bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2021–10–17
ten papers selected by
Sergio Marchini, Humanitas Research
  1. DNA methylation-based profiling reveals distinct clusters with survival heterogeneity in high-grade serous ovarian cancer.
  2. Emerging molecular alterations leading to histology-specific targeted therapies in ovarian cancer beyond PARP inhibitors.
  3. Preexisting TP53-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib.
  4. Germline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination.
  5. There is more to soft tissue sarcomas than just grade and size.
  6. Gene Expression Subtyping Reveals Immune alterations:TCGA Database for Prognosis in Ovarian Serous Cystadenocarcinoma.
  7. Differential expression of estrogen receptor subtypes in ovarian high-grade serous carcinoma and clear cell carcinoma.
  8. Pan-cancer analysis reveals homologous recombination deficiency score as a predictive marker for immunotherapy responders.
  9. sciCNV: high-throughput paired profiling of transcriptomes and DNA copy number variations at single-cell resolution.
  10. Comprehensive Analysis of m5C RNA Methylation Regulator Genes in Clear Cell Renal Cell Carcinoma.
  1. Clin Epigenetics. 2021 Oct 13. 13(1): 190
    DNA methylation-based profiling reveals distinct clusters with survival heterogeneity in high-grade serous ovarian cancer.
    Jieyu Wang, Jun Li, Ruifang Chen, Huiran Yue, Wenzhi Li, Beibei Wu, Yang Bai, Guohua Zhu, Xin Lu.
      High-grade serous ovarian cancer (HGSOC) is the most common type of epigenetically heterogeneous ovarian cancer. Methylation typing has previously been used in many tumour types but not in HGSOC. Methylation typing in HGSOC may promote the development of personalized care. The present study used DNA methylation data from The Cancer Genome Atlas database and identified four unique methylation subtypes of HGSOC. With the poorest prognosis and high frequency of residual tumours, cluster 4 featured hypermethylation of a panel of genes, which indicates that demethylation agents may be tested in this group and that neoadjuvant chemotherapy may be used to reduce the possibility of residual lesions. Cluster 1 and cluster 2 were significantly associated with metastasis genes and metabolic disorders, respectively. Two feature CpG sites, cg24673765 and cg25574024, were obtained through Cox proportional hazards model analysis of the CpG sites. Based on the methylation level of the two CpG sites, the samples were classified into high- and low-risk groups to identify the prognostic information. Similar results were obtained in the validation set. Taken together, these results explain the epigenetic heterogeneity of HGSOC and provide guidance to clinicians for the prognosis of HGSOC based on DNA methylation sites.
    Keywords:  DNA profiling; High-grade serous ovarian cancer; Methylation subtypes; Ovarian cancer; Prognosis
    DOI:  https://doi.org/10.1186/s13148-021-01178-3
  2. Cancer Treat Rev. 2021 Sep 29. pii: S0305-7372(21)00146-8. [Epub ahead of print]101 102298
    Emerging molecular alterations leading to histology-specific targeted therapies in ovarian cancer beyond PARP inhibitors.
    M Bartoletti, L Musacchio, G Giannone, V Tuninetti, A Bergamini, G Scambia, D Lorusso, G Valabrega, G Mangili, F Puglisi, S Pignata.
      After more than 30 years of a one-size-fits-all approach in the management of advanced ovarian cancer, in 2018 the SOLO1 trial results have introduced a new era of personalized medicine. A deeper knowledge of ovarian cancer biology and the development of new drugs targeting specific molecular pathways have led to biomarker-driven phase 3 trials with practice changing results. Thereafter, platinum-based combinations are no longer the only therapeutic options available in first line setting and poly-ADP ribose polymerase inhibitors maintenance therapy has become the mainstay in patients with tumor harboring a homologous recombination defect. However, most of the recent therapeutic breakthroughs regard high grade serous carcinoma, the most frequent ovarian cancer subtype, and only few improvements have occurred in the management of less common histotypes. Moving towards the next challenges, we aimed to investigate and review new potential molecular targets in ovarian cancer, according to histotype, starting from promising molecular drivers and matched drugs that have been investigated in early and late-stage clinical trials or conceptualized in preclinical studies.
