bims-ovdlit 2024-10-06 papers

Issue of 2024–10–06
ten papers selected by
Lara Paracchini, Humanitas Research

bioRxiv. 2024 Sep 18. pii: 2024.09.17.612958. [Epub ahead of print]

Mutant p53 Misfolding and Aggregation Precedes Transformation into High-Grade Serous Ovarian Carcinoma.

Sara Sartini, Lexi Omholt, Neda A Moatamed, Alice Soragni.

High Grade Serous Ovarian Cancer (HG-SOC), the most prevalent and aggressive gynecological malignancy, is marked by ubiquitous loss of functional p53, largely due to point mutations that arise very early in carcinogenesis. These mutations often lead to p53 protein misfolding and subsequent aggregation, yet the alterations in intracellular p53 dynamics throughout ovarian cancer progression remain poorly understood. HG-SOC originates from the fallopian tube epithelium, with a well-documented stepwise progression beginning with early pre-malignant p53 signatures. These signatures represent largely normal cells that express and accumulate mutant p53, which then transform into benign serous tubal intraepithelial lesions (STIL), progress into late pre-malignant serous tubal intraepithelial carcinoma (STIC), and ultimately lead to HGSOC. Here, we show that the transition from folded, soluble to aggregated mutant p53 occurs during the malignant transformation of benign precursor lesions into HGSOC. We analyzed fallopian tube tissue collected from ten salpingo-oophorectomy cases and determined the proportion of cells carrying soluble versus mis-folded/mutant p53 through conformation-sensitive staining and quantification. Misfolded p53 protein, prone to aggregation, is present in STICs and HG-SOCs, but notably absent from preneoplastic lesions and surrounding healthy tissue. Overall, our results indicate that aggregation of mutant p53 is a structural defect that distinguishes preneoplastic early lesions from late premalignant and malignant ones, offering a potential treatment window for targeting p53 aggregation and halting ovarian cancer progression.

DOI: https://doi.org/10.1101/2024.09.17.612958

Nat Commun. 2024 Oct 05. 15(1): 8641

Pre-ciliated tubal epithelial cells are prone to initiation of high-grade serous ovarian carcinoma.

Andrea Flesken-Nikitin, Coulter Q Ralston, Dah-Jiun Fu, Andrea J De Micheli, Daryl J Phuong, Blaine A Harlan, Christopher S Ashe, Amanda P Armstrong, David W McKellar, Sangeeta Ghuwalewala, Lora H Ellenson, John C Schimenti, Benjamin D Cosgrove, Alexander Yu Nikitin.

The distal region of the uterine (Fallopian) tube is commonly associated with high-grade serous carcinoma (HGSC), the predominant and most aggressive form of ovarian or extra-uterine cancer. Specific cell states and lineage dynamics of the adult tubal epithelium (TE) remain insufficiently understood, hindering efforts to determine the cell of origin for HGSC. Here, we report a comprehensive census of cell types and states of the mouse uterine tube. We show that distal TE cells expressing the stem/progenitor cell marker Slc1a3 can differentiate into both secretory (Ovgp1+) and ciliated (Fam183b+) cells. Inactivation of Trp53 and Rb1, whose pathways are commonly altered in HGSC, leads to elimination of targeted Slc1a3+ cells by apoptosis, thereby preventing their malignant transformation. In contrast, pre-ciliated cells (Krt5+, Prom1+, Trp73+) remain cancer-prone and give rise to serous tubal intraepithelial carcinomas and overt HGSC. These findings identify transitional pre-ciliated cells as a cancer-prone cell state and point to pre-ciliation mechanisms as diagnostic and therapeutic targets.

DOI: https://doi.org/10.1038/s41467-024-52984-1

Clin Obstet Gynecol. 2024 Sep 30.

Current Science and Practice of Surgical and Nonsurgical Opportunities for Ovarian Cancer Prevention.

Emily MacArthur, Rebecca Stone.

Due to improved understanding of ovarian cancer pathogenesis, we have an unprecedented chance to decrease the burden of disease by maximizing opportunities for prevention. Innovations in surgical options for prevention stem from the discovery that many cases directly or indirectly arise from the fallopian tube. Surgical prevention with salpingectomy alone decreases risk by ≥50%. Effective hormonal and nonhormonal chemopreventive agents are also available. Risk stratification is key to ensuring that options for prevention are appropriately matched to individual risk profile. This evidence-based review provides a critical appraisal of the translational health research endeavors supporting ovarian cancer prevention in clinical practice.

