bims-ovdlit 2024-03-17 papers

Issue of 2024‒03‒17
six papers selected by
Lara Paracchini, Humanitas Research

Eur J Cancer. 2024 Mar 02. pii: S0959-8049(24)00134-5. [Epub ahead of print]202 113978

Clinical evaluation of a low-coverage whole-genome test for detecting homologous recombination deficiency in ovarian cancer.

PAOLA-1/ ENGOT-ov25 Study Group

BACKGROUND: The PAOLA-1/ENGOT-ov25 trial showed that maintenance olaparib plus bevacizumab increases survival of advanced ovarian cancer patients with homologous recombination deficiency (HRD). However, decentralized solutions to test for HRD in clinical routine are scarce. The goal of this study was to retrospectively validate on tumor samples from the PAOLA-1 trial, the decentralized SeqOne assay, which relies on shallow Whole Genome Sequencing (sWGS) to capture genomic instability and targeted sequencing to determine BRCA status.METHODS: The study comprised 368 patients from the PAOLA-1 trial. The SeqOne assay was compared to the Myriad MyChoice HRD test (Myriad Genetics), and results were analyzed with respect to Progression-Free Survival (PFS).
RESULTS: We found a 95% concordance between the HRD status of the two tests (95% Confidence Interval (CI); 92%-97%). The Positive Percentage Agreement (PPA) of the sWGS test was 95% (95% CI; 91%-97%) like its Negative Percentage Agreement (NPA) (95% CI; 89%-98%). In patients with HRD-positive tumors treated with olaparib plus bevacizumab, the PFS Hazard Ratio (HR) was 0.38 (95% CI; 0.26-0.54) with SeqOne assay and 0.32 (95% CI; 0.22-0.45) with the Myriad assay. In patients with HRD-negative tumors, HR was 0.99 (95% CI; 0.68-1.42) and 1.05 (95% CI; 0.70-1.57) with SeqOne and Myriad assays. Among patients with BRCA-wildtype tumors, those with HRD-positive tumors, benefited from olaparib plus bevacizumab maintenance, with HR of 0.48 (95% CI: 0.29-0.79) and of 0.38 (95% CI: 0.23 to 0.63) with the SeqOne and Myriad assay.
CONCLUSION: The SeqOne assay offers a clinically validated approach to detect HRD.

Keywords: BRCA; Genomic instability; Homologous recombination deficiency; Low-pass sequencing; Ovarian cancer; PARP-inhibitor; Whole genome sequencing

DOI: https://doi.org/10.1016/j.ejca.2024.113978

Sci Transl Med. 2024 Mar 13. 16(738): eadj9283

Genome-wide repeat landscapes in cancer and cell-free DNA.

Akshaya V Annapragada, Noushin Niknafs, James R White, Daniel C Bruhm, Christopher Cherry, Jamie E Medina, Vilmos Adleff, Carolyn Hruban, Dimitrios Mathios, Zachariah H Foda, Jillian Phallen, Robert B Scharpf, Victor E Velculescu.

Genetic changes in repetitive sequences are a hallmark of cancer and other diseases, but characterizing these has been challenging using standard sequencing approaches. We developed a de novo kmer finding approach, called ARTEMIS (Analysis of RepeaT EleMents in dISease), to identify repeat elements from whole-genome sequencing. Using this method, we analyzed 1.2 billion kmers in 2837 tissue and plasma samples from 1975 patients, including those with lung, breast, colorectal, ovarian, liver, gastric, head and neck, bladder, cervical, thyroid, or prostate cancer. We identified tumor-specific changes in these patients in 1280 repeat element types from the LINE, SINE, LTR, transposable element, and human satellite families. These included changes to known repeats and 820 elements that were not previously known to be altered in human cancer. Repeat elements were enriched in regions of driver genes, and their representation was altered by structural changes and epigenetic states. Machine learning analyses of genome-wide repeat landscapes and fragmentation profiles in cfDNA detected patients with early-stage lung or liver cancer in cross-validated and externally validated cohorts. In addition, these repeat landscapes could be used to noninvasively identify the tissue of origin of tumors. These analyses reveal widespread changes in repeat landscapes of human cancers and provide an approach for their detection and characterization that could benefit early detection and disease monitoring of patients with cancer.

DOI: https://doi.org/10.1126/scitranslmed.adj9283

Nat Commun. 2024 Mar 12. 15(1): 2220

Cell type signatures in cell-free DNA fragmentation profiles reveal disease biology.

Kate E Stanley, Tatjana Jatsenko, Stefania Tuveri, Dhanya Sudhakaran, Lore Lannoo, Kristel Van Calsteren, Marie de Borre, Ilse Van Parijs, Leen Van Coillie, Kris Van Den Bogaert, Rodrigo De Almeida Toledo, Liesbeth Lenaerts, Sabine Tejpar, Kevin Punie, Laura Y Rengifo, Peter Vandenberghe, Bernard Thienpont, Joris Robert Vermeesch.