    Keywords:  Druggable alterations; Ovarian cancer; PARP inhibitors; Precision medicine; Target therapy; Treatment tailoring
    DOI:  https://doi.org/10.1016/j.ctrv.2021.102298
  3. JAMA Oncol. 2021 Oct 14.
    Preexisting TP53-Variant Clonal Hematopoiesis and Risk of Secondary Myeloid Neoplasms in Patients With High-grade Ovarian Cancer Treated With Rucaparib.
    Tanya T Kwan, Amit M Oza, Anna V Tinker, Isabelle Ray-Coquard, Ana Oaknin, Carol Aghajanian, Domenica Lorusso, Nicoletta Colombo, Andrew Dean, Johanne Weberpals, Eric Severson, Lan-Thanh Vo, Sandra Goble, Lara Maloney, Thomas Harding, Scott H Kaufmann, Jonathan A Ledermann, Robert L Coleman, Iain A McNeish, Kevin K Lin, Elizabeth M Swisher.
       Importance: A total of 1% to 3% of patients treated with a poly(adenosine diphosphate-ribose) polymerase inhibitor for high-grade ovarian cancer (HGOC) develop therapy-related myeloid neoplasms (t-MNs), which are rare but often fatal conditions. Although the cause of these t-MNs is unknown, clonal hematopoiesis of indeterminate potential (CHIP) variants can increase the risk of primary myeloid malignant neoplasms and are more frequent among patients with solid tumors.
    Objectives: To examine whether preexisting CHIP variants are associated with the development of t-MNs after rucaparib treatment and how these CHIP variants are affected by treatment.
    Design, Setting, and Participants: This retrospective genetic association study used peripheral blood cell (PBC) samples collected before rucaparib treatment from patients in the multicenter, single-arm ARIEL2 (Study of Rucaparib in Patients With Platinum-Sensitive, Relapsed, High-Grade Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer) (n = 491; between October 30, 2013, and August 9, 2016) and the multicenter, placebo-controlled, double-blind ARIEL3 (Study of Rucaparib as Switch Maintenance Following Platinum-Based Chemotherapy in Patients With Platinum-Sensitive, High-Grade Serous or Endometrioid Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer) (n = 561; between April 7, 2014, and July 19, 2016), which tested rucaparib as HGOC therapy in the treatment and maintenance settings, respectively. The follow-up data cutoff date was September 1, 2019. Of 1052 patients in ARIEL2 and ARIEL3, PBC samples from 20 patients who developed t-MNs (cases) and 44 randomly selected patients who did not (controls) were analyzed for the presence of CHIP variants using targeted next-generation sequencing. Additional longitudinal analysis was performed on available ARIEL2 samples collected during treatment and at the end of treatment.
    Main Outcomes and Measures: Enrichment analysis of preexisting variants in 10 predefined CHIP-associated genes in cases relative to controls; association with clinical correlates.
    Results: Among 1052 patients (mean [SE] age, 61.7 [0.3] years) enrolled and dosed in ARIEL2 and ARIEL3, 22 (2.1%) developed t-MNs. The t-MNs were associated with longer overall exposure to prior platinum therapies (13.2 vs 9.0 months in ARIEL2, P = .04; 12.4 vs 9.6 months in ARIEL3, P = .003). The presence of homologous recombination repair gene variants in the tumor, either germline or somatic, was associated with increased prevalence of t-MNs (15 [4.1%] of 369 patients with HGOC associated with an HRR gene variant vs 7 [1.0%] of 683 patients with wild-type HGOC, P = .002). The prevalence of preexisting CHIP variants in TP53 but not other CHIP-associated genes at a variant allele frequency of 1% or greater was significantly higher in PBCs from cases vs controls (9 [45.0%] of 20 cases vs 6 [13.6%] of 44 controls, P = .009). TP53 CHIP was associated with longer prior exposure to platinum (mean 14.0 months of 15 TP53 CHIP cases vs 11.1 months of 49 non-TP53 CHIP cases; P = .02). Longitudinal analysis showed that preexisting TP53 CHIP variants expanded in patients who developed t-MNs.
    Conclusions and Relevance: The findings of this genetic association study suggest that preexisting TP53 CHIP variants may be associated with t-MNs after rucaparib treatment.
    DOI:  https://doi.org/10.1001/jamaoncol.2021.4664
  4. NPJ Breast Cancer. 2021 Oct 11. 7(1): 135
    Germline RAD51B variants confer susceptibility to breast and ovarian cancers deficient in homologous recombination.
