bims-tumhet 2024-01-28 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2024–01–28
ten papers selected by
Sergio Marchini, Humanitas Research

Chromatin Remodelers Are Regulators of the Tumor Immune Microenvironment.
FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA.
Pan-cancer copy number variant analysis identifies optimized size thresholds and co-occurrence models for individualized risk-stratification.
Plasma Cell-Free Tumor Methylome as a Biomarker in Solid Tumors: Biology and Applications.
Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review.
Spatial transcriptomics data and analytical methods: An updated perspective.
Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes.
BRAF - a tumour-agnostic drug target with lineage-specific dependencies.
Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor resistant advanced breast cancer.
Limitations and potential of immunotherapy in ovarian cancer.

Cancer Res. 2024 Jan 24.

Chromatin Remodelers Are Regulators of the Tumor Immune Microenvironment.

Apoorvi Chaudhri, Gregory Lizee, Patrick Hwu, Kunal Rai.

Immune checkpoint inhibitors show remarkable responses in a wide range of cancers, yet patients develop adaptive resistance. This necessitates the identification of alternate therapies that synergize with immunotherapies. Epigenetic modifiers are potent mediators of tumor intrinsic mechanisms and have been shown to regulate immune response genes, making them prime targets for therapeutic combinations with immune checkpoint inhibitors. Some success has been observed in early clinical studies that combined immunotherapy with agents targeting DNA methylation and histone modification; however, less is known about chromatin remodeler targeted therapies. Here, we provide a discussion on the regulation of tumor immunogenicity by the chromatin remodeling SWI/SNF complex through multiple mechanisms associated with immunotherapy response that broadly include interferon signaling, DNA damage, mismatch repair, regulation of oncogenic programs, and PRC antagonism. Context-dependent targeting of SWI/SNF subunits can elicit opportunities for synthetic lethality and reduce T cell exhaustion. In summary, alongside the significance of SWI/SNF subunits in predicting immunotherapy outcomes, their ability to modulate the tumor immune landscape offers opportunities for therapeutic intervention.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2244
bioRxiv. 2024 Jan 02. pii: 2024.01.02.573710. [Epub ahead of print]

FinaleMe: Predicting DNA methylation by the fragmentation patterns of plasma cell-free DNA.

Yaping Liu, Sarah C Reed, Christopher Lo, Atish D Choudhury, Heather A Parsons, Daniel G Stover, Gavin Ha, Gregory Gydush, Justin Rhoades, Denisse Rotem, Samuel Freeman, David Katz, Ravi Bandaru, Haizi Zheng, Hailu Fu, Viktor A Adalsteinsson, Manolis Kellis.

Analysis of DNA methylation in cell-free DNA (cfDNA) reveals clinically relevant biomarkers but requires specialized protocols and sufficient input material that limits its applicability. Millions of cfDNA samples have been profiled by genomic sequencing. To maximize the gene regulation information from the existing dataset, we developed FinaleMe, a non-homogeneous Hidden Markov Model (HMM), to predict DNA methylation of cfDNA and, therefore, tissues-of-origin directly from plasma whole-genome sequencing (WGS). We validated the performance with 80 pairs of deep and shallow-coverage WGS and whole-genome bisulfite sequencing (WGBS) data.

DOI: https://doi.org/10.1101/2024.01.02.573710
Res Sq. 2024 Jan 11. pii: rs.3.rs-3443805. [Epub ahead of print]

Pan-cancer copy number variant analysis identifies optimized size thresholds and co-occurrence models for individualized risk-stratification.

David Raleigh, Minh Nguyen, William Chen, Naomi Zakimi, Kanish Mirchia, Calixto-Hope Lucas.

Chromosome instability leading to accumulation of copy number gains or losses is a hallmark of cancer. Copy number variant (CNV) signatures are increasingly used for clinical risk-stratification, but size thresholds for defining CNVs are variable and the biological or clinical implications of CNV size heterogeneity or co-occurrence patterns are incompletely understood. Here we analyze CNV and clinical data from 565 meningiomas and 9,885 tumors from The Cancer Genome Atlas (TCGA) to develop tumor- and chromosome-specific CNV size-dependent and co-occurrence models for clinical outcomes. Our results reveal prognostic CNVs with optimized size thresholds and co-occurrence patterns that refine risk-stratification across a diversity of human cancers.

DOI: https://doi.org/10.21203/rs.3.rs-3443805/v1
Curr Oncol. 2024 Jan 13. 31(1): 482-500

Plasma Cell-Free Tumor Methylome as a Biomarker in Solid Tumors: Biology and Applications.

Danielle Benedict Sacdalan, Sami Ul Haq, Benjamin H Lok.

