bims-ovdlit 2025-03-02 papers

Issue of 2025–03–02
seven papers selected by
Lara Paracchini, Humanitas Research

Int J Gynecol Cancer. 2025 Feb 05. pii: S1048-891X(25)00192-6. [Epub ahead of print]35(3): 101667

Controversies in the management of serous tubal intra-epithelial carcinoma lesions of the fallopian tube.

Olivia Le Saux, Iain McNeish, Maurizio D'Incalci, Fabrice Narducci, Isabelle Ray-Coquard.

High-grade serous carcinoma is the most lethal gynecological malignancy. Although serous tubal intra-epithelial carcinoma is increasingly recognized as a precursor to high-grade serous carcinoma, its optimal management remains controversial. This review examines the controversies in serous tubal intra-epithelial carcinoma pathogenesis, diagnosis, management, and follow-up, highlighting the need for collaboration, standardized guidelines, and further research to improve patient outcomes.

Keywords: Carcinogenesis; Ovarian Cancer; Preneoplastic Lesion

DOI: https://doi.org/10.1016/j.ijgc.2025.101667

J Gynecol Oncol. 2025 Feb 11.

Clinical outcome and pattern of care for isolated or incidental serous tubal intraepithelial carcinoma: a multicenter retrospective cohort study.

Bo Ra Kim, Se Ik Kim, Sang Wun Kim, Chel Hun Choi, Shin-Wha Lee, Myong Cheol Lim, Yun Hwan Kim.

OBJECTIVE: Serous tubal intraepithelial carcinoma (STIC), a potential precursor of high-grade serous carcinoma, is associated with subsequent carcinomas development. This study aimed to identify cases of STIC and serous tubal intraepithelial lesions (STIL) and examine clinical outcomes and patterns of care in BRCA1/2 mutations carriers undergoing risk-reducing salpingo-oophorectomy (RRSO), as well as patients with incidental STIC/STIL after benign gynecologic surgery.
METHODS: This retrospective study was conducted at six institutions to examine patients with isolated STIC/STIL. Demographic, adjuvant treatment, and follow-up data were collected from the date of implementation of Sectioning and Extensively Examining the Fimbriated end protocol, which varied from 2006 to 2015, until December 2022.
RESULTS: We analyzed the data of 1,119 women who underwent RRSO and were carriers of BRCA1/2 mutations. The detection rate of isolated STIC/STIL was 1.70%. No patient with STIC/STIL received adjuvant chemotherapy or staging operations. The institutions used different surveillance intervals and methods, with the most common being a 3-6 month interval (11 of 19 patients) and gynecological sonography (17 of 19 patients). All patients remained with no evidence of disease (NED) throughout the follow-up period (2-121 months). Additionally, we analyzed data from five women with incidental STIC/STIL diagnosed after benign gynecological surgery; one woman underwent staging surgery. During the follow-up period (3-46 months), all patients remained in NED.
CONCLUSION: While patient monitoring after STIC/STIL detection may be considered due to the minimal risk of carcinoma, excessive concern may not be necessary. Furthermore, adjuvant chemotherapy should be considered only with caution.

Keywords: Carcinoma in Situ; Genes, BRCA1; Genes, BRCA2; Prophylactic Surgical Procedures; Salpingo-oophorectomy; Serous Ovarian Neoplasms

DOI: https://doi.org/10.3802/jgo.2025.36.e68

Curr Treat Options Oncol. 2025 Feb 27.

Gynecologic Cancer Screening and Prevention: State of the Science and Practice.

C Tran, H Diaz-Ayllon, D Abulez, S Chinta, M Y Williams-Brown, N Desravines.

OPINION STATEMENT: Gynecological cancers, including cervical, endometrial, ovarian, and vulvovaginal cancer, have increasing incidence and mortality globally over the last three decades. In that time, there have been advances in medical therapies and paradigm shifts in surgical treatment which have resulted in a greater quality of life for patients. Clinicians have also refocused efforts to preventing gynecologic cancer. The state of screening and prevention is varied in each of the cancer types. The most comprehensive screening program and only preventable gynecological cancer is cervical cancer, which has been heavily studied since the 1900s. Cervical cytology, primary high-risk human papillomavirus (HPV) testing only, and co-testing are all effective in detecting cervical dysplasia and touted by the major medical. An additional arsenal is prevention through vaccination which has been shown to decrease cervical cancer. Unfortunately, the other gynecological cancers do not have effective screening strategies. The high rates of symptoms in endometrial cancer facilitate detection at an early stage but thus far, asymptomatic screening is only advocated in very high-risk population due to the invasive nature. Novel non-invasive mechanisms are currently under study though none have translated into clinical practice as of yet. Ovarian cancer remains the most innocuous with vague symptoms at onset resulting in late-stage diagnosis. Recommendations for prophylactic oophorectomy only apply to subsets of the population with predisposing genetic mutations. This has led to an ardent push for creative strategies such as opportunistic salpingectomy and a national genetic screening program. These efforts are in addition to the investigations underway researching radiologic, liquid biopsy, and genetic marker screening modalities for all gynecologic cancer. This review article discusses the state of screening, prevention, and recent advancements and pilot studies for each gynecological cancer.

