bims-ovdlit 2024-02-25 papers

Issue of 2024–02–25
four papers selected by
Lara Paracchini, Humanitas Research

Cells. 2024 Feb 15. pii: 345. [Epub ahead of print]13(4):

Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer-Genetic Instability and Clinical Implications.

Marek Murawski, Adam Jagodziński, Aleksandra Bielawska-Pohl, Aleksandra Klimczak.

Ovarian cancer is a leading cause of death among women with gynecological cancers, and is often diagnosed at advanced stages, leading to poor outcomes. This review explores genetic aspects of high-grade serous, endometrioid, and clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in high-grade serous and BRAF/KRAS in low-grade serous carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, and c-myc amplification, offers potential therapeutic targets. This review underscores TP53's pivotal role and advocates p53 immunohistochemical staining for mutational analysis. BRCA1/2 mutations' significance as genetic risk factors and their relevance in PARP inhibitor therapy are discussed, emphasizing the importance of genetic testing. This review also addresses the paradoxical better prognosis linked to KRAS and BRAF mutations in ovarian cancer. ARID1A, PIK3CA, and PTEN alterations in platinum resistance contribute to the genetic landscape. Therapeutic strategies, like restoring WT p53 function and exploring PI3K/AKT/mTOR inhibitors, are considered. The evolving understanding of genetic factors in ovarian carcinomas supports tailored therapeutic approaches based on individual tumor genetic profiles. Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery.

Keywords: ARID1A mutations; BRAF mutations; BRCA1 mutations; BRCA2 mutations; CTNNB1 mutations; PIK3CA mutations; PTEN mutations; RAS mutations; RRSO; TP53 mutations; c-myc amplification; genetic instability; oncogenesis; ovarian cancer

DOI: https://doi.org/10.3390/cells13040345

Gynecol Oncol Rep. 2024 Feb;51 101334

Serous tubal intraepithelial carcinoma (STIC) outcomes in an average risk population.

Kimberly T Stewart, Lien Hoang, Janice S Kwon.

Objective: Serous tubal intraepithelial carcinoma (STIC) are precursors for high grade serous carcinomas (HGSC) of tubo-ovarian origin. It is a rare entity, most commonly described in patients with a BRCA pathogenic variant (PV) undergoing risk-reducing surgery. Little is known about the risk of subsequent HGSC in patients found to have an isolated STIC without a genetic PV. The objective of this study is to report the outcomes of STIC diagnosed in patients with negative genetic testing ("average risk").
Methods: Retrospective population-based cohort study from British Columbia, Canada. Chart review of patients diagnosed with an isolated STIC from January 2012 to May 2022. Average risk patients are defined as individuals with known negative genetic testing results. Treatment and outcomes are described in the "average risk", BRCA PV, and total cohorts.
Results: Twenty-nine patients with isolated STIC were identified. Ten patients had a BRCA PV, four had other variants identified (BRIP1, MLH1, BRIP1 VUS, BRCA 2 VUS), nine had no PV identified ("average risk"), and six were unknown (no genetic testing). Of the nine "average risk" patients, eight (89%) underwent surgical staging. Three (33.3%) had subsequent HGSC diagnosed 29, 70 and 86 months after STIC diagnosis.
Conclusions: STIC identified in patients with negative genetic testing are at risk of subsequent HGSC. Patients developed primary peritoneal HGSC despite surgical staging. These patients should also be included in future meta-analysis to determine outcomes and optimal treatment.

DOI: https://doi.org/10.1016/j.gore.2024.101334

Nat Genet. 2024 Feb 22.

Chromosome evolution screens recapitulate tissue-specific tumor aneuploidy patterns.

Emma V Watson, Jake June-Koo Lee, Doga C Gulhan, Giorgio E M Melloni, Sergey V Venev, Rayna Y Magesh, Abdulrazak Frederick, Kunitoshi Chiba, Eric C Wooten, Kamila Naxerova, Job Dekker, Peter J Park, Stephen J Elledge.

Whole chromosome and arm-level copy number alterations occur at high frequencies in tumors, but their selective advantages, if any, are poorly understood. Here, utilizing unbiased whole chromosome genetic screens combined with in vitro evolution to generate arm- and subarm-level events, we iteratively selected the fittest karyotypes from aneuploidized human renal and mammary epithelial cells. Proliferation-based karyotype selection in these epithelial lines modeled tissue-specific tumor aneuploidy patterns in patient cohorts in the absence of driver mutations. Hi-C-based translocation mapping revealed that arm-level events usually emerged in multiples of two via centromeric translocations and occurred more frequently in tetraploids than diploids, contributing to the increased diversity in evolving tetraploid populations. Isogenic clonal lineages enabled elucidation of pro-tumorigenic mechanisms associated with common copy number alterations, revealing Notch signaling potentiation as a driver of 1q gain in breast cancer. We propose that intrinsic, tissue-specific proliferative effects underlie tumor copy number patterns in cancer.

DOI: https://doi.org/10.1038/s41588-024-01665-2