  DNA methylation is a fundamental mechanism of epigenetic control in cells and its dysregulation is strongly implicated in cancer development. Cancers possess an extensively hypomethylated genome with focal regions of hypermethylation at CPG islands. Due to the highly conserved nature of cancer-specific methylation, its detection in cell-free DNA in plasma using liquid biopsies constitutes an area of interest in biomarker research. The advent of next-generation sequencing and newer computational technologies have allowed for the development of diagnostic and prognostic biomarkers that utilize methylation profiling to diagnose disease and stratify risk. Methylome-based predictive biomarkers can determine the response to anti-cancer therapy. An additional emerging application of these biomarkers is in minimal residual disease monitoring. Several key challenges need to be addressed before cfDNA-based methylation biomarkers become fully integrated into practice. The first relates to the biology and stability of cfDNA. The second concerns the clinical validity and generalizability of methylation-based assays, many of which are cancer type-specific. The third involves their practicability, which is a stumbling block for translating technologies from bench to clinic. Future work on developing pan-cancer assays with their respective validities confirmed using well-designed, prospective clinical trials is crucial in pushing for the greater use of these tools in oncology.

Keywords:  5-methylcytosine; DNA methylation; biomarkers; cell-free DNA; liquid biopsy

DOI:  https://doi.org/10.3390/curroncol31010033
Int J Mol Sci. 2024 Jan 06. pii: 752. [Epub ahead of print]25(2):

Biology and Development of DNA-Targeted Drugs, Focusing on Synthetic Lethality, DNA Repair, and Epigenetic Modifications for Cancer: A Review.

Kiyotaka Watanabe, Nobuhiko Seki.

  DNA-targeted drugs constitute a specialized category of pharmaceuticals developed for cancer treatment, directly influencing various cellular processes involving DNA. These drugs aim to enhance treatment efficacy and minimize side effects by specifically targeting molecules or pathways crucial to cancer growth. Unlike conventional chemotherapeutic drugs, recent discoveries have yielded DNA-targeted agents with improved effectiveness, and a new generation is anticipated to be even more specific and potent. The sequencing of the human genome in 2001 marked a transformative milestone, contributing significantly to the advancement of targeted therapy and precision medicine. Anticipated progress in precision medicine is closely tied to the continuous development in the exploration of synthetic lethality, DNA repair, and expression regulatory mechanisms, including epigenetic modifications. The integration of technologies like circulating tumor DNA (ctDNA) analysis further enhances our ability to elucidate crucial regulatory factors, promising a more effective era of precision medicine. The combination of genomic knowledge and technological progress has led to a surge in clinical trials focusing on precision medicine. These trials utilize biomarkers for identifying genetic alterations, molecular profiling for potential therapeutic targets, and tailored cancer treatments addressing multiple genetic changes. The evolving landscape of genomics has prompted a paradigm shift from tumor-centric to individualized, genome-directed treatments based on biomarker analysis for each patient. The current treatment strategy involves identifying target genes or pathways, exploring drugs affecting these targets, and predicting adverse events. This review highlights strategies incorporating DNA-targeted drugs, such as PARP inhibitors, SLFN11, methylguanine methyltransferase (MGMT), and ATR kinase.

Keywords:  ATR kinase; DNA-targeted drugs; MGMT; PARP inhibitors; SLFN11; epigenetic modification; next generation sequencing; targeted therapy

DOI:  https://doi.org/10.3390/ijms25020752
Drug Discov Today. 2024 Jan 18. pii: S1359-6446(24)00014-X. [Epub ahead of print] 103889

Spatial transcriptomics data and analytical methods: An updated perspective.

Danishuddin, Shawez Khan, Jong Joo Kim.

  Spatial transcriptomics (ST) is a newly emerging field that integrates high-resolution imaging and transcriptomic data to enable the high-throughput analysis of the spatial localization of transcripts in diverse biological systems. The rapid progress in this field necessitates the development of innovative computational methods to effectively tackle the distinct challenges posed by the analysis of ST data. These platforms, integrating AI techniques, offer a promising avenue for understanding disease mechanisms and expediting drug discovery. Despite significant advances in the development of ST data analysis techniques, there is an ongoing need to enhance these models for increased biological relevance. In this review, we briefly discuss the ST-related databases and current deep-learning-based models for spatial transcriptome data analyses and highlight their roles and future perspectives in biomedical applications.

Keywords:  deep learning; disease modeling; spatial omics databases; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.drudis.2024.103889
Cancer Cell. 2024 Jan 24. pii: S1535-6108(24)00006-0. [Epub ahead of print]

Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes.

Simon Heeke, Carl M Gay, Marcos R Estecio, Hai Tran, Benjamin B Morris, Bingnan Zhang, Ximing Tang, Maria Gabriela Raso, Pedro Rocha, Siqi Lai, Edurne Arriola, Paul Hofman, Veronique Hofman, Prasad Kopparapu, Christine M Lovly, Kyle Concannon, Luana Guimaraes De Sousa, Whitney Elisabeth Lewis, Kimie Kondo, Xin Hu, Azusa Tanimoto, Natalie I Vokes, Monique B Nilsson, Allison Stewart, Maarten Jansen, Ildikó Horváth, Mina Gaga, Vasileios Panagoulias, Yael Raviv, Danny Frumkin, Adam Wasserstrom, Aharona Shuali, Catherine A Schnabel, Yuanxin Xi, Lixia Diao, Qi Wang, Jianjun Zhang, Peter Van Loo, Jing Wang, Ignacio I Wistuba, Lauren A Byers, John V Heymach.

  Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.

Keywords:  DNA methylation; SCLC; biomarker; cfDNA; ctDNA; epigenetics; gene expression; liquid biopsy; lung cancer; subtyping

DOI:  https://doi.org/10.1016/j.ccell.2024.01.001
Nat Rev Clin Oncol. 2024 Jan 26.

BRAF - a tumour-agnostic drug target with lineage-specific dependencies.

Aphrothiti J Hanrahan, Ziyu Chen, Neal Rosen, David B Solit.

In June 2022, the FDA granted Accelerated Approval to the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib for the treatment of adult and paediatric patients (≥6 years of age) with unresectable or metastatic BRAFV600E-mutant solid tumours, except for BRAFV600E-mutant colorectal cancers. The histology-agnostic approval of dabrafenib plus trametinib marks the culmination of two decades of research into the landscape of BRAF mutations in human cancers, the biochemical mechanisms underlying BRAF-mediated tumorigenesis, and the clinical development of selective RAF and MEK inhibitors. Although the majority of patients with BRAFV600E-mutant tumours derive clinical benefit from BRAF inhibitor-based combinations, resistance to treatment develops in most. In this Review, we describe the biochemical basis for oncogenic BRAF-induced activation of MAPK signalling and pan-cancer and lineage-specific mechanisms of intrinsic, adaptive and acquired resistance to BRAF inhibitors. We also discuss novel RAF inhibitors and drug combinations designed to delay the emergence of treatment resistance and/or expand the population of patients with BRAF-mutant cancers who benefit from molecularly targeted therapies.

DOI: https://doi.org/10.1038/s41571-023-00852-0
Ann Oncol. 2024 Jan 18. pii: S0923-7534(24)00010-3. [Epub ahead of print]

Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor resistant advanced breast cancer.

E Harvey-Jones, M Raghunandan, L Robbez-Masson, L Magraner-Pardo, T Alaguthurai, A Yablonovitch, J Yen, H Xiao, R Brough, J Frankum, F Song, J Yeung, T Savy, A Gulati, J Alexander, H Kemp, C Starling, A Konde, R Marlow, M Cheang, P Proszek, M Hubank, M Cai, J Trendell, R Lu, R Liccardo, N Ravindran, A Llop-Guevara, O Rodriguez, J Balmana, N Lukashchuk, M Dorschner, L Drusbosky, I Roxanis, V Serra, S Haider, S J Pettitt, C J Lord, A N J Tutt.

   BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple preclinically-validated mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease is unclear, as is how to target resistance.
PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was performed in 47 patients with metastatic BRCA1, BRCA2 or PALB2 mutant breast cancer treated with HRD-targeted therapy and developed progressive disease - 18 patients had primary resistance, 29 exhibited response followed by resistance. ctDNA isolated at multiple timepoints in the patient treatment course (before, on-treatment, and at progression) was sequenced using a novel >750 gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess functional RAD51 status.
RESULTS: BRCA1/2 reversion mutations were present in 60% of patients as the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA prior to clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen prior to commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional HRD based on RAD51 status. Although less frequent than reversions, non-reversion mechanisms (loss of function mutations in TP53BP1, RIF1 or PAXIP1) were evident in patients with acquired resistance and occasionally co-existed with reversions, challenging the notion that singular resistance mechanisms emerge in each patient.
CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Keywords:  Breast Cancer; Drug resistance; Homologous Recombination Deficiency (HRD); Liquid Biopsy; PARP inhibitors; Platinum

DOI:  https://doi.org/10.1016/j.annonc.2024.01.003
Front Immunol. 2023 ;14 1292166

Limitations and potential of immunotherapy in ovarian cancer.

Sandeep Kumar, Sayanti Acharya, Mahalakshmi Karthikeyan, Priyobrata Biswas, Sudha Kumari.

  Ovarian cancer (OC) is the third most common gynecological cancer and alone has an emergence rate of approximately 308,069 cases worldwide (2020) with dire survival rates. To put it into perspective, the mortality rate of OC is three times higher than that of breast cancer and it is predicted to only increase significantly by 2040. The primary reasons for such a high rate are that the physical symptoms of OC are detectable only during the advanced phase of the disease when resistance to chemotherapies is high and around 80% of the patients that do indeed respond to chemotherapy initially, show a poor prognosis subsequently. This highlights a pressing need to develop new and effective therapies to tackle advanced OC to improve prognosis and patient survival. A major advance in this direction is the emergence of combination immunotherapeutic methods to boost CD8+ T cell function to tackle OC. In this perspective, we discuss our view of the current state of some of the combination immunotherapies in the treatment of advanced OC, their limitations, and potential approaches toward a safer and more effective response.

Keywords:  T cells; checkpoint inhibitors; immunosuppression; immunotherapy; ovarian cancer

DOI:  https://doi.org/10.3389/fimmu.2023.1292166