    Jeremy Setton, Pier Selenica, Semanti Mukherjee, Rachna Shah, Isabella Pecorari, Biko McMillan, Isaac X Pei, Yelena Kemel, Ozge Ceyhan-Birsoy, Margaret Sheehan, Kaitlyn Tkachuk, David N Brown, Liying Zhang, Karen Cadoo, Simon Powell, Britta Weigelt, Mark Robson, Nadeem Riaz, Kenneth Offit, Jorge S Reis-Filho, Diana Mandelker.
      Pathogenic germline mutations in the RAD51 paralog genes RAD51C and RAD51D, are known to confer susceptibility to ovarian and triple-negative breast cancer. Here, we investigated whether germline loss-of-function variants affecting another RAD51 paralog gene, RAD51B, are also associated with breast and ovarian cancer. Among 3422 consecutively accrued breast and ovarian cancer patients consented to tumor/germline sequencing, the observed carrier frequency of loss-of-function germline RAD51B variants was significantly higher than control cases from the gnomAD population database (0.26% vs 0.09%), with an odds ratio of 2.69 (95% CI: 1.4-5.3). Furthermore, we demonstrate that tumors harboring biallelic RAD51B alteration are deficient in homologous recombination DNA repair deficiency (HRD), as evidenced by analysis of sequencing data and in vitro functional assays. Our findings suggest that RAD51B should be considered as an addition to clinical germline testing panels for breast and ovarian cancer susceptibility.
    DOI:  https://doi.org/10.1038/s41523-021-00339-0
  5. Cancer. 2021 Oct 13.
    There is more to soft tissue sarcomas than just grade and size.
    Robert S Benjamin.
       LAY SUMMARY: Sarculator is better at predicting patients with sarcoma at the highest risk of death than current staging systems and should be used to determine appropriate patients for future studies.
    Keywords:  Sarculator; anthracycline; clinical trial; ifosfamide; sarcoma
    DOI:  https://doi.org/10.1002/cncr.33896
  6. Front Mol Biosci. 2021 ;8 619027
    Gene Expression Subtyping Reveals Immune alterations:TCGA Database for Prognosis in Ovarian Serous Cystadenocarcinoma.
    Chunxia Feng, Yan Xu, Yuanyuan Liu, Lixia Zhu, Le Wang, Xixi Cui, Jingjing Lu, Yan Zhang, Lina Zhou, Minbin Chen, Zhiqin Zhang, Ping Li.
      Serous ovarian cancer is the most common and primary death type in ovarian cancer. In recent studies, tumor microenvironment and tumor immune infiltration significantly affect the prognosis of ovarian cancer. This study analyzed the four gene expression types of ovarian cancer in TCGA database to extract differentially expressed genes and verify the prognostic significance. Meanwhile, functional enrichment and protein interaction network analysis exposed that these genes were related to immune response and immune infiltration. Subsequently, we proved these prognostic genes in an independent data set from the GEO database. Finally, multivariate cox regression analysis revealed the prognostic significance of TAP1 and CXCL13. The genetic alteration and interaction network of these two genes were shown. Then, we established a nomogram model related to the two genes and clinical risk factors. This model performed well in Calibration plot and Decision Curve Analysis. In conclusion, we have obtained a list of genes related to the immune microenvironment with a better prognosis for serous ovarian cancer, and based on this, we have tried to establish a clinical prognosis model.
    Keywords:  TCGA; nomogram; prognosis; serous ovarian cancer; tumor immune infiltration
    DOI:  https://doi.org/10.3389/fmolb.2021.619027
  7. Reprod Med Biol. 2021 Oct;20(4): 467-476
    Differential expression of estrogen receptor subtypes in ovarian high-grade serous carcinoma and clear cell carcinoma.
    Daiken Osaku, Tetsuro Oishi, Naoshi Kawamura, Yuki Iida, Hiroaki Komatsu, Akiko Kudoh, Jun Chikumi, Shinya Sato, Tasuku Harada.
       Purpose: To investigate the role of estrogen receptors (ERs) in high-grade serous carcinoma (HGSC) and clear cell carcinoma (CCC) of the ovary and evaluate ERs as prognostic biomarkers for ovarian cancer.
