bims-ovdlit 2021-10-24 papers

Issue of 2021–10–24
five papers selected by
Lara Paracchini, Humanitas Research

Cancers (Basel). 2021 Oct 19. pii: 5240. [Epub ahead of print]13(20):

Precision Oncology of High-Grade Ovarian Cancer Defined through Targeted Sequencing.

Sandra Wessman, Beatriz Bohorquez Fuentes, Therese Törngren, Anders Kvist, Georgia Kokaraki, Hanna Menkens, Elisabet Hjerpe, Ythalo Hugo, Tirzah Braz Petta, Åke Borg, Joseph W Carlson.

BACKGROUND: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets.
METHODS: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation sequencing using a targeted panel.
RESULTS: Patients with high-grade ovarian epithelial cancer were consented to prospective molecular characterization. Clinical information was extracted from their medical record. Tumour DNA was subjected to sequencing, and selected patients received PARP inhibitor therapy.
CONCLUSIONS: Tumours from 274 women were sequenced, including high-grade serous carcinoma (n = 252), clear cell carcinoma (n = 4), carcinosarcoma (n = 9), endometrioid carcinoma (n = 3), undifferentiated carcinoma (n = 1), and mixed tumours (n = 5). Genomic profiling did not influence histologic diagnosis. Mutations were identified in TP53, BRCA1, BRCA2, as well as additional homologous recombination repair pathway genes BARD1, ATR, CHEK2, PALB2, RAD51D, RAD50, SLX4, FANCA, RAD51C, and RAD54L. In addition, mutations in PTEN and CDKN2A were identified. Several somatic mutations with implications for germline testing were identified, including RMI1, STK11, and CDH1. Germline testing identified 16 previously unknown BRCA1/2 carriers. Finally, 20 patients were treated with the PARP inhibitor olaparib based on the sequencing results.

Keywords: genetics; genomics; ovarian cancer; targeted therapy

DOI: https://doi.org/10.3390/cancers13205240

Biomedicines. 2021 Sep 26. pii: 1315. [Epub ahead of print]9(10):

Liquid Biopsies in Sarcoma Clinical Practice: Where Do We Stand?

Pia van der Laan, Winan J van Houdt, Daan van den Broek, Neeltje Steeghs, Winette T A van der Graaf.

Sarcomas are rare tumors of bone and soft tissue with a mesenchymal origin. This uncommon type of cancer is marked by a high heterogeneity, consisting of over 70 subtypes. Because of this broad spectrum, their treatment requires a subtype-specific therapeutic approach. Tissue biopsy is currently the golden standard for sarcoma diagnosis, but it has its limitations. Over the recent years, methods to detect, characterize, and monitor cancer through liquid biopsy have evolved rapidly. The analysis of circulating biomarkers in peripheral blood, such as circulating tumor cells (CTC) or circulating tumor DNA (ctDNA), could provide real-time information on tumor genetics, disease state, and resistance mechanisms. Furthermore, it traces tumor evolution and can assess tumor heterogeneity. Although the first results in sarcomas are encouraging, there are technical challenges that need to be addressed for implementation in clinical practice. Here, we summarize current knowledge about liquid biopsies in sarcomas and elaborate on different strategies to integrate liquid biopsy into sarcoma clinical care.

Keywords: CTC; biomarker; cell-free DNA; clinical practice; ctDNA; liquid biopsy; sarcoma

DOI: https://doi.org/10.3390/biomedicines9101315

Commun Med. 2021 ;pii: 36. [Epub ahead of print]1

Next steps in the early detection of ovarian cancer.

Robert C Bast, Chae Young Han, Zhen Lu, Karen H Lu.

A recent ovarian cancer screening trial found no reduction in mortality, despite increased detection of early stage disease. Here, we discuss these findings and examine next steps to develop more effective approaches for the early detection of ovarian cancer.

DOI: https://doi.org/10.1038/s43856-021-00037-9

Int J Gynaecol Obstet. 2021 Oct;155 Suppl 1 61-85

Cancer of the ovary, fallopian tube, and peritoneum: 2021 update.

Jonathan S Berek, Malte Renz, Sean Kehoe, Lalit Kumar, Michael Friedlander.

In 2014, FIGO's Committee for Gynecologic Oncology revised the staging of ovarian cancer, incorporating ovarian, fallopian tube, and peritoneal cancer into the same system. Most of these malignancies are high-grade serous carcinomas (HGSC). Stage IC is now divided into three categories: IC1 (surgical spill); IC2 (capsule ruptured before surgery or tumor on ovarian or fallopian tube surface); and IC3 (malignant cells in the ascites or peritoneal washings). The updated staging includes a revision of Stage IIIC based on spread to the retroperitoneal lymph nodes alone without intraperitoneal dissemination. This category is now subdivided into IIIA1(i) (metastasis ≤10 mm in greatest dimension), and IIIA1(ii) (metastasis >10 mm in greatest dimension). Stage IIIA2 is now "microscopic extrapelvic peritoneal involvement with or without positive retroperitoneal lymph node" metastasis. This review summarizes the genetics, surgical management, chemotherapy, and targeted therapies for epithelial cancers, and the treatment of ovarian germ cell and stromal malignancies.

Keywords: FIGO Cancer Report; cancer staging; chemotherapy; fallopian tube; ovarian; ovary; peritoneum

DOI: https://doi.org/10.1002/ijgo.13878

Nature. 2021 Oct 20.

eccDNAs are apoptotic products with high innate immunostimulatory activity.

Yuangao Wang, Meng Wang, Mohamed Nadhir Djekidel, Huan Chen, Di Liu, Frederick W Alt, Yi Zhang.

Extrachromosomal circular DNA elements (eccDNAs) have been described in the literature for several decades, and are known for their broad existence across different species1,2. However, their biogenesis and functions are largely unknown. By developing a new circular DNA enrichment method, here we purified and sequenced full-length eccDNAs with Nanopore sequencing. We found that eccDNAs map across the entire genome in a close to random manner, suggesting a biogenesis mechanism of random ligation of genomic DNA fragments. Consistent with this idea, we found that apoptosis inducers can increase eccDNA generation, which is dependent on apoptotic DNA fragmentation followed by ligation by DNA ligase 3. Importantly, we demonstrated that eccDNAs can function as potent innate immunostimulants in a manner that is independent of eccDNA sequence but dependent on eccDNA circularity and the cytosolic DNA sensor Sting. Collectively, our study not only revealed the origin, biogenesis and immunostimulant function of eccDNAs but also uncovered their sensing pathway and potential clinical implications in immune response.

DOI: https://doi.org/10.1038/s41586-021-04009-w