DOI: https://doi.org/10.1097/GRF.0000000000000900

Cancer Discov. 2024 Sep 30.

Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers.

Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity >99% and sensitivity of 72%, 69%, 87%, and 100% for stages I-IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I-IV. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC=0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0393

Nat Genet. 2024 Oct 02.

Aneuploidy as a driver of human cancer.

Eran Sdeor, Hajime Okada, Ron Saad, Tal Ben-Yishay, Uri Ben-David.

Aneuploidy, an abnormal chromosome composition, is a major contributor to cancer development and progression and an important determinant of cancer therapeutic responses and clinical outcomes. Despite being recognized as a hallmark of human cancer, the exact role of aneuploidy as a 'driver' of cancer is still largely unknown. Identifying the specific genetic elements that underlie the recurrence of common aneuploidies remains a major challenge of cancer genetics. In this Review, we discuss recurrent aneuploidies and their function as drivers of tumor development. We then delve into the context-dependent identification and functional characterization of the driver genes underlying driver aneuploidies and examine emerging strategies to uncover these driver genes using cancer genomics data and cancer models. Lastly, we explore opportunities for targeting driver aneuploidies in cancer by leveraging the functional consequences of these common genetic alterations.

DOI: https://doi.org/10.1038/s41588-024-01916-2

Pathol Res Pract. 2024 Sep 26. pii: S0344-0338(24)00528-4. [Epub ahead of print]263 155617

PARP inhibitors in ovarian cancer: Mechanisms, resistance, and the promise of combination therapy.

Tejas Bhatia, Gaurav Doshi, Angel Godad.

Current approaches to treating ovarian cancer focus mainly on surgical cytoreduction and chemotherapy using platinum-based drugs, while newer methods such as immunotherapy are being investigated to enhance treatment outcomes. Treating ovarian cancer is complicated by challenges such as late-stage detection, tumor diversity, and limited treatment choices. Therefore, innovative strategies such as precision medicine and targeted therapies like PARPi (Poly ADP-Ribose Polymerase inhibitors) are increasingly necessary. The article highlights the significance of an innovative therapeutic approach focusing on PARPi in revolutionizing ovarian cancer treatment and improving patient outcomes. It covers the basic knowledge of PARP, its structure, and its function in DNA repair. It further emphasizes how inhibiting PARP can help in treating ovarian cancer. It elaborates on the mechanism of action of PARPi. It covers the clinical trials governing PARPi and the combination of drugs used with PARPi. It mentions how the resistance is developed to PARPi and the strategies to overcome the resistance developed.

Keywords: Cancer; Mutations; Ovarian cancer; PARP inhibitors; Poly ADP-ribose polymerase

DOI: https://doi.org/10.1016/j.prp.2024.155617

J Clin Med. 2024 Sep 13. pii: 5445. [Epub ahead of print]13(18):

Screening Strategies to Improve Early Diagnosis in Endometrial Cancer.

Silvia Cabrera, Irene de la Calle, Sonia Baulies, Antonio Gil-Moreno, Eva Colas.

Endometrial cancer is the most common gynecological malignancy in high-income countries and the sixth most common cancer in women. Overall incidence has risen in the last few decades as a consequence of the increase in the prevalence of its risk factors, mainly obesity and the aging of the population, and although diagnoses have increased across all age groups, the incidence rates have doubled in women under the age of 40 years. The survival rates of endometrial cancer are highly dependent on its stage at diagnosis, bringing to the fore the importance of early diagnosis. The aim of a screening strategy in this type of tumor should be to detect the disease in the pre-invasive or early stage (before developing myometrial invasion), which would improve cure rates, reduce the morbidity associated with aggressive treatment and offer uterus-sparing management options for younger women. The ideal screening tool in this scenario would be a minimally invasive, inexpensive and easy-to-perform test or auto-test, which could be implemented in a routine gynecologic checkup of patients at-risk or in the general adult population. In this comprehensive review, we aim to define the populations at higher risk of developing endometrial cancer, to assess the performance of current diagnostic tools when used in a screening setting and to discuss the accuracy of new molecular screening strategies.

Keywords: diagnosis; endometrial cancer; high-risk population; screening

DOI: https://doi.org/10.3390/jcm13185445

Lancet Oncol. 2024 Oct;pii: S1470-2045(24)00406-6. [Epub ahead of print]25(10): 1371-1386

Risk-prediction models in postmenopausal patients with symptoms of suspected ovarian cancer in the UK (ROCkeTS): a multicentre, prospective diagnostic accuracy study.