    Methods: This study included 79 patients with HGSC (n = 38) or CCC (n = 41) treated at our institution between 2005 and 2014. Immunohistochemistry examined protein expression of ERα, ERβ, and G protein-coupled estrogen receptor-1 (GPER-1); relationships between ERα, ERβ, and GPER-1 with patient survival were evaluated. Additionally, cell proliferation assay and phosphokinase proteome profiling were performed.
    Results: In HGSC patients, expression of ERα, cytoplasmic GPER-1, or nuclear GPER-1 was associated with poor progression-free survival (PFS) (P = .041, P = .010, or P = .013, respectively). Cytoplasmic GPER-1 was an independent prognostic factor for PFS in HGSC patients (HR = 2.83, 95% CI = 1.03-9.16, P = .007). ER expressions were not associated with prognosis in CCC patients. GPER-1 knockdown by siRNA reduced the cells number to 60% of siRNA-control-treated cells (P < .05), and GPER-1 antagonist, G-15 inhibited two HGSC cell lines proliferation (KF and UWB1.289) in a dose-dependent manner. Phosphoprotein array revealed that GPER-1 silencing decreased relative phosphorylation of glycogen synthase kinase-3.
    Conclusions: High GPER-1 expression is an independent prognostic factor for PFS in HGSC patients, and GPER-1 may play a role in HGSC cell proliferation.
    Keywords:  G protein‐coupled estrogen receptor‐1; high‐grade serous carcinoma of the ovary; ovarian clear cell carcinoma; progression‐free survival; proliferation
    DOI:  https://doi.org/10.1002/rmb2.12402
  8. Hum Cell. 2021 Oct 10.
    Pan-cancer analysis reveals homologous recombination deficiency score as a predictive marker for immunotherapy responders.
    Can Yang, Zijing Zhang, Xuemei Tang, Xinju Zhang, Yuming Chen, Tingting Hu, Huating Zhang, Ming Guan, Xiuming Zhang, Zhiyuan Wu.
      The immune context of the tumor microenvironment (TME) is critical for effective immunotherapy. Nonetheless, DNA-based biomarkers for the immune-sensitive TME and the identification of immune checkpoint inhibitor (ICI) responders are under-explored. This study aims to comprehensively landscape the homologous recombination deficiency (HRD) score, an emerging hallmark for tumor genome instability that triggers immune responsiveness across major cancer types, and to unveil their link to the TME and immunotherapeutic response. The HRD-associated genomic scars were characterized in 9088 tumor samples across 32 cancer types from TCGA. We evaluated the HRD score's performance in classifying ICI responders using an independent breast cancer cohort (GSE87049) and 11 in vivo murine mammary tumor models treated with anti-PD1/CTLA4 regimen (GSE124821). This study revealed a broad association between HRD-high genotype and neoantigenesis in the major cancer types including bladder cancer, breast cancer, head and neck squamous carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, and sarcoma. Tumors with high HRD score bears increased leukocyte infiltration and lymphocyte fraction and demonstrated immune-sensitive microenvironment. The tumor immune dysfunction and exclusion (TIDE) model further confirmed HRD score-high genotype as a potential predictor for ICI immunotherapy responders in breast cancer. In conclusion, tumors with high HRD score exhibit an immune-sensitive TME. The HRD-high genotype is a promising marker for identifying ICI therapy responders among breast cancer patients.
    Keywords:  Homologous recombination deficiency; Immune checkpoint inhibitor; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s13577-021-00630-z
  9. Brief Bioinform. 2021 Oct 15. pii: bbab413. [Epub ahead of print]
    sciCNV: high-throughput paired profiling of transcriptomes and DNA copy number variations at single-cell resolution.
    Ali Mahdipour-Shirayeh, Natalie Erdmann, Chungyee Leung-Hagesteijn, Rodger E Tiedemann.
