bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2023‒04‒23
seven papers selected by
Sergio Marchini
Humanitas Research
  1. Clinical relevance of BRCA1 promoter methylation testing in ovarian cancer patients.
  2. In-house homologous recombination deficiency testing in ovarian cancer: a multi-institutional Italian pilot study.
  3. Graph deep learning enabled spatial domains identification for spatial transcriptomics.
  4. Investigation of poly ADP-ribose polymerase inhibitor resistance based on serially collected circulating tumor DNA in patients with BRCA-mutated ovarian cancer.
  5. Genetic analysis for mucinous ovarian carcinoma with infiltrative and expansile invasion and mucinous borderline tumor: a retrospective analysis.
  6. Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical implications.
  7. Epigenetic liquid biopsies for minimal residual disease, what's around the corner?
  1. Clin Cancer Res. 2023 Apr 17. pii: CCR-22-3328. [Epub ahead of print]
    Clinical relevance of BRCA1 promoter methylation testing in ovarian cancer patients.
    Félix Blanc-Durand, Roseline Tang, Margaux Pommier, Marzieh Nashvi, Sophie Cotteret, Catherine Genestie, Audrey Le Formal, Patricia Pautier, Judith Michels, Maria Kfoury, Robert Hervé, Sylvie Mengue, Estelle Wafo, Antoine Elies, Gregoire Miailhe, Jennifer Uzan, Etienne Rouleau, Alexandra Leary.
      PURPOSE: Homologous-recombination deficiency (HRD) is closely related to PARPi benefit in ovarian cancer (OC). The capacity of BRCA1 promoter methylation to predict prognosis and HRD status remains unclear. We aimed to correlate BRCA1 promoter methylation levels in patients with high-grade OC to HRD status and clinical behavior to assess its clinical relevance.DESIGN: This is a retrospective monocentric analysis of patients centrally tested for genomic-instability score (GIS) by MyChoice CDx (Myriad Genetics). The detection of BRCA1 promoter methylation and quantification of methylation levels were performed by quantitative ddPCR methodology. High BRCA1 methylation was defined as ≥70% and deemed to be associated with homozygous silencing.
    RESULTS: Of 100 patients, 11% harbored a deleterious BRCA1/2 mutation. GIS was considered positive (score≥42) for 52 patients and negative for 48 patients. Using a 70% cutoff, 19% (15/79) of BRCA-wild-type OC had high BRCA1 methylation levels. All of the highly methylated tumors were classified HRD achieving a positive predictive value of 100%. We detected 14% (11/79) low methylated tumors (1-69%) and all of them were also classified as HRD. Mean GIS was 61.5 for BRCAmut, 66.4 for high-BRCAmeth, 58.9 for low-BRCAmeth and 33.3 for BRCAwt unmethylated (P<0.001). Low methylation levels detected in samples previously exposed to chemotherapy appeared to be associated with poor outcome post-platinum.
    CONCLUSIONS: OC patients with high levels of BRCA1 hypermethylation are very likely to have high GIS and therefore represent good candidates for PARPi treatment. These results may be relevant to other tumor types for HRD prediction.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3328
  2. J Clin Pathol. 2023 Apr 18. pii: jcp-2023-208852. [Epub ahead of print]
    In-house homologous recombination deficiency testing in ovarian cancer: a multi-institutional Italian pilot study.
    Francesco Pepe, Elena Guerini-Rocco, Matteo Fassan, Nicola Fusco, Davide Vacirca, Alberto Ranghiero, Konstantinos Venetis, Alessandra Rappa, Sergio Vincenzo Taormina, Gianluca Russo, Elena Rebellato, Giada Munari, Andrea Moreno-Manuel, Carmine De Angelis, Claudio Zamagni, Giorgio Valabrega, Umberto Malapelle, Giancarlo Troncone, Massimo Barberis, Antonino Iaccarino.
      AIMS: Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPIs) represent a standard of care for the clinical management of high-grade serous ovarian cancer (HGSOC). The recognition of homologous recombination deficiency (HRD) has emerged as a predictive biomarker of response for first-line PARPIs treatment in patients with HGOSC. On the other hand, this test is extremely complex and therefore it is often externalised. Regrettably, the reliability of outsourced HRD testing can be troubled by inconclusive results and high rejection rates. In this methodological study, we assessed the technical feasibility, interassay and interlaboratory reproducibility of in-house HRD testing using three different commercially available next-generation sequencing assays.METHODS: A total of n=20 epithelial ovarian cancer samples previously analysed with MyChoice CDx were subjected to HRD retesting using three different platforms in three different major pathology laboratories, that is, SOPHiA DDM HRD Solution, HRD focus and Oncomine homologous recombination repair pathway predesigned panel. Concordance was calculated by Cohen's (dual) and Fleiss (triple) κ coefficients.
