bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2021–09–05
ten papers selected by
Sergio Marchini, Humanitas Research
  1. Evolutionary Mechanisms of Cancer Suggest Rational Therapeutic Approaches.
  2. Immune microenvironment composition in high-grade serous ovarian cancers based on BRCA mutational status.
  3. Scratching Below the Ovarian Cancer GWAS Surface.
  4. Single-cell transcriptomes reveal heterogeneity of high-grade serous ovarian carcinoma.
  5. Cell-free DNA is abundant in ascites and represents a liquid biopsy of ovarian cancer.
  6. Size Distribution of Cell-free DNA in Oncology.
  7. Genome-wide sequencing of cell-free DNA enables detection of copy number alterations in cancer patients where tissue biopsy is not feasible.
  8. The Landmark Discovery That Paved the Way to a Mechanistic Understanding of P53 Gain of Function and Personalized Medicine.
  9. Real-world Experience of Niraparib in Newly-diagnosed Epithelial Ovarian Cancer.
  10. Roles of circRNAs in cancer chemoresistance (Review).
  1. Cytogenet Genome Res. 2021 Aug 30. 1-10
    Evolutionary Mechanisms of Cancer Suggest Rational Therapeutic Approaches.
    Alessio Balzerano, Elena Paccosi, Luca Proietti-De-Santis.
      The goal in personalized therapeutic approaches for cancer medicine is to identify specific mutations with prognostic and therapeutic value in order to tailor the therapy for the single patient. The most powerful obstacle for personalized medicine arises from intratumor heterogeneity and clonal evolution, which can promote drug resistance. In this scenario, new technologies, such as next-generation sequencing, have emerged as a central diagnostic tool to profile cancer (epi)genomic landscapes. Therefore, a better understanding of the biological mechanisms underlying cancer evolution is mandatory and represents the current challenge to accurately predict whether cancer will recur after chemotherapy with the aim to tailor rational therapeutic approaches.
    Keywords:  Cancer (epi)genomic landscapes; Cancer evolution; Circulating tumor DNA; Intratumor heterogeneity; Liquid biopsy
    DOI:  https://doi.org/10.1159/000516530
  2. J Cancer Res Clin Oncol. 2021 Sep 02.
    Immune microenvironment composition in high-grade serous ovarian cancers based on BRCA mutational status.
    Sara Corvigno, Jared K Burks, Wei Hu, Yanping Zhong, Nicholas B Jennings, Nicole D Fleming, Shannon N Westin, Bryan Fellman, Jinsong Liu, Anil K Sood.
       PURPOSE: An in-depth analysis of the tumor microenvironment of ovarian cancer is needed. The purpose of this study was to elucidate the architecture of the immune microenvironment of high-grade serous ovarian cancers (HGSCs) with or without BRCA1 and BRCA2 mutations.
    METHODS: A cohort of highly annotated HGSC patients with known germline BRCA1 and BRCA2 status was selected, and pretreatment tumor tissue specimens were analyzed with a multiplexed staining technique aimed at detecting lymphocytes, macrophages, and fibroblasts in the whole tumor area and in specific regions including epithelium, stroma, and perivascular areas.
    RESULTS: BRCA1- or BRCA2-mutated tumors showed a more immunogenic microenvironment, characterized by a higher abundance of CD8+ and PD-L1+ cells, than did tumors with wild-type BRCA1 and BRCA2. High numbers of PD-L1+ and PD-L1+CD8+ cells were prognostic for event-free survival (hazard ratio [HR]: 0.41, 95% CI 0.21-0.79, p = 0.008 and HR 0.49, 95% CI 0.26-0.91, p = 0.025, respectively), as were high numbers of epithelial PD-L1+ and FAP+PD-L1+ cells (HR 0.52, 95% CI 0.28-0.96, p = 0.037 and HR 0.27, 95% CI 0.08-0.87, p = 0.029) and CD8+ cells (HR 0.51, 95% CI 0.28-0.93, p = 0.027).
    CONCLUSIONS: This study reveals substantial differences between the immune microenvironment composition of germline BRCA-mutated and BRCA wild-type HGSC.
    Keywords:  BRCA; Fibroblasts; Immune cells; Lymphocytes; Multiple staining; Serous ovarian cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00432-021-03778-1
  3. Cancer Epidemiol Biomarkers Prev. 2021 Sep;30(9): 1604-1606
    Scratching Below the Ovarian Cancer GWAS Surface.