      Chromosome copy number variations (CNVs) are a near-universal feature of cancer; however, their individual effects on cellular function are often incompletely understood. Single-cell ribonucleic acid (RNA) sequencing (scRNA-seq) might be leveraged to reveal the function of intra-clonal CNVs; however, it cannot directly link cellular gene expression to CNVs. Here, we report a high-throughput scRNA-seq analysis pipeline that provides paired CNV profiles and transcriptomes for single cells, enabling exploration of the effects of CNVs on cellular programs. RTAM1 and -2 normalization methods are described, and are shown to improve transcriptome alignment between cells, increasing the sensitivity of scRNA-seq for CNV detection. We also report single-cell inferred chromosomal copy number variation (sciCNV), a tool for inferring single-cell CNVs from scRNA-seq at 19-46 Mb resolution. Comparison of sciCNV with existing RNA-based CNV methods reveals useful advances in sensitivity and specificity. Using sciCNV, we demonstrate that scRNA-seq can be used to examine the cellular effects of cancer CNVs. As an example, sciCNV is used to identify subclonal multiple myeloma (MM) cells with +8q22-24. Studies of the gene expression of intra-clonal MM cells with and without the CNV demonstrate that +8q22-24 upregulates MYC and MYC-target genes, messenger RNA processing and protein synthesis, which is consistent with established models. In conclusion, we provide new tools for scRNA-seq that enable paired profiling of the CNVs and transcriptomes of single cells, facilitating rapid and accurate deconstruction of the effects of cancer CNVs on cellular programming.
    Keywords:  RTAM; copy number variation (CNV); multi-omics; multiple myeloma; normalization; sciCNV; single-cell RNA sequencing (scRNA-seq)
    DOI:  https://doi.org/10.1093/bib/bbab413
  10. Int J Genomics. 2021 ;2021 3803724
    Comprehensive Analysis of m5C RNA Methylation Regulator Genes in Clear Cell Renal Cell Carcinoma.
    Jiajin Wu, Chao Hou, Yuhao Wang, Zhongyuan Wang, Pu Li, Zengjun Wang.
       Background: Recent research found that N5-methylcytosine (m5C) was involved in the development and occurrence of numerous cancers. However, the function and mechanism of m5C RNA methylation regulators in clear cell renal cell carcinoma (ccRCC) remains undiscovered. This study is aimed at investigating the predictive and clinical value of these m5C-related genes in ccRCC.
    Methods: Based on The Cancer Genome Atlas (TCGA) database, the expression patterns of twelve m5C regulators and matched clinicopathological characteristics were downloaded and analyzed. To reveal the relationships between the expression levels of m5C-related genes and the prognosis value in ccRCC, consensus clustering analysis was carried out. By univariate Cox analysis and last absolute shrinkage and selection operator (LASSO) Cox regression algorithm, a m5C-related risk signature was constructed in the training group and further validated in the testing group and the entire cohort. Then, the predictive ability of survival of this m5C-related risk signature was analyzed by Cox regression analysis and nomogram. Functional annotation and single-sample Gene Set Enrichment Analysis (ssGSEA) were applied to further explore the biological function and potential signaling pathways. Furthermore, we performed qRT-PCR experiments and measured global m5C RNA methylation level to validate this signature in vitro and tissue samples.
    Results: In the TCGA-KIRC cohort, we found significant differences in the expression of m5C RNA methylation-related genes between ccRCC tissues and normal kidney tissues. Consensus cluster analysis was conducted to separate patients into two m5C RNA methylation subtypes. Significantly better outcomes were observed in ccRCC patients in cluster 1 than in cluster 2. m5C RNA methylation-related risk score was calculated to evaluate the prognosis of ccRCC patients by seven screened m5C RNA methylation regulators (NOP2, NSUN2, NSUN3, NSUN4, NSUN5, TET2, and DNMT3B) in the training cohort. The AUC for the 1-, 2-, and 3-year survival in the training cohort were 0.792, 0.675, and 0.709, respectively, indicating that the risk signature had an excellent prognosis prediction in ccRCC. Additionally, univariate and multivariate Cox regression analyses revealed that the risk signature could be an independent prognostic factor in ccRCC. The results of ssGSEA suggested that the immune cells with different infiltration degrees between the high-risk and low-risk groups were T cells including follicular helper T cells, Th1_cells, Th2_cells, and CD8+_T_cells, and the main differences in immune-related functions between the two groups were the interferon response and T cell costimulation. In addition, qRT-PCR experiments confirmed our results in renal cell lines and tissue samples.
    Conclusions: According to the seven selected regulatory factors of m5C RNA methylation, a risk signature associated with m5C methylation that can independently predict prognosis in patients with ccRCC was developed and further verified the predictive efficiency.
    DOI:  https://doi.org/10.1155/2021/3803724
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