bims-ovdlit 2024-03-10 papers

Issue of 2024‒03‒10
six papers selected by
Lara Paracchini, Humanitas Research

NPJ Genom Med. 2024 Mar 05. 9(1): 19

Genome-wide association analyses of ovarian cancer patients undergoing primary debulking surgery identify candidate genes for residual disease.

AOCS Group

Survival from ovarian cancer depends on the resection status after primary surgery. We performed genome-wide association analyses for resection status of 7705 ovarian cancer patients, including 4954 with high-grade serous carcinoma (HGSOC), to identify variants associated with residual disease. The most significant association with resection status was observed for rs72845444, upstream of MGMT, in HGSOC (p = 3.9 × 10-8). In gene-based analyses, PPP2R5C was the most strongly associated gene in HGSOC after stage adjustment. In an independent set of 378 ovarian tumours from the AGO-OVAR 11 study, variants near MGMT and PPP2R5C correlated with methylation and transcript levels, and PPP2R5C mRNA levels predicted progression-free survival in patients with residual disease. MGMT encodes a DNA repair enzyme, and PPP2R5C encodes the B56γ subunit of the PP2A tumour suppressor. Our results link heritable variation at these two loci with resection status in HGSOC.

DOI: https://doi.org/10.1038/s41525-024-00395-y

Genome Biol. 2024 Mar 04. 25(1): 62

scAbsolute: measuring single-cell ploidy and replication status.

Michael P Schneider, Amy E Cullen, Justina Pangonyte, Jason Skelton, Harvey Major, Elke Van Oudenhove, Maria J Garcia, Blas Chaves Urbano, Anna M Piskorz, James D Brenton, Geoff Macintyre, Florian Markowetz.

Cancer cells often exhibit DNA copy number aberrations and can vary widely in their ploidy. Correct estimation of the ploidy of single-cell genomes is paramount for downstream analysis. Based only on single-cell DNA sequencing information, scAbsolute achieves accurate and unbiased measurement of single-cell ploidy and replication status, including whole-genome duplications. We demonstrate scAbsolute's capabilities using experimental cell multiplets, a FUCCI cell cycle expression system, and a benchmark against state-of-the-art methods. scAbsolute provides a robust foundation for single-cell DNA sequencing analysis across different technologies and has the potential to enable improvements in a number of downstream analyses.

Keywords: Cell cycle stage; Ploidy estimation; Singe-cell genomics; Single-cell DNA sequencing; Whole-genome doubling; Whole-genome duplication

DOI: https://doi.org/10.1186/s13059-024-03204-y

Nat Commun. 2024 Mar 06. 15(1): 2025

Evolving copy number gains promote tumor expansion and bolster mutational diversification.

Zicheng Wang, Yunong Xia, Lauren Mills, Athanasios N Nikolakopoulos, Nicole Maeser, Scott M Dehm, Jason M Sheltzer, Ruping Sun.

The timing and fitness effect of somatic copy number alterations (SCNA) in cancer evolution remains poorly understood. Here we present a framework to determine the timing of a clonal SCNA that encompasses multiple gains. This involves calculating the proportion of time from its last gain to the onset of population expansion (lead time) as well as the proportion of time prior to its first gain (initiation time). Our method capitalizes on the observation that a genomic segment, while in a specific copy number (CN) state, accumulates point mutations proportionally to its CN. Analyzing 184 whole genome sequenced samples from 75 patients across five tumor types, we commonly observe late gains following early initiating events, occurring just before the clonal expansion relevant to the sampling. These include gains acquired after genome doubling in more than 60% of cases. Notably, mathematical modeling suggests that late clonal gains may contain final-expansion drivers. Lastly, SCNAs bolster mutational diversification between subpopulations, exacerbating the circle of proliferation and increasing heterogeneity.

DOI: https://doi.org/10.1038/s41467-024-46414-5

Elife. 2024 Mar 07. pii: RP89830. [Epub ahead of print]12

Identification of fallopian tube microbiota and its association with ovarian cancer.

Bo Yu, Congzhou Liu, Sean C Proll, Enna Manhardt, Shuying Liang, Sujatha Srinivasan, Elizabeth Swisher, David N Fredricks.

Investigating the human fallopian tube (FT) microbiota has significant implications for understanding the pathogenesis of ovarian cancer (OC). In this large prospective study, we collected swabs intraoperatively from the FT and other surgical sites as controls to profile the microbiota in the FT and to assess its relationship with OC. Eighty-one OC and 106 non-cancer patients were enrolled and 1001 swabs were processed for 16S rRNA gene PCR and sequencing. We identified 84 bacterial species that may represent the FT microbiota and found a clear shift in the microbiota of the OC patients when compared to the non-cancer patients. Of the top 20 species that were most prevalent in the FT of OC patients, 60% were bacteria that predominantly reside in the gastrointestinal tract, while 30% normally reside in the mouth. Serous carcinoma had higher prevalence of almost all 84 FT bacterial species compared to the other OC subtypes. The clear shift in the FT microbiota in OC patients establishes the scientific foundation for future investigation into the role of these bacteria in the pathogenesis of OC.

Keywords: 16S rRNA gene sequencing; cancer biology; fallopian tube; human; infectious disease; microbiology; microbiome; microbiota; ovarian cancer; prospective

DOI: https://doi.org/10.7554/eLife.89830

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