bims-tumhet 2024-03-10 papers

Issue of 2024–03–10
three papers selected by
Sergio Marchini, Humanitas Research

Mol Oncol. 2024 Mar 08.

Pleural mesothelioma (PMe): The evolving molecular knowledge of a rare and aggressive cancer.

Manuel Rigon, Luciano Mutti, Michelangelo Campanella.

Mesothelioma is a type of late-onset cancer that develops in cells covering the outer surface of organs. Although it can affect the peritoneum, heart, or testicles, it mainly targets the lining of the lungs, making pleural mesothelioma (PMe) the most common and widely studied mesothelioma type. PMe is caused by exposure to fibres of asbestos, which when inhaled leads to inflammation and scarring of the pleura. Despite the ban on asbestos by most Western countries, the incidence of PMe is on the rise, also facilitated by a lack of specific symptomatology and diagnostic methods. Therapeutic options are also limited to mainly palliative care, making this disease untreatable. Here we present an overview of biological aspects underlying PMe by listing genetic and molecular mechanisms behind its onset, aggressive nature, and fast-paced progression. To this end, we report on the role of deubiquitinase BRCA1-associated protein-1 (BAP1), a tumour suppressor gene with a widely acknowledged role in the corrupted signalling and metabolism of PMe. This review aims to enhance our understanding of this devastating malignancy and propel efforts for its investigation.

Keywords: BAP1 and therapy; asbestos; mesothelioma

DOI: https://doi.org/10.1002/1878-0261.13591

Gynecol Oncol. 2024 Mar 06. pii: S0090-8258(24)00137-9. [Epub ahead of print]185 194-201

Mutations in cancer-relevant genes are ubiquitous in histologically normal endometrial tissue.

OBJECTIVE: Endometrial cancer (EndoCA) is the most common gynecologic cancer and incidence and mortality rate continue to increase. Despite well-characterized knowledge of EndoCA-defining mutations, no effective diagnostic or screening tests exist. To lay the foundation for testing development, our study focused on defining the prevalence of somatic mutations present in non-cancerous uterine tissue.
METHODS: We obtained ≥8 uterine samplings, including separate endometrial and myometrial layers, from each of 22 women undergoing hysterectomy for non-cancer conditions. We ultra-deep sequenced (>2000× coverage) samples using a 125 cancer-relevant gene panel.
RESULTS: All women harbored complex mutation patterns. In total, 308 somatic mutations were identified with mutant allele frequencies ranging up to 96.0%. These encompassed 56 unique mutations from 24 genes. The majority of samples possessed predicted functional cancer mutations but curiously no growth advantage over non-functional mutations was detected. Functional mutations were enriched with increasing patient age (p = 0.045) and BMI (p = 0.0007) and in endometrial versus myometrial layers (68% vs 39%, p = 0.0002). Finally, while the somatic mutation landscape shared similar mutation prevalence in key TCGA-defined EndoCA genes, notably PIK3CA, significant differences were identified, including NOTCH1 (77% vs 10%), PTEN (9% vs 61%), TP53 (0% vs 37%) and CTNNB1 (0% vs 26%).
CONCLUSIONS: An important caveat for future liquid biopsy/DNA-based cancer diagnostics is the repertoire of shared and distinct mutation profiles between histologically unremarkable and EndoCA tissues. The lack of selection pressure between functional and non-functional mutations in histologically unremarkable uterine tissue may offer a glimpse into an unrecognized EndoCA protective mechanism.

Keywords: Endometrial cancer; Histological normal uterus; Liquid biopsy; cancer-driver gene mutation in normal tissue

DOI: https://doi.org/10.1016/j.ygyno.2024.02.027

Clin Chem Lab Med. 2024 Mar 07.

Circulating tumor DNA methylation: a promising clinical tool for cancer diagnosis and management.

Binliang Wang, Meng Wang, Ya Lin, Jinlan Zhao, Hongcang Gu, Xiangjuan Li.

Cancer continues to pose significant challenges to the medical community. Early detection, accurate molecular profiling, and adequate assessment of treatment response are critical factors in improving the quality of life and survival of cancer patients. Accumulating evidence shows that circulating tumor DNA (ctDNA) shed by tumors into the peripheral blood preserves the genetic and epigenetic information of primary tumors. Notably, DNA methylation, an essential and stable epigenetic modification, exhibits both cancer- and tissue-specific patterns. As a result, ctDNA methylation has emerged as a promising molecular marker for noninvasive testing in cancer clinics. In this review, we summarize the existing techniques for ctDNA methylation detection, describe the current research status of ctDNA methylation, and present the potential applications of ctDNA-based assays in the clinic. The insights presented in this article could serve as a roadmap for future research and clinical applications of ctDNA methylation.

Keywords: cancer; ctDNA; detection technology; early diagnosis; methylation

DOI: https://doi.org/10.1515/cclm-2023-1327