bims-tumhet Biomed News
on Tumor Heterogeneity
Issue of 2021–05–30
seven papers selected by
Sergio Marchini, Humanitas Research
  1. Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer.
  2. Clinical Quality Considerations when Using Next-Generation Sequencing (NGS) in Clinical Drug Development.
  3. Integrated analysis of methylation-driven genes and pretreatment prognostic factors in patients with hepatocellular carcinoma.
  4. Management of advanced ovarian cancer in Spain: an expert Delphi consensus.
  5. Liquid biopsy in cholangiocarcinoma: Current status and future perspectives.
  6. Chromosomal copy number heterogeneity predicts survival rates across cancers.
  7. DNA methylation signatures associated with prognosis of gastric cancer.
  1. BMC Cancer. 2021 May 26. 21(1): 611
    Comprehensive analysis of DNA damage repair genes reveals pathogenic variants beyond BRCA and suggests the need for extensive genetic testing in pancreatic cancer.
    Ilario Giovanni Rapposelli, Valentina Zampiga, Ilaria Cangini, Valentina Arcangeli, Mila Ravegnani, Martina Valgiusti, Sara Pini, Stefano Tamberi, Giulia Bartolini, Alessandro Passardi, Giovanni Martinelli, Daniele Calistri, Giovanni Luca Frassineti, Fabio Falcini, Rita Danesi.
       BACKGROUND: Pancreatic cancer (PC) is a major cause of cancer death. In an effort to improve treatment strategies and outcomes, DNA damage repair (DDR) pathways have been introduced as a new target in PC and in other cancers, through the exploitation of synthetic lethality. Furthermore, genes involved in DDR are among the major determinants of cancer susceptibility. In addition to the well-known BRCA1 and BRCA2 genes, a plethora of other targets in the same pathways are now emerging.
    METHODS: We analyzed samples from 60 patients, affected by PC and already tested for BRCA, using a panel with 24 other cancer susceptibility genes.
    RESULTS: We detected 8 pathogenic or likely pathogenic mutations (13.3% of samples analyzed), 4 of which were found in non-BRCA genes (2 in ATM, 1 each in PALB2 and RAD50). Furthermore, 4 pathogenic or likely pathogenic mutations were found in patients without a personal or familial history of cancer.
    CONCLUSIONS: Our results suggest that genetic testing with a comprehensive gene panel should be perfomed in all patients with PC, in order to allow screening for PC and other gene-related cancers in all at risk family members and to assess patients' eligibility for emerging therapeutic options.
    Keywords:  Cancer susceptibility; DNA damage repair; Gene panel; Pancreatic cancer; Targeted therapy
    DOI:  https://doi.org/10.1186/s12885-021-08368-5
  2. Ther Innov Regul Sci. 2021 May 27.
    Clinical Quality Considerations when Using Next-Generation Sequencing (NGS) in Clinical Drug Development.
    Timothé Ménard, Alaina Barros, Christopher Ganter.
      Next-generation sequencing (NGS) and decreased costs of genomic testing are changing the paradigm in precision medicine and continue to fuel innovation. Integration of NGS into clinical drug development has the potential to accelerate clinical trial conduct and ultimately will shape the landscape of clinical care by making it easier to identify patients who would benefit from particular therapy(ies) and to monitor treatment outcomes with less invasive tests. This has led to an increased use of NGS service providers by pharmaceutical sponsors: to screen patients for clinical trials eligibility and for patient stratification, expanded Companion Diagnostic (CDx) development for treatment recommendations and Comprehensive Genomic profiling (CGP). These changes are reshaping the face of clinical quality considerations for precision medicine. Although some clinical quality considerations do exist in Health Authorities (HA) guidances and regulations (e.g., International Conference of Harmonization Good Clinical Practices-GCP), there is currently no holistic GxP-like detailed framework for pharmaceutical sponsors using NGS service providers in clinical trials, or for the development of CDx and CGP. In this research, we identified existing and applicable regulations, guidelines and recommendations that could be translated into clinical quality considerations related to technology, data quality, patients and oversight. We propose these considerations as a basis for pharmaceutical sponsors using NGS service providers in clinical drug development to develop a set of guidelines for NGS clinical quality.
    Keywords:  Clinical quality; Clinical trials; Genetics; Genomics; Next-generation sequencing; Quality assurance
    DOI:  https://doi.org/10.1007/s43441-021-00308-6
  3. BMC Cancer. 2021 May 25. 21(1): 599
    Integrated analysis of methylation-driven genes and pretreatment prognostic factors in patients with hepatocellular carcinoma.
    Dongsheng He, Shengyin Liao, Lifang Cai, Weiming Huang, Xuehua Xie, Mengxing You.