    Lauren C Peres, Alvaro N Monteiro.
      Despite recent notable treatment advancements, ovarian cancer survival rates remain poor, with about half of women surviving five years after diagnosis. Uncovering novel prognostic factors is critical to better understand and reduce mortality from this deadly disease. While genome-wide association studies have identified numerous loci associated with risk of epithelial ovarian cancer, the investigation of genetic factors associated with outcomes among women with ovarian cancer has been limited due to several challenges summarized in the present commentary. Using data from the Ovarian Cancer Association Consortium, Quinn and colleagues conducted a genome-wide association study of patients with ovarian cancer receiving debulking surgery and standard chemotherapy as first-line treatment, revealing a locus at 12q24.33 associated with progression-free survival. Experimental evidence suggests that ULK1, a gene coding for a serine/threonine kinase implicated in autophagy, is the target of the association. We discuss the novelty of these findings, unanswered questions, and next steps for the road ahead in translating the work of Quinn and colleagues into clinical practice.See related article by Quinn et al., p. 1669.
    DOI:  https://doi.org/10.1158/1055-9965.EPI-21-0568
  4. Clin Transl Med. 2021 Aug;11(8): e500
    Single-cell transcriptomes reveal heterogeneity of high-grade serous ovarian carcinoma.
    Qian Hao, Jiajia Li, Qinghua Zhang, Fei Xu, Bangxiang Xie, Hua Lu, Xiaohua Wu, Xiang Zhou.
       BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive histotype of epithelial ovarian cancer. The heterogeneity and molecular basis of this disease remain incompletely understood.
    METHODS: To address this question, we have performed a single-cell transcriptomics analysis of matched primary and metastatic HGSOC samples.
    RESULTS: A total of 13 571 cells are categorized into six distinct cell types, including epithelial cells, fibroblast cells, T cells, B cells, macrophages, and endothelial cells. A subset of aggressive epithelial cells with hyperproliferative and drug-resistant potentials is identified. Several new markers that are highly expressed in epithelial cells are characterized, and their roles in ovarian cancer cell growth and migration are further confirmed. Dysregulation of multiple signaling pathways, including the translational machinery, is associated with ovarian cancer metastasis through the trajectory analysis. Moreover, single-cell regulatory network inference and clustering (SCENIC) analysis reveals the gene regulatory networks and suggests the JUN signaling pathway as a potential therapeutic target for treatment of ovarian cancer, which is validated using the JUN/AP-1 inhibitor T-5224. Finally, our study depicts the epithelial-fibroblast cell communication atlas and identifies several important receptor-ligand complexes in ovarian cancer development.
    CONCLUSIONS: This study uncovers new molecular features and the potential therapeutic target of HGSOC, which would advance the understanding and treatment of the disease.
    Keywords:  chemoresistance; gene regulatory network; intercellular communication; metastasis; single-cell RNA-seq
    DOI:  https://doi.org/10.1002/ctm2.500
  5. Gynecol Oncol. 2021 Sep;pii: S0090-8258(21)00524-2. [Epub ahead of print]162(3): 720-727
    Cell-free DNA is abundant in ascites and represents a liquid biopsy of ovarian cancer.
    INOVATe Investigators
       OBJECTIVE: Malignant ascites is a common clinical feature of ovarian cancer and represents a readily accessible sample of tumour cells and tumour DNA. This study aimed to characterise the cell-free DNA (cfDNA) in ascites in terms of its size profile, stability and cell-free tumour DNA (cftDNA) content.
    METHODS: Cell spheroids, loose cells and cell-free fluid was collected from ascites from 18 patients with ovarian cancer. cfDNA was isolated and assessed for size by electrophoresis, concentration by fluorometry,cftDNA content by methylation specific qPCR of HOXA9 and IFFO1 promoter regions and by targeted sequencing. Stability was assessed after ascites fluid was stored at 4 °C for 24 and 72 h before fractionating.
