bims-ovdlit 2022-11-06 papers

Issue of 2022–11–06
eight papers selected by
Lara Paracchini, Humanitas Research

Cancer Res Commun. 2022 Oct;2(10): 1282-1292

Uterine lavage identifies cancer mutations and increased TP53 somatic mutation burden in individuals with ovarian cancer.

Talayeh S Ghezelayagh, Brendan F Kohrn, Jeanne Fredrickson, Enna Manhardt, Marc R Radke, Ronit Katz, Heidi J Gray, Renata R Urban, Kathryn P Pennington, John B Liao, Kemi M Doll, Elise J Simons, Jennifer K Burzawa, Barbara A Goff, Paul Speiser, Elizabeth M Swisher, Barbara M Norquist, Rosa Ana Risques.

Current screening methods for ovarian cancer (OC) have failed to demonstrate a significant reduction in mortality. Uterine lavage combined with TP53 ultra-deep sequencing for the detection of disseminated OC cells has emerged as a promising tool, but this approach has not been tested for early-stage disease or non-serous histologies. In addition, lavages carry multiple background mutations, the significance of which is poorly understood. Uterine lavage was collected preoperatively in 34 patients undergoing surgery for suspected ovarian malignancy including 14 patients with benign disease and 20 patients with OC (6 non-serous and 14 high grade serous-like (serous)). Ultra-deep duplex sequencing (~3000x) with a panel of common OC genes identified the tumor mutation in 33% of non-serous (all early stage) and in 79% of serous cancers (including four early stage). In addition, all lavages carried multiple somatic mutations (average of 25 mutations per lavage), more than half of which corresponded to common cancer driver mutations. Driver mutations in KRAS, PIK3CA, PTEN, PPP2R1A and ARID1A presented as larger clones than non-driver mutations and with similar frequency in lavages from patients with and without OC, indicating prevalent somatic evolution in all patients. Driver TP53 mutations, however, presented as significantly larger clones and with higher frequency in lavages from individuals with OC, suggesting that TP53-specific clonal expansions are linked to ovarian cancer development. Our results demonstrate that lavages capture cancer cells, even from early-stage cancers, as well as other clonal expansions and support further exploration of TP53 mutation burden as a potential OC risk factor.

Keywords: Uterine lavage; clonal expansions; ovarian cancer; somatic evolution

DOI: https://doi.org/10.1158/2767-9764.crc-22-0314

Tumori. 2022 Oct 31. 3008916221133136

Multi-cancer early detection test sensitivity for cancers with and without current population-level screening options.

Spencer H Shao, Brian Allen, Jessica Clement, Gina Chung, Jingjing Gao, Earl Hubbell, Minetta C Liu, Charles Swanton, Wh Wilson Tang, Habte Yimer, Mohan Tummala.

There are four solid tumors with common screening options in the average-risk population aged 21 to 75 years (breast, cervical, colorectal, and, based on personalized risk assessment, prostate), but many cancers lack recommended population screening and are often detected at advanced stages when mortality is high. Blood-based multi-cancer early detection tests have the potential to improve cancer mortality through additional population screening. Reported here is a post-hoc analysis from the third Circulating Cell-free Genome Atlas substudy to examine multi-cancer early detection test performance in solid tumors with and without population screening recommendations and in hematologic malignancies. Participants with cancer in the third Circulating Cell-free Genome Atlas substudy analysis were split into three subgroups: solid screened tumors (breast, cervical, colorectal, prostate), solid unscreened tumors, and hematologic malignancies. In this post hoc analysis, sensitivity is reported for each subgroup across all ages and those aged ⩾50 years overall, by cancer, and by clinical cancer stage. Aggregate sensitivity in the solid screened, solid unscreened, and hematologic malignancy subgroups was 34%, 66%, and 55% across all cancer stages, respectively; restricting to participants aged ⩾50 years showed similar aggregate sensitivity. Aggregate sensitivity was 27%, 53%, and 60% across stages I to III, respectively. Within the solid unscreened subgroup, aggregate sensitivity was >75% in 8/18 cancers (44%) and >50% in 13/18 (72%). This multi-cancer early detection test detected cancer signals at high (>75%) sensitivity for multiple cancers without existing population screening recommendations, suggesting its potential to complement recommended screening programs.Clinical trial identifier: NCT02889978.

Keywords: Multi-cancer early detection; cancer screening; early detection; epidemiology and prevention; liquid biopsy; precision medicine

DOI: https://doi.org/10.1177/03008916221133136

Br J Cancer. 2022 Nov 02.

Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study.

