Demetri, Elisabeth G Demicco, Jayesh Desai, Mikael Eriksson, Hans Gelderblom, Suzanne George, Mrinal M Gounder, Alessandro Gronchi, Abha Gupta, Rick L Haas, Andrea Hayes-Jardon, Peter Hohenberger, Kevin B Jones, Robin L Jones, Bernd Kasper, Akira Kawai, David G Kirsch, Eugene S Kleinerman, Axel Le Cesne, Jiwon Lim, María Dolores Chirlaque López, Roberta Maestro, Rafael Marcos-Gragera, Javier Martin Broto, Tomohiro Matsuda, Olivier Mir, Shreyaskumar R Patel, Chandrajit P Raut, Albiruni R A Razak, Damon R Reed, Piotr Rutkowski, Roberta G Sanfilippo, Marta Sbaraglia, Inga-Marie Schaefer, Dirk C Strauss, Kirsten Sundby Hall, William D Tap, David M Thomas, Winette T A van der Graaf, Winan J van Houdt, Otto Visser, Margaret von Mehren, Andrew J Wagner, Breelyn A Wilky, Young-Joo Won, Christopher D M Fletcher, Angelo P Dei Tos, Annalisa Trama.

BACKGROUND: Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies.
METHODS: The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan.
RESULTS: It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types.
CONCLUSIONS: Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.

Keywords: drug development; incidence; rarity; registry; sarcoma; ultra-rare

DOI: https://doi.org/10.1002/cncr.33618