bims-ovdlit 2024-08-18 papers

Issue of 2024–08–18
four papers selected by
Lara Paracchini, Humanitas Research

Gynecol Oncol. 2024 Aug 10. pii: S0090-8258(24)01054-0. [Epub ahead of print]190 18-27

Increased TP53 somatic evolution in peritoneal washes of individuals with BRCA1 germline mutations.

Xin Ray Tee, Emma Hazard, Elena Latorre-Esteves, Brendan F Kohrn, Talayeh S Ghezelayagh, Jeanne Uy Fredrickson, CoohleenAnn Coombes, Marc R Radke, Enna Manhardt, Ronit Katz, T Rinda Soong, Elizabeth M Swisher, Barbara M Norquist, Rosa Ana Risques.

BACKGROUND: Individuals with germline BRCA1 and BRCA2 pathogenic variants (BRCA carriers) are at high risk of developing high grade serous ovarian carcinoma (HGSC). HGSC is predominantly driven by TP53 mutations, but mutations in this gene are also commonly found in non-cancerous tissue as a feature of normal human aging. We hypothesized that HGSC predisposition in BRCA carriers may be related to increased TP53 somatic evolution, which could be detectable by ultra-deep sequencing of TP53 mutations in gynecological liquid biopsies.
METHODS: Duplex sequencing was used to identify TP53 mutations with high sensitivity in peritoneal washes and cervical liquid-based cytology (LBC) collected at surgery from 60 individuals including BRCA1 and BRCA2 carriers, and non-carriers. TP53 mutation pathogenicity was compared across groups and with TP53 cancer mutations.
RESULTS: TP53 mutations were more abundant in cervical LBC than in peritoneal washes but increased with age in both sample types. In peritoneal washes, but not in cervical LBC, pathogenic TP53 mutation burden was increased in BRCA1 carriers compared to non-carriers, independently of age. Five individuals shared identical pathogenic TP53 mutations in peritoneal washes and cervical LBC, but not in blood.
CONCLUSIONS: Ultra-deep sequencing of TP53 mutations in peritoneal washes collected at surgery reveals increased burden of pathogenic TP53 mutations in BRCA1 carriers. This excess of pathogenic TP53 mutations might be linked to the elevated risk of HGSC in these individuals. In some patients, concordant TP53 mutations were found in peritoneal washes and cervical LBCs, but the cell of origin remains unknown and deserves further investigation.

Keywords: BRCA mutations; Clonal expansions; Ovarian cancer risk; Pap tests; Pathogenic mutations; TP53 mutations

DOI: https://doi.org/10.1016/j.ygyno.2024.07.690

Nat Rev Genet. 2024 Aug 12.

DNA methylation in mammalian development and disease.

Zachary D Smith, Sara Hetzel, Alexander Meissner.

The DNA methylation field has matured from a phase of discovery and genomic characterization to one seeking deeper functional understanding of how this modification contributes to development, ageing and disease. In particular, the past decade has seen many exciting mechanistic discoveries that have substantially expanded our appreciation for how this generic, evolutionarily ancient modification can be incorporated into robust epigenetic codes. Here, we summarize the current understanding of the distinct DNA methylation landscapes that emerge over the mammalian lifespan and discuss how they interact with other regulatory layers to support diverse genomic functions. We then review the rising interest in alternative patterns found during senescence and the somatic transition to cancer. Alongside advancements in single-cell and long-read sequencing technologies, the collective insights made across these fields offer new opportunities to connect the biochemical and genetic features of DNA methylation to cell physiology, developmental potential and phenotype.

DOI: https://doi.org/10.1038/s41576-024-00760-8

Surg Pathol Clin. 2024 Sep;pii: S1875-9181(24)00017-5. [Epub ahead of print]17(3): 431-439

Cervical Human Papillomavirus Testing: Current and Future Impact on Patient Care.

Carol N Rizkalla, Eric C Huang.

Cervical cancer is the fourth most common malignancy in women worldwide. The identification of human papillomavirus (HPV) as the main etiologic cause of cervical cancer has led to the development and adaptation of HPV molecular diagnostics as a cervical cancer screening and prevention tool. This article highlights six Food and Drug Administration-approved HPV molecular platforms, each with unique advantages and disadvantages. In addition, HPV vaccination and the emergence of HPV self-collection as an alternative testing strategy are discussed.

Keywords: Cervical cancer; FDA; Human papillomavirus; Molecular; Self-collection

DOI: https://doi.org/10.1016/j.path.2024.04.006