    RESULTS: In-house BRCA1/2 molecular testing yielded a concordance rate >90.0% among all participating centres. HRD scores were successfully calculated by each institution with a concordance rate of 76.5%. Concerning the external gold standard test, the overall percentage of agreement ranged from 80.0% to 90.0% with a positive percentage agreement ranging from 75.0% to 80.0% and a negative percentage agreement ranging from 80.0% to 100%.
    CONCLUSIONS: In-house testing for HRD can be reliably performed with commercially available next-generation sequencing assays.
    Keywords:  ovarian neoplasms; pathology, molecular; point-of-care testing
    DOI:  https://doi.org/10.1136/jcp-2023-208852
  3. Brief Bioinform. 2023 Apr 20. pii: bbad146. [Epub ahead of print]
    Graph deep learning enabled spatial domains identification for spatial transcriptomics.
    Teng Liu, Zhao-Yu Fang, Xin Li, Li-Ning Zhang, Dong-Sheng Cao, Ming-Zhu Yin.
      Advancing spatially resolved transcriptomics (ST) technologies help biologists comprehensively understand organ function and tissue microenvironment. Accurate spatial domain identification is the foundation for delineating genome heterogeneity and cellular interaction. Motivated by this perspective, a graph deep learning (GDL) based spatial clustering approach is constructed in this paper. First, the deep graph infomax module embedded with residual gated graph convolutional neural network is leveraged to address the gene expression profiles and spatial positions in ST. Then, the Bayesian Gaussian mixture model is applied to handle the latent embeddings to generate spatial domains. Designed experiments certify that the presented method is superior to other state-of-the-art GDL-enabled techniques on multiple ST datasets. The codes and dataset used in this manuscript are summarized at https://github.com/narutoten520/SCGDL.
    Keywords:  Bayesian Gaussian mixture models; deep graph infomax; graph deep learning; residual gated graph convolutional neural network; spatial clustering; spatial transcriptome
    DOI:  https://doi.org/10.1093/bib/bbad146
  4. Clin Cancer Res. 2023 Apr 17. pii: CCR-22-3715. [Epub ahead of print]
    Investigation of poly ADP-ribose polymerase inhibitor resistance based on serially collected circulating tumor DNA in patients with BRCA-mutated ovarian cancer.
    Yoo-Na Kim, Yeeun Shim, Jieun Seo, Zisun Choi, Yong Jae Lee, Saeam Shin, Sang Wun Kim, Sunghoon Kim, Jong Rak Choi, Jung-Yun Lee, Seung-Tae Lee.
      PURPOSE: Patient-specific molecular alterations leading to poly ADP-ribose polymerase inhibitor (PARPi) resistance are relatively unexplored. In this study, we analyzed serially collected circulating tumor DNA (ctDNA) from patients with BRCA1/2 mutations who received PARPis to investigate the resistance mechanisms and their significance in post-progression treatment response and survival.EXPERIMENTAL DESIGN: Patients were prospectively enrolled between January 2018 and December 2021 (NCT05458973). Whole-blood samples were obtained before PARPi administration and serially every 3 months until progression. ctDNA was extracted from the samples and sequenced with a 531-gene panel; gene sets for each resistance mechanism were curated.
    RESULTS: Fifty-four patients were included in this analysis. Mutation profiles of genes in pre-PARPi samples indicating a high tumor mutational burden and alterations in genes associated with replication fork stabilization and drug efflux were associated with poor progression-free survival on PARPis. BRCA hypomorphism and reversion were found in one and three patients, respectively. Among 29 patients with matched samples, mutational heterogeneity increased post-progression on PARPis, showing at least one post-specific mutation in 89.7% of the patients. These mutations indicate non-exclusive acquired resistance mechanisms-homologous recombination repair restoration (28%), replication fork stability (34%), upregulated survival pathway (41%), target loss (10%), and drug efflux (3%). We observed poor progression-free survival with subsequent chemotherapy in patients with homologous recombination repair restoration (P = 0.003) and those with the simultaneous involvement of two or more resistance mechanisms (P = 0.040).
    CONCLUSIONS: Analysis of serial ctDNAs highlighted multiple acquired resistance mechanisms, providing valuable insights for improving post-progression treatment and survival.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3715
  5. Diagn Pathol. 2023 Apr 20. 18(1): 49
    Genetic analysis for mucinous ovarian carcinoma with infiltrative and expansile invasion and mucinous borderline tumor: a retrospective analysis.
    Taira Hada, Morikazu Miyamoto, Yuka Ohtsuka, Jin Suminokura, Tsubasa Ito, Naohisa Kishimoto, Soko Nishitani, Minori Takada, Akari Imauji, Risa Tanabe, Masashi Takano.