ROCkeTS collaborators

BACKGROUND: Multiple risk-prediction models are used in clinical practice to triage patients as being at low risk or high risk of ovarian cancer. In the ROCkeTS study, we aimed to identify the best diagnostic test for ovarian cancer in symptomatic patients, through head-to-head comparisons of risk-prediction models, in a real-world setting. Here, we report the results for the postmenopausal cohort.
METHODS: In this multicentre, prospective diagnostic accuracy study, we recruited newly presenting female patients aged 16-90 years with non-specific symptoms and raised CA125 or abnormal ultrasound results (or both) who had been referred via rapid access, elective clinics, or emergency presentations from 23 hospitals in the UK. Patients with normal CA125 and simple ovarian cysts of smaller than 5 cm in diameter, active non-ovarian malignancy, or previous ovarian malignancy, or those who were pregnant or declined a transvaginal scan, were ineligible. In this analysis, only postmenopausal participants were included. Participants completed a symptom questionnaire, gave a blood sample, and had transabdominal and transvaginal ultrasounds performed by International Ovarian Tumour Analysis consortium (IOTA)-certified sonographers. Index tests were Risk of Malignancy 1 (RMI1) at a threshold of 200, Risk of Malignancy Algorithm (ROMA) at multiple thresholds, IOTA Assessment of Different Neoplasias in the Adnexa (ADNEX) at thresholds of 3% and 10%, IOTA SRRisk model at thresholds of 3% and 10%, IOTA Simple Rules (malignant vs benign, or inconclusive), and CA125 at 35 IU/mL. In a post-hoc analysis, the Ovarian Adnexal and Reporting Data System (ORADS) at 10% was derived from IOTA ultrasound variables using established methods since ORADS was described after completion of recruitment. Index tests were conducted by study staff masked to the results of the reference standard. The comparator was RMI1 at the 250 threshold (the current UK National Health Service standard of care). The reference standard was surgical or biopsy tissue histology or cytology within 3 months, or a self-reported diagnosis of ovarian cancer at 12 month follow-up. The primary outcome was diagnostic accuracy at predicting primary invasive ovarian cancer versus benign or normal histology, assessed by analysing the sensitivity, specificity, C-index, area under receiver operating characteristic curve, positive and negative predictive values, and calibration plots in participants with conclusive reference standard results and available index test data. This study is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN17160843).
FINDINGS: Between July 13, 2015, and Nov 30, 2018, 1242 postmenopausal patients were recruited, of whom 215 (17%) had primary ovarian cancer. 166 participants had missing, inconclusive, or other reference standard results; therefore, data from a maximum of 1076 participants were used to assess the index tests for the primary outcome. Compared with RMI1 at 250 (sensitivity 82·9% [95% CI 76·7 to 88·0], specificity 87·4% [84·9 to 89·6]), IOTA ADNEX at 10% was more sensitive (difference of -13·9% [-20·2 to -7·6], p<0·0001) but less specific (difference of 28·5% [24·7 to 32·3], p<0·0001). ROMA at 29·9 had similar sensitivity (difference of -3·6% [-9·1 to 1·9], p=0·24) but lower specificity (difference of 5·2% [2·5 to 8·0], p=0·0001). RMI1 at 200 had similar sensitivity (difference of -2·1% [-4·7 to 0·5], p=0·13) but lower specificity (difference of 3·0% [1·7 to 4·3], p<0·0001). IOTA SRRisk model at 10% had similar sensitivity (difference of -4·3% [-11·0 to -2·3], p=0·23) but lower specificity (difference of 16·2% [12·6 to 19·8], p<0·0001). IOTA Simple Rules had similar sensitivity (difference of -1·6% [-9·3 to 6·2], p=0·82) and specificity (difference of -2·2% [-5·1 to 0·6], p=0·14). CA125 at 35 IU/mL had similar sensitivity (difference of -2·1% [-6·6 to 2·3], p=0·42) but higher specificity (difference of 6·7% [4·3 to 9·1], p<0·0001). In a post-hoc analysis, when compared with RMI1 at 250, ORADS achieved similar sensitivity (difference of -2·1%, 95% CI -8·6 to 4·3, p=0·60) and lower specificity (difference of 10·2%, 95% CI 6·8 to 13·6, p<0·0001).
INTERPRETATION: In view of its higher sensitivity than RMI1 at 250, despite some loss in specificity, we recommend that IOTA ADNEX at 10% should be considered as the new standard-of-care diagnostic in ovarian cancer for postmenopausal patients.
FUNDING: UK National Institute of Heath Research.

DOI: https://doi.org/10.1016/S1470-2045(24)00406-6