bims-ovdlit 2023-10-08 papers

Issue of 2023–10–08
five papers selected by
Lara Paracchini, Humanitas Research

Am J Hum Genet. 2023 Oct 05. pii: S0002-9297(23)00290-2. [Epub ahead of print]110(10): 1616-1627

Current and new frontiers in hereditary cancer surveillance: Opportunities for liquid biopsy.

CHARM consortium

At least 5% of cancer diagnoses are attributed to a causal pathogenic or likely pathogenic germline genetic variant (hereditary cancer syndrome-HCS). These individuals are burdened with lifelong surveillance monitoring organs for a wide spectrum of cancers. This is associated with substantial uncertainty and anxiety in the time between screening tests and while the individuals are awaiting results. Cell-free DNA (cfDNA) sequencing has recently shown potential as a non-invasive strategy for monitoring cancer. There is an opportunity for high-yield cancer early detection in HCS. To assess clinical validity of cfDNA in individuals with HCS, representatives from eight genetics centers from across Canada founded the CHARM (cfDNA in Hereditary and High-Risk Malignancies) Consortium in 2017. In this perspective, we discuss operationalization of this consortium and early data emerging from the most common and well-characterized HCSs: hereditary breast and ovarian cancer, Lynch syndrome, Li-Fraumeni syndrome, and Neurofibromatosis type 1. We identify opportunities for the incorporation of cfDNA sequencing into surveillance protocols; these opportunities are backed by examples of earlier cancer detection efficacy in HCSs from the CHARM Consortium. We seek to establish a paradigm shift in early cancer surveillance in individuals with HCSs, away from highly centralized, regimented medical screening visits and toward more accessible, frequent, and proactive care for these high-risk individuals.

Keywords: cell-free DNA; genetic predisposition; hereditary cancer syndromes; liquid biopsy; surveillance

DOI: https://doi.org/10.1016/j.ajhg.2023.08.014

Lancet Oncol. 2023 Oct;pii: S1470-2045(23)00390-X. [Epub ahead of print]24(10): e415-e423

Measuring ovarian toxicity in clinical trials: an American Society of Clinical Oncology research statement.

Anticancer agents can impair ovarian function, resulting in premature menopause and associated long-term health effects. Ovarian toxicity is not usually adequately assessed in trials of anticancer agents, leaving an important information gap for patients facing therapy choices. This American Society of Clinical Oncology (ASCO) statement provides information about the incorporation of ovarian toxicity measures in trial design. ASCO recommends: (1) measurement of ovarian toxicity in relevant clinical trials of anticancer agents that enrol post-pubertal, pre-menopausal patients; (2) collection of ovarian function measures at baseline and at 12-24 months after anticancer agent cessation, as a minimum, and later in line with the trial schedule; and (3) assessment of both clinical measures and biomarkers of ovarian function. ASCO recognises that routine measurement of ovarian toxicity and function in cancer clinical trials will add additional complexity and burden to trial resources but asserts that this issue is of such importance to patients that it cannot continue to be overlooked.

DOI: https://doi.org/10.1016/S1470-2045(23)00390-X

Lancet Oncol. 2023 Oct;pii: S1470-2045(23)00465-5. [Epub ahead of print]24(10): 1053

Patient first; person first.

The Lancet Oncology.

DOI: https://doi.org/10.1016/S1470-2045(23)00465-5

Nature. 2023 Oct;622(7981): 41-47

The status of the human gene catalogue.

Scientists have been trying to identify every gene in the human genome since the initial draft was published in 2001. In the years since, much progress has been made in identifying protein-coding genes, currently estimated to number fewer than 20,000, with an ever-expanding number of distinct protein-coding isoforms. Here we review the status of the human gene catalogue and the efforts to complete it in recent years. Beside the ongoing annotation of protein-coding genes, their isoforms and pseudogenes, the invention of high-throughput RNA sequencing and other technological breakthroughs have led to a rapid growth in the number of reported non-coding RNA genes. For most of these non-coding RNAs, the functional relevance is currently unclear; we look at recent advances that offer paths forward to identifying their functions and towards eventually completing the human gene catalogue. Finally, we examine the need for a universal annotation standard that includes all medically significant genes and maintains their relationships with different reference genomes for the use of the human gene catalogue in clinical settings.

DOI: https://doi.org/10.1038/s41586-023-06490-x

Int J Radiat Oncol Biol Phys. 2023 Oct 01. pii: S0360-3016(23)06247-8. [Epub ahead of print]117(2S): e531

Defining the Transcriptional Landscapes of the Tumor Microenvironment of Cervical and Vaginal Cancers at Single-Cell Resolution.

M K Graham, S Mao, A N Viswanathan, R Wang, B Wodu, A Gupta, A Vaghasia, J Leitzel, K Lowe, S Di Pasquale, D Kaplin, T L DeWeese, S Yegnasubramanian.

PURPOSE/OBJECTIVE(S): Malignancies found within vaginal tissue are often diagnosed as cancers of the cervix, vulva, or urethra and are clinically treated with similar modalities. However, the rarity of vaginal cancer may be an artifice of categorization; current treatment paradigms do not take into account tissue-specific mutations and differences in mechanistic pathways intracellularly. Understanding the shared and distinctly different transcriptional profiles of vaginal and cervical tumors at a single-cell resolution will provide insights in vaginal tumor biology and will open avenues for future clinical interventions.
MATERIALS/METHODS: Biopsies of tumor and adjacent normal tissue from 9 patients (3 adenocarcinomas (ADC), 3 squamous cell carcinomas (SCC) from the cervix, and 3 vaginal SCC) were collected and analyzed by single-cell RNA sequencing (scRNA-seq) to compare the tumor, immune, and stromal features of cervical and vaginal cancers.
RESULTS: Collectively, over 50,000 cells were analyzed by scRNA-seq in this study. We performed dimensionality reduction and clustering analysis of the single-cell transcriptomes to identify the major cell types composing the vaginal and cervical tumor tissues. Compared to Cervical SCC, Vaginal SCC tissues showed reduced fractions of macrophages (-2.7 log2-fold; padj < 0.02) and T cells (-3.7 log2-fold; padj < 0.02) by differential cell proportion analysis (RAISIN). Likewise, the vaginal SCC epithelial cell compartments showed downregulation of inflammatory pathways including TNF signaling via NFKB (NES = -5.7, padj = 5.0 × 10-19), IL2 STAT5 signaling (NES = -4.5, padj = 1.6 × 10-12), and interferon gamma response (NES = -4.3, padj = 9.4 × 10-12), among the Hallmark pathway collection. On the other hand, vaginal SCC epithelial cells showed significant upregulation of oxidative phosphorylation (NES = 4.8, padj = 1.7 × 10-17), p53 pathway (NES = 4.2, padj = 1.8 × 10-13), mTORC1 signaling (NES = 4.2, padj = 1.9 × 10-13), and estrogen early and late response (NES = 4.0, padj < 7.5 × 10-12) compared to cervical SCC.
CONCLUSION: These results highlight distinct differences in the cell type composition and cancer epithelial pathways in vaginal vs. cervical SCC. Among upregulated pathways in vaginal SCC, ER and mTORC1 pathway activation may represent targets for therapeutic intervention worthy of further investigation.

DOI: https://doi.org/10.1016/j.ijrobp.2023.06.1813