    RESULTS: The concentration of cfDNA in ascites ranged from 6.6 to 300 ng/mL. cfDNA size distribution resembled blood plasma-derived cfDNA, with major peaks corresponding to mono- and di-nucleosome DNA fragments. High molecular weight cfDNA was observed in 7 of 18 patients and appeared to be associated with extracellular vesicles. IFFO1 and HOXA9 methylation was proportionately higher in cfDNA than spheroid- and loose-cell fractions and was not observed in healthy primary cells. Variant allele frequency was highest in cfDNA compared to single cells and spheroids from ascites. Though cancer cell numbers in ascites declined to near zero in recurrent ascites from one patient undertaking chemotherapy, cftDNA could still be sampled. cfDNA size, concentration and tumour content was stable over 72 h.
    CONCLUSION: cfDNA in ovarian cancer ascites demonstrates inter-patient variability, yet is consistently a rich source of cftDNA, which is a stable substrate. This supports the wider clinical use of ascites in the molecular analysis of ovarian cancer.
    Keywords:  Ascites; Cell-free DNA; Extracellular vesicles; IFFO1; Methylation-specific qPCR; Ovarian cancer
    DOI:  https://doi.org/10.1016/j.ygyno.2021.06.028
  6. Crit Rev Oncol Hematol. 2021 Aug 28. pii: S1040-8428(21)00243-2. [Epub ahead of print] 103455
    Size Distribution of Cell-free DNA in Oncology.
    Sasimol Udomruk, Santhasiri Orrapin, Dumnoensun Pruksakorn, Parunya Chaiyawat.
      Tumor-specific, circulating cell-free DNA (cfDNA) in liquid biopsy test is a novel promising biomarker in the advancement of cancer management, including early diagnosis, screening, prognosis, identification of actionable targets, and serial tumor monitoring. The specific size pattern of DNA fragments derived from cancer cells is observed to differ from that of cfDNA fragments shed by non-cancer cells. Research into the physiological and biological properties of cfDNA reveals the molecular signature carried by each cfDNA fragments, which can reflect their tissue origins, as well as the mutational profiles with significant genetic alterations. Understanding the fragmentation and size distribution of cfDNA might be a valuable hotspot in liquid biopsy research, with the potential to drive innovation in oncology.
    Keywords:  Cancer; Cell-free DNA; Circulating tumor DNA; Fragment size distribution; Liquid biopsy; Mutation allele frequency
    DOI:  https://doi.org/10.1016/j.critrevonc.2021.103455
  7. Mol Cancer Ther. 2021 Aug 31. pii: molcanther.1066.2020. [Epub ahead of print]
    Genome-wide sequencing of cell-free DNA enables detection of copy number alterations in cancer patients where tissue biopsy is not feasible.
    Taylor J Jensen, Aaron M Goodman, Christopher K Ellison, Kimberly A Holden, Shumei Kato, Lisa Kim, Gregory A Daniels, Kerry Fitzgerald, Erin McCarthy, Prachi Nakashe, Amin R Mazloom, Eyad Almasri, Graham McLennan, Daniel S Grosu, Marcia Eisenberg, Razelle Kurzrock.
      When tissue biopsy is not medically prudent or tissue is insufficient for molecular testing, alternative methods are needed. Since cell-free DNA (cfDNA) has been shown to provide a representative surrogate for tumor tissue, we sought to evaluate its utility in this clinical scenario. cfDNA was isolated from the plasma of patients and assayed with low-coverage (~0.3X), genome-wide sequencing. Copy number alterations (CNAs) were identified and characterized using analytical methods originally developed for noninvasive prenatal testing (NIPT) and quantified using the genomic instability number (GIN), a metric that reflects the quantity and magnitude of CNAs across the genome. The technical variability of the GIN was first evaluated in an independent cohort comprising genome-wide sequencing results from 27,754 women who consented to have their samples used for research and whose NIPT results yielded no detected CNAs to establish a detection threshold. Subsequently, cfDNA sequencing data from 96 patients with known cancers but for whom a tissue biopsy could not be obtained are presented. An elevated GIN was detected in 35% of patients and detection rates varied by tumor origin. Collectively, CNAs covered 96.6% of all autosomes. Survival was significantly reduced in patients with an elevated GIN relative to those without. Overall, these data provide a proof-of-concept for the use of low coverage, genome-wide sequencing of cfDNA from cancer patients in order to obtain relevant molecular information in instances where tissue is difficult to access. These data may ultimately serve as an informative complement to other molecular tests.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-20-1066
  8. Cancer Res. 2021 Sep 01. 81(17): 4394-4396
    The Landmark Discovery That Paved the Way to a Mechanistic Understanding of P53 Gain of Function and Personalized Medicine.
