bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2022‒02‒13
ten papers selected by
Sergio Marchini
Humanitas Research

  1. Gynecol Oncol Rep. 2022 Feb;39 100926
      Objectives: We quantitatively characterized the change in temporospatial expression of repressive and stimulatory checkpoints across immune cell populations in the tumor microenvironment in a cohort of high grade serous ovarian carcinomas (HGSOC) using matched samples before and after neoadjuvant platinum-based chemotherapy.Methods: Using retrospectively collected matched tissue samples from 9 patients, cell populations were assessed using multiplex immunofluorescence using the Vectra Multispectral Imaging System (Perkin Elmer). We used multiple panels to assess: tumor (AE1/AE3), T cells (CD3, CD8, FOXP3), macrophages (CD68) as well as immune checkpoints (C3aR, PD-1, PD-L1, LAG3, IDO, ICOS, GITR). IHC staining was performed for folate receptor status. Changes in immune cell populations as well as intensities of associated repressive and stimulatory proteins were assessed pre- to post-treatment.
    Results: We observed a consistently high pre-treatment stromal macrophage population which is reduced post-chemotherapy with post-treatment enrichment in macrophage PD-L1 expression. While inhibitory checkpoint expression on T cells was heterogeneous post-chemotherapy, we observed a change in the ThICOS+:Treg ratio which resulted in ThICOS+ cells outnumbering Treg cells post-treatment. Spatial analysis revealed the proximity of Treg cells to ThICOS+ T cells decreased post-treatment. We also observed upward shifts in Teff:Treg T cell ratios with retention of immune checkpoints PD-1, LAG3 and GITR.
    Conclusions: In this unique dataset of pre and post matched chemotherapy treated HGSOC patients, we observed changes in immune cell subsets expressing repressive or stimulatory proteins resulting in immune compositions more favorable to checkpoint modulations, suggesting novel therapeutic strategies in the recurrent setting.
    Keywords:  Immunotherapy; Ovarian cancer; Tumor microenvironment
  2. Chin J Cancer Res. 2021 Dec 31. 33(6): 708-718
      The profiling of plasma cell-free DNA (cfDNA) is becoming a valuable tool rapidly for tumor diagnosis, monitoring and prognosis. Diverse plasma cfDNA technologies have been in routine or emerging use, including analyses of mutations, copy number alterations, gene fusions and DNA methylation. Recently, new technologies in cfDNA analysis have been developed in laboratories, and potentially reflect the status of epigenetic modification, the immune microenvironment and the microbiome in tumor tissues. In this review, the authors discuss the principles, methods and effects of the current cfDNA assays and provide an overview of studies that may inform clinical applications in the near future.
    Keywords:  cancer diagnosis; cfDNA; liquid biopsy; recurrence monitoring; therapy response
  3. Lancet. 2022 Feb 05. pii: S0140-6736(21)02175-9. [Epub ahead of print]399(10324): 541-553
      BACKGROUND: Low-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma.METHODS: This international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40-50 mg/m2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with, NCT02101788, and is active but not recruiting.
    FINDINGS: Between Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9-15·0) compared with 7·2 months (5·6-9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36-0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths.
    INTERPRETATION: Trametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma.
    FUNDING: NRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis.
  4. Future Oncol. 2022 Feb 07.
      Background: The aim of the current study is to analyze and summarize the latest research on improving therapy in ovarian cancer. Materials & methods: Data analysis was based on a review of publications from 2011 to 2021 in the PubMed database with use of the search terms including 'EGFR ovarian cancer', 'folate receptor inhibitors ovarian cancer', 'VEGF ovarian cancer', 'PDGF ovarian cancer' and 'CTLA-4 ovarian cancer'. Results: 6643 articles were found; 238 clinical trials and randomized control trials were analyzed; 122 studies were rejected due to inconsistency with the topic of the work. Conclusion: Extensive research on the treatment of ovarian cancer increases the chance of developing the most effective therapy suited to the individual needs of the patient.