AOCs group

BACKGROUND: Recently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC.
METHODS: Two prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis.
RESULTS: Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p < 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with >35% GMNN expression showed a trend for better outcomes, though this was not significant.
CONCLUSION: We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

DOI: https://doi.org/10.1038/s41416-022-02014-y

N Engl J Med. 2022 11 03. pii: 10.1056/NEJMc2212426#sa2. [Epub ahead of print]387(18): 1723-1724

Lesions of the Ovary and Fallopian Tube. Reply.

Rachel C Sisodia, Marcela G Del Carmen.

DOI: https://doi.org/10.1056/NEJMc2212426

N Engl J Med. 2022 11 03. pii: 10.1056/NEJMc2212426#sa1. [Epub ahead of print]387(18): 1723

Lesions of the Ovary and Fallopian Tube.

Stefan Timmerman, Ben Van Calster, Wouter Froyman.

DOI: https://doi.org/10.1056/NEJMc2212426

J Adv Res. 2022 Oct 30. pii: S2090-1232(22)00241-7. [Epub ahead of print]

Improvement of large copy number variant detection by whole genome nanopore sequencing.

Javier Cuenca-Guardiola, Belén de la Morena-Barrio, Juan L García, Alba Sanchis-Juan, Javier Corral, Jesualdo T Fernández-Breis.

INTRODUCTION: Whole-genome sequencing using nanopore technologies can uncover structural variants, which are DNA rearrangements larger than 50 base pairs. Nanopore technologies can also characterize their boundaries with single-base accuracy, owing to the kilobase-long reads that encompass either full variants or their junctions. Other methods, such as next-generation short read sequencing or PCR assays, are limited in their capabilities to detect or characterize structural variants. However, the existing software for nanopore sequencing data analysis still reports incomplete variant sets, which also contain erroneous calls, a considerable obstacle for the molecular diagnosis or accurate genotyping of populations.
METHODS: We compared multiple factors affecting variant calling, such as reference genome version, aligner (minimap2, NGMLR, and lra) choice, and variant caller combinations (Sniffles, CuteSV, SVIM, and NanoVar), to find the optimal group of tools for calling large (>50 kb) deletions and duplications, using data from seven patients exhibiting gross gene defects on SERPINC1 and from a reference variant set as the control. The goal was to obtain the most complete, yet reasonably specific group of large variants using a single cell of PromethION sequencing, which yielded lower depth coverage than short-read sequencing. We also used a custom method for the statistical analysis of the coverage value to refine the resulting datasets.
RESULTS: We found that for large deletions and duplications (>50 kb), the existing software performed worse than for smaller ones, in terms of both sensitivity and specificity, and newer tools had not improved this. Our novel software, disCoverage, could polish variant callers' results, improving specificity by up to 62% and sensitivity by 15%, the latter requiring other data or samples.
CONCLUSION: We analyzed the current situation of >50-kb copy number variants with nanopore sequencing, which could be improved. The methods presented in this work could help to identify the known deletions and duplications in a set of patients, while also helping to filter out erroneous calls for these variants, which might aid the efforts to characterize a not-yet well-known fraction of genetic variability in the human genome.

Keywords: SERPINC1; nanopore; structural variant; third-generation sequencing

DOI: https://doi.org/10.1016/j.jare.2022.10.012

Nat Commun. 2022 Oct 30. 13(1): 6498

De novo analysis of bulk RNA-seq data at spatially resolved single-cell resolution.

Uncovering the tissue molecular architecture at single-cell resolution could help better understand organisms' biological and pathological processes. However, bulk RNA-seq can only measure gene expression in cell mixtures, without revealing the transcriptional heterogeneity and spatial patterns of single cells. Herein, we introduce Bulk2Space ( https://github.com/ZJUFanLab/bulk2space ), a deep learning framework-based spatial deconvolution algorithm that can simultaneously disclose the spatial and cellular heterogeneity of bulk RNA-seq data using existing single-cell and spatial transcriptomics references. The use of bulk transcriptomics to validate Bulk2Space unveils, in particular, the spatial variance of immune cells in different tumor regions, the molecular and spatial heterogeneity of tissues during inflammation-induced tumorigenesis, and spatial patterns of novel genes in different cell types. Moreover, Bulk2Space is utilized to perform spatial deconvolution analysis on bulk transcriptome data from two different mouse brain regions derived from our in-house developed sequencing approach termed Spatial-seq. We have not only reconstructed the hierarchical structure of the mouse isocortex but also further annotated cell types that were not identified by original methods in the mouse hypothalamus.

DOI: https://doi.org/10.1038/s41467-022-34271-z