bims-ovdlit 2021-12-05 papers

Issue of 2021‒12‒05
four papers selected by
Lara Paracchini
Humanitas Research

Ann Oncol. 2021 Nov 30. pii: S0923-7534(21)04828-6. [Epub ahead of print]

European Experts Consensus: BRCA/Homologous Recombination Deficiency Testing in First-Line Ovarian Cancer.

European experts consensus group

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. Homologous recombination repair deficiency (HRR deficiency) is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition.DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (N=14) and contributors (N=84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the PRISMA guidelines.
RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive.
CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer.

Keywords: BRCA1/2, homologous recombination deficiency; Ovarian cancer; PARP inhibition; genetic counselling; mainstream genetic testing

DOI: https://doi.org/10.1016/j.annonc.2021.11.013

Cell Death Differ. 2021 Nov 29.

Single cell-derived spheroids capture the self-renewing subpopulations of metastatic ovarian cancer.

Tania Velletri, Carlo Emanuele Villa, Domenica Cilli, Bianca Barzaghi, Pietro Lo Riso, Michela Lupia, Raffaele Luongo, Alejandro López-Tobón, Marco De Simone, Raoul J P Bonnal, Luca Marelli, Stefano Piccolo, Nicoletta Colombo, Massimiliano Pagani, Ugo Cavallaro, Saverio Minucci, Giuseppe Testa.

High Grade Serous Ovarian cancer (HGSOC) is a major unmet need in oncology, due to its precocious dissemination and the lack of meaningful human models for the investigation of disease pathogenesis in a patient-specific manner. To overcome this roadblock, we present a new method to isolate and grow single cells directly from patients' metastatic ascites, establishing the conditions for propagating them as 3D cultures that we refer to as single cell-derived metastatic ovarian cancer spheroids (sMOCS). By single cell RNA sequencing (scRNAseq) we define the cellular composition of metastatic ascites and trace its propagation in 2D and 3D culture paradigms, finding that sMOCS retain and amplify key subpopulations from the original patients' samples and recapitulate features of the original metastasis that do not emerge from classical 2D culture, including retention of individual patients' specificities. By enabling the enrichment of uniquely informative cell subpopulations from HGSOC metastasis and the clonal interrogation of their diversity at the functional and molecular level, this method provides a powerful instrument for precision oncology in ovarian cancer.

DOI: https://doi.org/10.1038/s41418-021-00878-w

Int J Gynecol Cancer. 2021 Nov 29. pii: ijgc-2021-003153. [Epub ahead of print]

Tubal histopathological abnormalities in BRCA1/2 mutation carriers undergoing prophylactic salpingo-oophorectomy: a case-control study.

OBJECTIVE: To describe tubal histopathological abnormalities in women with germline BRCA1/2 mutations and in controls.METHODS: Consecutive women with BRCA1/2 mutations undergoing bilateral salpingo-oophorectomy between 2010 and 2020 in two centers (San Gerardo Hospital, Monza and San Matteo Hospital, Pavia) were considered in this analysis and compared with controls who had the same surgical procedure for benign conditions. Frequency of p53 signature, serous tubal intraepithelial carcinoma, and high-grade serous ovarian cancer were compared between the two groups.
RESULTS: A total of 194 women with pathogenic BRCA1/2 mutations underwent prophylactic salpingo-oophorectomy. Of these, 138 women (71%) had a completely negative histological examination, while in 56 (29%) patients an ovarian or tubal alteration was reported. Among controls, 84% of patients had a p53wt signature, while 16% had a p53 signature. There was no difference in the frequency of a p53 signature between cases and controls; however, women with BRCA1/2 mutations were more likely to have pre-malignant or invasive alterations of tubal or ovarian epithelium (p=0.015). Among mutation carriers, older age both at genetic testing and at surgery was associated with an increased risk of having malignancies (OR=1.07, p=0.006 and OR=1.08, p=0.004, respectively). The risk of malignancy seems to be increased in patients with a familial history of high-grade serous ovarian cancer. Previous therapy with tamoxifen was significantly more frequent in patients with malignant lesions (40.0% vs 21.3%, p=0.006).
CONCLUSION: We found that a p53 signature is a frequent finding both in BRCA1/2 mutation carriers and in controls, while pre-invasive and invasive lesions are more frequent in BRCA1/2 mutation carriers. Genetic and clinical characteristics are likely to affect the progression to malignancy.

Keywords: BRCA1 protein; BRCA2 protein; gynecologic surgical procedures; ovarian diseases

DOI: https://doi.org/10.1136/ijgc-2021-003153

Pancreas. 2021 Oct 01. 50(9): 1267-1273

Methylation-based Cell-free DNA Signature for Early Detection of Pancreatic Cancer.

Lee Ying, Anup Sharma, Ankit Chhoda, Nensi Ruzgar, Nesrin Hasan, Ruby Kwak, Christopher L Wolfgang, Tza Huei Wang, John W Kunstman, Ronald R Salem, Laura D Wood, Christine Iacobuzio-Donahue, Eric B Schneider, James J Farrell, Nita Ahuja.

OBJECTIVES: The potential of DNA methylation alterations in early pancreatic cancer (PC) detection among pancreatic tissue cell-free DNA seems promising. This study investigates the diagnostic capacity of the 4-gene methylation biomarker panel, which included ADAMTS1, BNC1, LRFN5, and PXDN genes, in a case-control study.METHODS: A genome-wide pharmacoepigenetic approach identified ADAMTS1, BNC1, LRFN5, and PXDN genes as putative targets. Tissue samples including stage I-IV PC (n = 44), pancreatic intraepithelial neoplasia (n = 15), intraductal papillary mucinous neoplasms (n = 24), and normal pancreas (n = 8), and cell-free DNA, which was acquired through methylation on beads technology from PC (n = 22) and control patients (n = 10), were included. The 2-∆ct was the outcome of interest and underwent receiver operating characteristic analysis to determine the diagnostic accuracy of the panel.
RESULTS: Receiver operating characteristic analysis revealed an area under the curve of 0.93 among ADAMTS1, 0.76 among BNC1, 0.75 among PXDN, and 0.69 among LRFN5 gene. The combination gene methylation panel (ADAMTS1, BNC1, LRFN5, and PXDN) had an area under the curve of 0.94, with a sensitivity of 100% and specificity of 90%.
CONCLUSIONS: This methylation-based biomarker panel had promising accuracy for PC detection and warranted further validation in prospective PC surveillance trials.

DOI: https://doi.org/10.1097/MPA.0000000000001919