Keywords: Cervical cancer; Endometrial cancer; Gynecological cancer; Ovarian cancer; Prevention; Screening

DOI: https://doi.org/10.1007/s11864-025-01301-z

Clin Cancer Res. 2025 Feb 28.

Germline-Somatic Interactions in BRCA-Associated Cancers: Unique Molecular Profiles and Clinical Outcomes Linking ATM to TP53 Synthetic Essentiality.

BACKGROUND: Germline alterations in homologous recombination repair (gHRR) genes impact the pathogenesis, treatment options, and survival of cancer patients. However, distinct gHRR gene alterations may differentially impact treatment response and oncogenic signaling. Here we interrogated genomic and transcriptomic data and assessed clinical outcomes of patients with gHRR mutations across four BRCA-associated cancers (breast, ovarian, pancreatic, and prostate cancers) to identify therapeutic vulnerabilities.
METHODS: We assessed 24,309 patients undergoing matched tumor/normal next-generation DNA and RNA sequencing. Annotated gHRR gene variants (gBRCA1, gBRCA2, gPALB2, gATM, gCHEK2) were analyzed. Hazard ratios were used to assess survival outcomes comparing germline versus sporadic groups. Somatic alterations and their frequencies were compared across gHRR-altered groups. Differential gene expression and gene set enrichment analysis was used to compare transcriptomic profiles.
RESULTS: Somatic TP53 mutations were depleted in gATM carriers (p<0.05) across all four BRCA-associated cancers by up to 2.5-fold. Tumors with gBRCA1/2 mutations were associated with improved survival in ovarian cancer patients, and had consistent enrichment of TP53 mutations in all four cancers. gATM mutations displayed elevated p53 transcriptional activity in all four cancers, with significance reached in breast and prostate cancers (p<0.01). In breast, ovarian, and prostate cancers, gATM tumors demonstrated significantly increased inflammatory pathways (p<0.001). Finally, using gene-dependency data, we found that cell lines that were highly dependent on ATM were co-dependent on canonical p53 function.
CONCLUSION: gATM-associated cancers appear to require intact p53 activity and this synthetic essentiality may be used to guide targeted therapies that perturb canonical TP53 function.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-2058

Front Endocrinol (Lausanne). 2025 ;16 1555914

Editorial: Genetics and epigenetics in ovarian aging.

Honey V Reddi.

Keywords: endocrinology; epigenetics; genetics; mitochondria; ovarian aging

DOI: https://doi.org/10.3389/fendo.2025.1555914

Clin Transl Med. 2025 Feb;15(2): e70248

Spatial genomics uncovers cytokines promoting ovarian tumour heterogeneity and immunotherapy resistance.

Gurkan Mollaoglu, Brian D Brown, Alessia Baccarini.

Keywords: IL‐4; immunotherapy; ovarian cancer; tumour immunology

DOI: https://doi.org/10.1002/ctm2.70248

Nature. 2025 Feb 26.

Rare disease gene association discovery in the 100,000 Genomes Project.

Valentina Cipriani, Letizia Vestito, Emma F Magavern, Julius O B Jacobsen, Gavin Arno, Elijah R Behr, Katherine A Benson, Marta Bertoli, Detlef Bockenhauer, Michael R Bowl, Kate Burley, Li F Chan, Patrick Chinnery, Peter J Conlon, Marcos A Costa, Alice E Davidson, Sally J Dawson, Elhussein A E Elhassan, Sarah E Flanagan, Marta Futema, Daniel P Gale, Sonia García-Ruiz, Cecilia Gonzalez Corcia, Helen R Griffin, Sophie Hambleton, Amy R Hicks, Henry Houlden, Richard S Houlston, Sarah A Howles, Robert Kleta, Iris Lekkerkerker, Siying Lin, Petra Liskova, Hannah H Mitchison, Heba Morsy, Andrew D Mumford, William G Newman, Ruxandra Neatu, Edel A O'Toole, Albert C M Ong, Alistair T Pagnamenta, Shamima Rahman, Neil Rajan, Peter N Robinson, Mina Ryten, Omid Sadeghi-Alavijeh, John A Sayer, Claire L Shovlin, Jenny C Taylor, Omri Teltsh, Ian Tomlinson, Arianna Tucci, Clare Turnbull, Albertien M van Eerde, James S Ware, Laura M Watts, Andrew R Webster, Sarah K Westbury, Sean L Zheng, Mark Caulfield, Damian Smedley.

Up to 80% of rare disease patients remain undiagnosed after genomic sequencing1, with many probably involving pathogenic variants in yet to be discovered disease-gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project2. A total of 141 new associations were identified, including five for which independent disease-gene evidence was recently published. Following in silico triaging and clinical expert review, 69 associations were prioritized, of which 30 could be linked to existing experimental evidence. The five associations with strongest overall genetic and experimental evidence were monogenic diabetes with the known β cell regulator3,4 UNC13A, schizophrenia with GPR17, epilepsy with RBFOX3, Charcot-Marie-Tooth disease with ARPC3 and anterior segment ocular abnormalities with POMK. Further confirmation of these and other associations could lead to numerous diagnoses, highlighting the clinical impact of large-scale statistical approaches to rare disease-gene association discovery.

DOI: https://doi.org/10.1038/s41586-025-08623-w