    Marco Napoli, Avani A Deshpande, Elsa R Flores.
      In 1990, Baker and colleagues reported their seminal findings in Cancer Research focusing on the transition from adenoma to carcinoma of the colon. By sequencing the TP53 locus in 58 colorectal tumors (25 adenomas and 33 carcinomas) and measuring its allelic deletions, they discovered that this transition requires the loss of one TP53 allele and the mutation of the other one. Here, we discuss how this landmark discovery shed a new light on p53 mutations, prompting the generation of novel mouse models that definitively proved the mutant p53 gain-of-function hypothesis suggested by these results. Finally, we evaluate the implications that the Vogelstein model of cancer progression had on numerous aspects of cancer biology and cancer care, including the characterization of tumor evolution and the response to therapy, and how it ultimately contributed to the wider adoption of early detection screenings and personalized medicine.See related article by Baker and colleagues, Cancer Res 1990;50:7717-22.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-2382
  9. Anticancer Res. 2021 Sep;41(9): 4603-4607
    Real-world Experience of Niraparib in Newly-diagnosed Epithelial Ovarian Cancer.
    Wonkyo Shin, Joseph J Noh, Seung Hun Baek, Byoung-Gie Kim, Myong Cheol Lim, Sang-Yoon Park.
       BACKGROUND/AIM: Niraparib is effective against epithelial ovarian cancer (EOC), but with adverse effects. In this study, we retrospectively investigated niraparib maintenance treatment feasibility in Korean patients newly diagnosed with EOC.
    PATIENTS AND METHODS: The medical records of 35 patients were reviewed. Data on the baseline clinical characteristics were collected, and adverse effects were described.
    RESULTS: Sixteen patients underwent treatment suspension or dose reduction. There was no significant difference in adverse effects (A/E) due to the interval between adjuvant chemotherapy conclusion and niraparib initiation. The two groups had similar International Federation of Gynaecology and Obstetrics (FIGO) stages. The number of patients with a history of bevacizumab use was higher in the dose modification group than in the standard dose group.
    CONCLUSION: Niraparib use must be considered in those previously treated with bevacizumab. There is a need for prospective research on lower dose (<200 mg) treatments in patients with risk factors.
    Keywords:  Epithelial ovarian cancer; haematological problems; niraparib
    DOI:  https://doi.org/10.21873/anticanres.15273
  10. Oncol Rep. 2021 Oct;pii: 225. [Epub ahead of print]46(4):
    Roles of circRNAs in cancer chemoresistance (Review).
    Chuan Xin, Fei Huang, Jiongke Wang, Jing Li, Qianming Chen.
      Circular RNA (circRNA) is a type of endogenous, high‑stability, noncoding RNA. circRNAs exhibit various biological functions, and are involved in physiological and pathological processes occurring in various diseases, including cancers. They can not only act as microRNA and protein sponges, but also interact with proteins, translated peptides, and transcriptional and translational regulators, and compete with pre‑mRNA splicing. Chemotherapy is one of the most important types of cancer treatment. However, the resistance of cancer cells to chemotherapy is a leading reason for the failure of chemotherapy. It has been reported that circRNAs play important roles in cancer resistance via a number of mechanisms. The functions of the circRNAs provide insight into their roles in chemoresistance pathways. In addition, some circRNAs may serve as novel biomarkers for the diagnosis and prognosis of cancer resistance. Obtaining improved understanding of the molecular regulatory networks featuring circRNAs in tumors and searching for markers for the diagnosis and treatment of cancer resistance are leading issues in circRNA research. The present review introduced the functions of circRNAs, illustrated the mechanisms underlying drug resistance in cancer, described the contributions of circRNAs to this resistance and discussed the potential application of circRNAs in the treatment of drug‑resistant cancer. In particular, the review aimed to reveal the main mechanisms of circRNAs in cancer drug resistance, including mechanisms involving drug transport and metabolism, alterations of drug targets, DNA damage repair, downstream resistance mechanisms, adaptive responses and the tumor microenvironment. The findings may provide novel therapeutic targets for clinical treatment of cancer chemoresistance.
    Keywords:  cancer drug resistance; cancer therapy; chemoresistance; circular RNA
    DOI:  https://doi.org/10.3892/or.2021.8176
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