    Keywords:  CTLA-4; EGFR; PARP; PD-1; PDGF; VEGF; ovarian cancer
  5. Nat Commun. 2022 Feb 11. 13(1): 835
      The majority of high-grade serous ovarian cancers (HGSCs) are deficient in homologous recombination (HR) DNA repair, most commonly due to mutations or hypermethylation of the BRCA1/2 genes. We aimed to discover how BRCA1/2 mutations shape the cellular phenotypes and spatial interactions of the tumor microenvironment. Using a highly multiplex immunofluorescence and image analysis we generate spatial proteomic data for 21 markers in 124,623 single cells from 112 tumor cores originating from 31 tumors with BRCA1/2 mutation (BRCA1/2mut), and from 13 tumors without alterations in HR genes. We identify a phenotypically distinct tumor microenvironment in the BRCA1/2mut tumors with evidence of increased immunosurveillance. Importantly, we report a prognostic role of a proliferative tumor-cell subpopulation, which associates with enhanced spatial tumor-immune interactions by CD8+ and CD4 + T-cells in the BRCA1/2mut tumors. The single-cell spatial landscapes indicate distinct patterns of spatial immunosurveillance with the potential to improve immunotherapeutic strategies and patient stratification in HGSC.
  6. Cancer Treat Res Commun. 2022 Feb 01. pii: S2468-2942(22)00019-3. [Epub ahead of print]31 100528
      Clinical responses to anticancer therapies in advanced soft tissue sarcoma (STS) are unfortunately limited to a small subset of patients. Much of the inter-individual variability in treatment efficacy and risk of toxicities is as result of polymorphisms in genes encoding proteins involved in drug pharmacokinetics and pharmacodynamics. Therefore, the detection of pharmacogenomics (PGx) biomarkers that might predict drug response and toxicity can be useful to explain the genetic basis for the differences in treatment efficacy and toxicity among STS patients. PGx markers are frequently located in transporters, drug-metabolizing enzyme genes, drug targets, or HLA alleles. Along this line, genetic variability harbouring in the germline genome of the patients can influence systemic pharmacokinetics and pharmacodynamics of the treatments, acting as predictive biomarkers for drug-induced toxicity and treatment efficacy. By linking drug activity to the functional complexity of cancer genomes, also systematic pharmacogenomic profiling in cancer cell lines and primary STS samples represents area of active investigation that could eventually lead to enhanced efficacy and offer a powerful biomarker discovery platform to optimize current treatments and improve the knowledge about the individual's drug response in STS patients into the clinical practice.
    Keywords:  Biomarker; Cancer pharmacogenetic; Clinical outcomes; Germline mutation; Pharmacogenomics; Single-nucleotide polymorphisms; Soft tissue sarcoma; Toxicity
  7. Brief Bioinform. 2022 Feb 02. pii: bbab610. [Epub ahead of print]
      Numerous cancer types have shown to present hypermethylation of CpG islands, also known as a CpG island methylator phenotype (CIMP), often associated with survival variation. Despite extensive research on CIMP, the etiology of this variability remains elusive, possibly due to lack of consistency in defining CIMP. In this work, we utilize a pan-cancer approach to further explore CIMP, focusing on 26 cancer types profiled in the Cancer Genome Atlas (TCGA). We defined CIMP systematically and agnostically, discarding any effects associated with age, gender or tumor purity. We then clustered samples based on their most variable DNA methylation values and analyzed resulting patient groups. Our results confirmed the existence of CIMP in 19 cancers, including gliomas and colorectal cancer. We further showed that CIMP was associated with survival differences in eight cancer types and, in five, represented a prognostic biomarker independent of clinical factors. By analyzing genetic and transcriptomic data, we further uncovered potential drivers of CIMP and classified them in four categories: mutations in genes directly involved in DNA demethylation; mutations in histone methyltransferases; mutations in genes not involved in methylation turnover, such as KRAS and BRAF; and microsatellite instability. Among the 19 CIMP-positive cancers, very few shared potential driver events, and those drivers were only IDH1 and SETD2 mutations. Finally, we found that CIMP was strongly correlated with tumor microenvironment characteristics, such as lymphocyte infiltration. Overall, our results indicate that CIMP does not exhibit a pan-cancer manifestation; rather, general dysregulation of CpG DNA methylation is caused by heterogeneous mechanisms.
    Keywords:  CIMP; CpG island methylator phenotype; DNA methylation; cancer; genomic drivers; prognosis
  8. Clin Cancer Res. 2022 Feb 11. pii: clincanres.1242.2021. [Epub ahead of print]
      PURPOSE: Cell-free DNA (cfDNA) offers a non-invasive approach to monitor cancer. Here we develop a method using whole-exome sequencing (WES) of cfDNA for simultaneously monitoring the full spectrum of cancer treatment outcomes, including MRD, recurrence, evolution, and second primary cancers.EXPERIMENTAL DESIGN: Three simulation datasets were generated from 26 cancer patients to benchmark the detection performance of MRD/recurrence and second primary cancers. For further validation, cfDNA samples (n=76) from cancer patients (n=35) with six different cancer types were used for performance validation during various treatments.