Circulating cell-free DNA (cfDNA) fragments have characteristics that are specific to the cell types that release them. Current methods for cfDNA deconvolution typically use disease tailored marker selection in a limited number of bulk tissues or cell lines. Here, we utilize single cell transcriptome data as a comprehensive cellular reference set for disease-agnostic cfDNA cell-of-origin analysis. We correlate cfDNA-inferred nucleosome spacing with gene expression to rank the relative contribution of over 490 cell types to plasma cfDNA. In 744 healthy individuals and patients, we uncover cell type signatures in support of emerging disease paradigms in oncology and prenatal care. We train predictive models that can differentiate patients with colorectal cancer (84.7%), early-stage breast cancer (90.1%), multiple myeloma (AUC 95.0%), and preeclampsia (88.3%) from matched controls. Importantly, our approach performs well in ultra-low coverage cfDNA datasets and can be readily transferred to diverse clinical settings for the expansion of liquid biopsy.

DOI: https://doi.org/10.1038/s41467-024-46435-0

J Womens Health (Larchmt). 2024 Mar 15.

Ovarian Cancer Risk-Reduction and Screening in BRCA1/2 Mutation Carriers.

Jessica B DiSilvestro, Jessica Haddad, Katina Robison, Lindsey Beffa, Jessica Laprise, Jennifer Scalia-Wilbur, Christina Raker, Melissa A Clark, Elizabeth Lokich, Erin Hofstatter, Disha Dalela, Amy Brown, Leslie Bradford, Maris Toland, Ashley Stuckey.

Objective: To determine the utilization of risk-reducing strategies and screening protocols for ovarian cancer in female BRCA1/2 carriers. Methods: This study was a sub-analysis of female participants from a larger multicenter, cross-sectional survey of BRCA1/2 mutation carriers unaffected by cancer. The questionnaire was administered electronically via email at four institutions located in the northeast United States. Data were analyzed with Fisher's exact test. Results: The survey was completed by 104 female BRCA mutation carriers. BRCA subtypes included 54.3% BRCA2, 41.0% BRCA1, and 2.9% both. The age at which patients underwent genetic testing varied 21.2% were 18-24 years, 25.0% were 25-34 years, 29.8% were 35-44 years, and 24.0% were 45 years or older. Nearly, all respondents (97.1%) reported that a provider had discussed risk-reducing surgeries. Of the 79 females who underwent genetic testing before 45 years of age, 53.2% reported that a health care provider recommended taking combined oral contraceptive pills (COCs) to reduce their risk of ovarian cancer, and, of these women, 88.1% chose to use them. COCs were offered at higher rates among women who were younger at the age of genetic testing (18-24: 86%, 25-34: 62%, 35-44: 23%; p < 0.0001). Approximately half (55.8%) of the respondents reported having been offered increased screening for possible early detection of ovarian cancer, of which 81.0% chose to undergo screening. The majority utilized a combination of transvaginal ultrasound and serum CA125 measurements. There were no differences observed in screening utilization based on BRCA mutation type. Conclusion: In our cohort of female BRCA mutation carriers, risk-reducing surgery was offered to almost all women, whereas only half were offered risk-reducing medication and/or increased screening. Further investigation is needed to identify barriers to the utilization of risk-reducing strategies among this high-risk population.

Keywords: BRCA; cancer screening; genetic counseling; ovarian cancer; risk management

DOI: https://doi.org/10.1089/jwh.2023.0621

Curr Treat Options Oncol. 2024 Mar 12.

Circulating Tumor DNA (ctDNA) and Its Role in Gynecologic Malignancies.

Tali Pomerantz, Rebecca Brooks.

OPINION STATEMENT: Circulating tumor DNA (ctDNA) refers to small fragments of DNA released into the bloodstream by cancer cells. It is obtained through "liquid biopsy;" which most commonly refers to plasma or blood samples, but can be obtained from a number of bodily fluids including ascitic fluid, saliva, and even urine and stool. ctDNA is detected via polymerase chain reaction (PCR) or next-generation sequencing (NGS). The DNA from these samples is analyzed for the detection of point mutations, copy-number alterations, gene fusion, and DNA methylation. These results have the potential for use in cancer diagnosis, determining prognosis, targeting gene-specific therapies, and monitoring for/predicting disease recurrence and response to treatment. ctDNA offers an alternative to tissue biopsy; it is less invasive and can be monitored serially over time without multiple procedures. Moreover it may have the ability to detect disease recurrence or predict behavior in a way that solid tissue biopsies, tumor marker surveillance, and imaging cannot. Recent explosion in interest in ctDNA shows promising developments for widespread adoption of these techniques in cancer care. However, the use of ctDNA in diagnosis and treatment of gynecologic malignancies is currently limited, compared to adoption in other solid-organ tumors such as breast and colorectal cancers. Compared to other cancer types, there appear to be fewer comprehensive studies and clinical validations specifically focusing on the use of ctDNA in gynecologic cancers. More research is needed in this area to advance the potential for use of ctDNA in ovarian, endometrial, and cervical cancers before this can be routinely adopted to improve care for patients with gynecologic malignancies.

Keywords: Cell-free DNA; Circulating tumor DNA; Circulating tumor cells (CTC); Liquid biopsy; Next-generation sequencing; PCR; Precision oncology

DOI: https://doi.org/10.1007/s11864-024-01180-w