       BACKGROUND: The potential reversibility of aberrant DNA methylation indicates an opportunity for oncotherapy. This study aimed to integrate methylation-driven genes and pretreatment prognostic factors and then construct a new individual prognostic model in hepatocellular carcinoma (HCC) patients.
    METHODS: The gene methylation, gene expression dataset and clinical information of HCC patients were downloaded from The Cancer Genome Atlas (TCGA) database. Methylation-driven genes were screened with a Pearson's correlation coefficient less than - 0.3 and a P value less than 0.05. Univariable and multivariable Cox regression analyses were performed to construct a risk score model and identify independent prognostic factors from the clinical parameters of HCC patients. The least absolute shrinkage and selection operator (LASSO) technique was used to construct a nomogram that might act to predict an individual's OS, and then C-index, ROC curve and calibration plot were used to test the practicability. The correlation between clinical parameters and core methylation-driven genes of HCC patients was explored with Student's t-test.
    RESULTS: In this study, 44 methylation-driven genes were discovered, and three prognostic signatures (LCAT, RPS6KA6, and C5orf58) were screened to construct a prognostic risk model of HCC patients. Five clinical factors, including T stage, risk score, cancer status, surgical method and new tumor events, were identified from 13 clinical parameters as pretreatment-independent prognostic factors. To avoid overfitting, LASSO analysis was used to construct a nomogram that could be used to calculate the OS in HCC patients. The C-index was superior to that from previous studies (0.75 vs 0.717, 0.676). Furthermore, LCAT was found to be correlated with T stage and new tumor events, and RPS6KA6 was found to be correlated with T stage.
    CONCLUSION: We identified novel therapeutic targets and constructed an individual prognostic model that can be used to guide personalized treatment in HCC patients.
    Keywords:  Hepatocellular carcinoma; Methylation-driven genes; Nomogram; Prognosis
    DOI:  https://doi.org/10.1186/s12885-021-08314-5
  4. J Ovarian Res. 2021 May 26. 14(1): 72
    Management of advanced ovarian cancer in Spain: an expert Delphi consensus.
    Andres Redondo, Ana Oaknin, Maria Jesus Rubio, Maria-Pilar Barretina-Ginesta, Ana de Juan, Luis Manso, Ignacio Romero, Cristina Martin-Lorente, Andres Poveda, Antonio Gonzalez-Martin.
       BACKGROUND: To determine the state of current practice and to reach a consensus on recommendations for the management of advanced ovarian cancer using a Delphi survey with a group of Spanish gynecologists and medical oncologists specially dedicated to gynecological tumors.
    METHODS: The questionnaire was developed by the byline authors. All questions but one were answered using a 9-item Likert-like scale with three types of answers: frequency, relevance and agreement. We performed two rounds between December 2018 and July 2019. A consensus was considered reached when at least 75% of the answers were located within three consecutive points of the Likert scale.
    RESULTS: In the first round, 32 oncologists and gynecologists were invited to participate, and 31 (96.9%) completed the online questionnaire. In the second round, 27 (87.1%) completed the online questionnaire. The results for the questions on first-line management of advanced disease, treatment of patients with recurrent disease for whom platinum might be the best option, and treatment of patients with recurrent disease for whom platinum might not be the best option are presented.
    CONCLUSIONS: This survey shows a snapshot of current recommendations by this selected group of physicians. Although the majority of the agreements and recommendations are aligned with the recently published ESMO-ESGO consensus, there are some discrepancies that can be explained by differences in the interpretation of certain clinical trials, reimbursement or accessibility issues.
    Keywords:  Advanced disease; Consensus; Management; Ovarian cancer; Recurrent disease
    DOI:  https://doi.org/10.1186/s13048-021-00816-x
  5. World J Gastrointest Oncol. 2021 May 15. 13(5): 332-350
    Liquid biopsy in cholangiocarcinoma: Current status and future perspectives.
    Gianluca Rompianesi, Marcello Di Martino, Alex Gordon-Weeks, Roberto Montalti, Roberto Troisi.
      Cholangiocarcinoma (CCA) are a heterogeneous group of tumors in terms of aetiology, natural history, morphological subtypes, molecular alterations and management, but all sharing complex diagnosis, management, and poor prognosis. Several mutated genes and epigenetic changes have been detected in CCA, with the potential to identify diagnostic and prognostic biomarkers and therapeutic targets. Accessing tumoral components and genetic material is therefore crucial for the diagnosis, management and selection of targeted therapies; but sampling tumor tissue, when possible, is often risky and difficult to be repeated at different time points. Liquid biopsy (LB) represents a way to overcome these issues and comprises a diverse group of methodologies centering around detection of tumor biomarkers from fluid samples. Compared to the traditional tissue sampling methods LB is less invasive and can be serially repeated, allowing a real-time monitoring of the tumor genetic profile or the response to therapy. In this review, we analysis the current evidence on the possible roles of LB (circulating DNA, circulating RNA, exosomes, cytokines) in the diagnosis and management of patients affected by CCA.