    RESULTS: We present a cfDNA-based cancer monitoring method, named cfTrack Taking advantage of the broad genome coverage of WES data, cfTrack can sensitively detect MRD and cancer recurrence by integrating signals across known clonal tumor mutations of a patient. In addition, cfTrack detects tumor evolution and second primary cancers by de novo identifying emerging tumor mutations. A series of machine learning and statistical denoising techniques are applied to enhance the detection power. On the simulation data,cfTrack achieved an average AUC of 99% on the validation dataset and 100% on the independent dataset in detecting recurrence in samples with tumor fractions {greater than or equal to}0.05%. In addition,cfTrack yielded an average AUC of 88% in detecting second primary cancers in samples with tumor fractions {greater than or equal to}0.2%. On real data, cfTrack accurately monitors tumor evolution during treatment, which cannot be accomplished by previous methods.
    CONCLUSION: Our results demonstrated that cfTrack can sensitively and specifically monitor the full spectrum of cancer treatment outcomes using exome-wide mutation analysis of cfDNA.
  9. Cancer Lett. 2022 Feb 05. pii: S0304-3835(22)00062-3. [Epub ahead of print]532 215587
      The CpG island methylator phenotype (CIMP) is associated with prognosis and drug sensitivity in multiple cancer types. In gastric cancer, the CIMP is closely associated with Epstein-Barr virus (EBV) infection and AT-rich interactive domain 1A (ARID1A) mutations, a component of the SWI/SNF chromatin remodeling complex. However, the involvement of SWI/SNF defects in CIMP induction has been unclear. In this study, we demonstrate a causal role of ARID1A loss-of-function in CIMP induction. Mutations of SWI/SNF components, especially ARID1A, was associated with the CIMP, as well as EBV infection, in gastric cancers, and also in uterine endometrial and colorectal cancers, which are not affected by EBV infection. Genome-wide DNA methylation analysis showed that ARID1A knockout (KO) in cultured 293FT cells and gastric epithelial cells, GES1, induced aberrant DNA methylation of a substantial number of CpG sites. DNA methylation was induced at genomic regions with high levels of pre-existing histone H3 lysine 27 trimethylation (H3K27me3) and those with acquired H3K27me3 by ARID1A KO. These results showed that the ARID1A mutation induced aberrant DNA methylation, and this is likely to be one of the potential mechanisms of CIMP induction.
    Keywords:  ARID1A; CIMP; Chromatin remodeling; DNA methylation; Epigenetics
  10. Gynecol Oncol. 2022 Feb 02. pii: S0090-8258(22)00066-X. [Epub ahead of print]
      OBJECTIVE: To determine the activity of key signal transduction pathways in serous tubal intraepithelial carcinoma (STIC) and concurrent high-grade serous carcinoma (HGSC) and compare this to pathway activity in normal Fallopian tube epithelium (FTE).METHODS: We assessed mRNA expression levels of pathway-specific target genes with RT-qPCR in STIC and concurrent HGSC (n = 8) and normal FTE (n = 8). Subsequently, signal transduction pathway assays were used to assess functional activity of the androgen (AR) and estrogen receptor (ER), phosphoinositide-3-kinase (PI3K), Hedgehog (HH), transforming growth factor beta (TGF-β) and canonical wingless-type MMTV integration site (Wnt) pathways.
    RESULTS: There were no statistically significant differences in pathway activity between STIC and HGSC, but STIC and HGSC demonstrated significantly lower ER and higher PI3K and HH pathway activity in comparison to normal FTE, suggesting these pathways as putative early drivers. In addition, we determined FOXO3a protein expression by immunohistochemistry and found loss of FOXO3a protein expression in STIC and HGSC compared to normal FTE. This observation confirmed that activation of PI3K signaling by loss of FOXO is an early hallmark of serous carcinogenesis. Furthermore, HGSC demonstrated significant loss of AR and Wnt pathway activity in relation to FTE, suggesting these pathways contribute to disease progression.
    CONCLUSION: Our observations, together with the previously described associations between p53 signaling and both PI3K and HH pathway activity, provide evidence that increased PI3K and HH pathway activity and loss of ER pathway activity may be underlying events contributing to neoplastic transformation of FTE into STIC.
    Keywords:  Molecular biology; PI3K-FOXO signaling; Serous carcinogenesis; Serous tubal intraepithelial carcinoma