      BACKGROUND: Mucinous carcinoma (MC) is a histological subtype of ovarian cancer that has a worse prognosis at advanced stages than the most prevalent histological subtype, high-grade serous carcinomas. Invasive patterns have been recognized as prognostic factors for MCs. MCs with infiltrative invasion were more aggressive than those with expansile invasion. MC with an expansile pattern exhibited behavior similar to mucinous borderline tumors (MBT). However, genomic analysis of invasive patterns is insufficient. This study aimed to compare genetic information between groups with MC and infiltrative invasion (Group A) and those with MC with expansile invasion or MBT (Group B).METHODS: Ten cases each of MC with infiltrative invasion, MC with expansile invasion, and MBT between 2005 and 2020 were identified. Deoxyribonucleic acid (DNA) extraction from formalin-fixed paraffin-embedded tissues was performed, and cases with DNA fragmentation or the possibility of DNA fragmentation were excluded. Mutant base candidates and tumor mutation burden (TMB) values (mutations/megabase) were calculated.
    RESULTS: After assessing the quality of purified DNA, seven cases of MC with infiltrative invasion, five cases of MC with expansile invasion, and three cases of MBT were included. More patients in group A experienced recurrence or progression (p < 0.01) and died of disease (p = 0.03). Moreover, the TMB value was statistically higher in group A than in group B (p = 0.049). There were no statistical differences in the incidence of the mutations of KRAS, TP53, and CREBBP. KRAS, TP53, and CREBBP mutations were discovered in 8/15 (53.3%), 6/15 (40.0%), and 5/15 (33.3%) cases, respectively.
    CONCLUSIONS: Genetic analysis revealed that Group A had higher TMB than Group B. Therefore, this result might be useful for future treatment.
    Keywords:  Expansile invasion; Genetic examination; Infiltrative invasion; Mucinous borderline tumor; Ovarian mucinous carcinoma; Tumor mutation burden
    DOI:  https://doi.org/10.1186/s13000-023-01340-w
  6. Clin Cancer Res. 2023 Apr 16. pii: CCR-23-0090. [Epub ahead of print]
    Tumor-Agnostic Precision Medicine from the AACR GENIE Database: Clinical implications.
    Mohamed A Gouda, Blessie Elizabeth Nelson, Lars Buschhorn, Adam Wahida, Vivek Subbiah.
      Biomarker-driven cancer therapy has revolutionized precision oncology. With a better understanding of tumor biology, tissue-agnostic targets have been characterized and explored which ultimately led to therapeutics with pan-cancer efficacy. To date, five molecular biomarkers have obtained FDA tissue-agnostic approval for targeted therapies and immunotherapies. Those include BRAF V600E mutations, RET fusions, NTRK fusions, high tumor mutation burden (TMB), and deficient mismatch repair (dMMR/MSI-High). Herein, we have used data from AACR project GENIE to explore the clinico-genomic landscape of these alterations. AACR GENIE is a publicly accessible registry of genomic data from multiple collaborating cancer centers. Current database (version 13.0) includes sequencing data of 168,423 samples collected from patients with different cancers. We were able to identify BRAF V600E, RET fusions, NTRK fusions, and high TMB in 2.9%, 1.6%, 1.5%, and 15.2% of pan-cancer samples; respectively. In this article, we describe the distribution of those tissue-agnostic targets among different cancer types. In addition, we summarize the current prospect on the biology of these alterations and evidence on approved drugs including pembrolizumab, dostarilmab, larotrectinib, entrectinib, selpercatinib, and dabrafenib/trametinib combination.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-0090
  7. Front Oncol. 2023 ;13 1103797
    Epigenetic liquid biopsies for minimal residual disease, what's around the corner?
    Andrew D Johnston, Jason P Ross, Chenkai Ma, Kim Y C Fung, Warwick J Locke.
      Liquid biopsy assays for minimal residual disease (MRD) are used to monitor and inform oncological treatment and predict the risk of relapse in cancer patients. To-date, most MRD assay development has focused on targeting somatic mutations. However, epigenetic changes are more frequent and universal than genetic alterations in cancer and circulating tumor DNA (ctDNA) retains much of these changes. Here, we review the epigenetic signals that can be used to detect MRD, including DNA methylation alterations and fragmentation patterns that differentiate ctDNA from noncancerous circulating cell-free DNA (ccfDNA). We then summarize the current state of MRD monitoring; highlight the advantages of epigenetics over genetics-based approaches; and discuss the emerging paradigm of assaying both genetic and epigenetic targets to monitor treatment response, detect disease recurrence, and inform adjuvant therapy.
    Keywords:  DNA methylation; MRD; cancer; ccfDNA (circulating cell-freeDNA); ctDNA (circulating tumor DNA); epigenetics; fragmentomics; liquid biopsy
    DOI:  https://doi.org/10.3389/fonc.2023.1103797
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