    Keywords:  Biliary tumors; Cholangiocarcinoma; Circulating DNA; Circulating RNA; Circulating biomarkers; Cytokines; Exosomes; Liquid biopsy
    DOI:  https://doi.org/10.4251/wjgo.v13.i5.332
  6. Nat Commun. 2021 May 27. 12(1): 3188
    Chromosomal copy number heterogeneity predicts survival rates across cancers.
    Erik van Dijk, Tom van den Bosch, Kristiaan J Lenos, Khalid El Makrini, Lisanne E Nijman, Hendrik F B van Essen, Nico Lansu, Michiel Boekhout, Joris H Hageman, Rebecca C Fitzgerald, Cornelis J A Punt, Jurriaan B Tuynman, Hugo J G Snippert, Geert J P L Kops, Jan Paul Medema, Bauke Ylstra, Louis Vermeulen, Daniël M Miedema.
      Survival rates of cancer patients vary widely within and between malignancies. While genetic aberrations are at the root of all cancers, individual genomic features cannot explain these distinct disease outcomes. In contrast, intra-tumour heterogeneity (ITH) has the potential to elucidate pan-cancer survival rates and the biology that drives cancer prognosis. Unfortunately, a comprehensive and effective framework to measure ITH across cancers is missing. Here, we introduce a scalable measure of chromosomal copy number heterogeneity (CNH) that predicts patient survival across cancers. We show that the level of ITH can be derived from a single-sample copy number profile. Using gene-expression data and live cell imaging we demonstrate that ongoing chromosomal instability underlies the observed heterogeneity. Analysing 11,534 primary cancer samples from 37 different malignancies, we find that copy number heterogeneity can be accurately deduced and predicts cancer survival across tissues of origin and stages of disease. Our results provide a unifying molecular explanation for the different survival rates observed between cancer types.
    DOI:  https://doi.org/10.1038/s41467-021-23384-6
  7. BMC Cancer. 2021 May 25. 21(1): 610
    DNA methylation signatures associated with prognosis of gastric cancer.
    Jin Dai, Akihiro Nishi, Zhe-Xuan Li, Yang Zhang, Tong Zhou, Wei-Cheng You, Wen-Qing Li, Kai-Feng Pan.
       BACKGROUND: Few studies have examined prognostic outcomes-associated molecular signatures other than overall survival (OS) for gastric cancer (GC). We aimed to identify DNA methylation biomarkers associated with multiple prognostic outcomes of GC in an epigenome-wide association study.
    METHODS: Based on the Cancer Genome Atlas (TCGA), DNA methylation loci associated with OS (n = 381), disease-specific survival (DSS, n = 372), and progression-free interval (PFI, n = 383) were discovered in training set subjects (false discovery rates < 0.05) randomly selected for each prognostic outcome and were then validated in remaining subjects (P-values < 0.05). Key CpGs simultaneously validated for OS, DSS, and PFI were further assessed for disease-free interval (DFI, n = 247). Gene set enrichment analyses were conducted to explore the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways simultaneously enriched for multiple GC prognostic outcomes. Methylation correlated blocks (MCBs) were identified for co-methylation patterns associated with GC prognosis. Based on key CpGs, risk score models were established to predict four prognostic outcomes. Spearman correlation analyses were performed between key CpG sites and their host gene mRNA expression.
    RESULTS: We newly identified DNA methylation of seven CpGs significantly associated with OS, DSS, and PFI of GC, including cg10399824 (GRK5), cg05275153 (RGS12), cg24406668 (MMP9), cg14719951(DSC3), and cg25117092 (MED12L), and two in intergenic regions (cg11348188 and cg11671115). Except cg10399824 and cg24406668, five of them were also significantly associated with DFI of GC. Neuroactive ligand-receptor interaction pathway was suggested to play a key role in the effect of DNA methylation on GC prognosis. Consistent with individual CpG-level association, three MCBs involving cg11671115, cg14719951, and cg24406668 were significantly associated with multiple prognostic outcomes of GC. Integrating key CpG loci, two risk score models performed well in predicting GC prognosis. Gene body DNA methylation of cg14719951, cg10399824, and cg25117092 was associated with their host gene expression, whereas no significant associations between their host gene expression and four clinical prognostic outcomes of GC were observed.
    CONCLUSIONS: We newly identified seven CpGs associated with OS, DSS, and PFI of GC, with five of them also associated with DFI, which might inform patient stratification in clinical practices.
    Keywords:  Bioinformatics; Biomarkers; Epigenetics; Gastric cancer; Heterogeneity; Methylation; Precision medicine; Prognosis; Survival; The Cancer Genome Atlas
    DOI:  https://doi.org/10.1186/s12885-021-08389-0
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