bims-tumhet 2024-12-01 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2024–12–01
nine papers selected by
Sergio Marchini, Humanitas Research

Beyond HRD status: Unraveling Genetic Variants Impacting PARP Inhibitor Sensitivity in Advanced Ovarian Cancer.
Homologous recombination deficiency testing in patients with high grade ovarian cancer: factors influencing test success.
Serous Tubal Intraepithelial Carcinoma (STIC): A Review of the Literature on the Incidence at the Time of Prophylactic Surgery.
Cancer liquid biopsies by Oxford Nanopore Technologies sequencing of cell-free DNA: from basic research to clinical applications.
Characterizing the evolutionary dynamics of cancer proliferation in single-cell clones with SPRINTER.
Genetic and therapeutic heterogeneity shape the baseline and longitudinal immune ecosystem of ovarian clear cell carcinoma.
Biomarkers in high grade serous ovarian cancer.
Metabolomics of Papanicolaou Tests for the Discovery of Ovarian Cancer Biomarkers.
LINE-1 cfDNA Methylation as an Emerging Biomarker in Solid Cancers.

Cancer Res Commun. 2024 Nov 26.

Beyond HRD status: Unraveling Genetic Variants Impacting PARP Inhibitor Sensitivity in Advanced Ovarian Cancer.

Maj K Kjeldsen, Morten Jørgensen, Dina Sofie B Grønseth, Martin Schønemann-Lund, Gitte-Bettina Nyvang, Charlotte Aaquist Haslund, Anja Oer Knudsen, Anne Krejbjerg Motavaf, Susanne Malander, Maarit Anttila, Gabriel Lindahl, Johanna Mäenpää, Maria Dimoula, Theresa L Werner, Trine Zeeberg Iversen, Sakari Hietanen, Lars Fokdal, Hanna Dahlstrand, Line Bjorge, Michael J Birrer, Mansoor R Mirza, Maria Rossing.

The management of advanced ovarian cancer (AOC) has undergone significant advancements with the emergence of molecular diagnostics, particularly in predicting responses to poly(ADP-ribose) polymerase inhibitors (PARPi) based on homologous recombination deficiency (HRD) status. However, understanding sensitivity and resistance beyond HRD status remains elusive. This study aims to explore molecular factors that may elucidate why HRD status does not consistently predict PARPi sensitivity. Therefore, we conducted a post hoc translational analysis of formalin-fixed paraffin-embedded tumor samples from the ENGOT-ov24/NSGO-AVANOVA part 1 and 2 trial (AVANOVA1&2; NCT02354131), focusing on alterations pertaining radiological response and progression-free survival (PFS). DNA sequencing was performed using the TruSight Oncology 500 HT gene panel, with variants classified according to recent guidelines. HRD status had been assessed by Myriad MyChoice® CDx. We identified, among 92 patients in the AVANOVA1&2 trial, 151 pathogenic or likely pathogenic variants across 81 samples. PARPi sensitizing variants were found in two out of ten HRDneg samples from patients with clinical benefit (PFS ≥ 12 months), while three out of ten HRDpos samples from patients having no benefit (PFS ≤ 6 months) harbored variants associated with PARPi resistance. Additionally, analysis of BRCA1 variants revealed that truncating variants in exon 11 correlated with clinical benefit when niraparib was combined with bevacizumab. Conclusively, our findings highlight the complexity of PARPi response in AOC and underscore the importance of exploring somatic variants beyond HRD status. Further investigation into exon 11 variants of BRCA1 and the potential of combination treatment is warranted.

DOI: https://doi.org/10.1158/2767-9764.CRC-24-0294
Future Oncol. 2024 Nov 29. 1-7

Homologous recombination deficiency testing in patients with high grade ovarian cancer: factors influencing test success.

Ashton Hunt, Daria Ditri, Ankit Chadha, Georgina Keogh, Jack Thompson, Will Loughborough, Iain McNeish, Jonathan Krell, Jacqueline McDermott, Laura Tookman, Sadaf Ghaem-Maghami.

   INTRODUCTION: Testing for tumor BRCA mutations and homologous recombination deficiency (HRD) is recommended for all patients with advanced high-grade epithelial ovarian cancer. Delays in the HRD testing process can significantly affect the treatment offered to patients.
METHODS: HRD testing pathways and sampling processes were analyzed for tests sent from a tertiary gynae-oncology referral center between December 2020 and January 2023.
RESULTS: A total of 148 hRD tests were performed in 125 patients. The overall success rate of HRD testing was 69.6%. The success rates of obtaining results were: from diagnostic image-guided biopsy 66.7% (n = 40/60), at primary surgery 91.5% (n = 42/47), and at interval debulking surgery 51.2% (n = 21/41). The use of a larger 16-gauge needle used at image-guided biopsy produced a 100% success rate. Of 148 tests carried out, the median time for result was 28 days (range 14-158 days), with only 27% returned results in 21 or fewer days. In successful tests, 44.7% were classified as HRD-positive. 97% of patients with HRD-positive tumors treated at the center received a PARP inhibitor as part of their first-line maintenance treatment.
CONCLUSIONS: By optimizing the factors affecting HRD test success, we can obtain faster results and offer patients appropriate treatment at earlier time points to improve patient outcomes.

Keywords:  BRCA1; BRCA2; HRD; Ovarian cancer; PARPi; genetic mutation; genomic testing

DOI:  https://doi.org/10.1080/14796694.2024.2433412
Diagnostics (Basel). 2024 Nov 16. pii: 2577. [Epub ahead of print]14(22):

Serous Tubal Intraepithelial Carcinoma (STIC): A Review of the Literature on the Incidence at the Time of Prophylactic Surgery.

Daniela Luvero, Roberto Angioli, Erika Notaro, Francesco Plotti, Corrado Terranova, Anna Maria Angioli, Asia Festa, Andi Stermasi, Serena Manco, Miriana Diserio, Roberto Montera.

   BACKGROUND: Serous tubal intraepithelial carcinoma (STIC) is an early-stage cancerous lesion found in the fallopian tubes, often at the fimbrial end. It is strongly associated with high-grade serous carcinoma (HGSC), a highly aggressive type of ovarian cancer. STIC is considered a precursor to many HGSC cases, originating in the fallopian tubes. Its development is frequently linked to mutations in the TP53 gene, leading to the formation of a p53 signature, an early abnormality that may progress to HGSC. This signature is more common in BRCA mutation carriers, explaining the higher incidence of STIC in this group. The aim of this review is to evaluate the literature on the incidence of serous tubal intraepithelial carcinoma in patients (both BRCA-positive and BRCA-negative) undergoing preventive salpingo-oophorectomy, analysing the available data and identifying associations between specific characteristics and the onset of STIC.
METHODS: A comprehensive review of the literature from 2016 to 2023 was conducted using PubMed, focusing on studies analysing the incidence of STIC in BRCA-positive patients undergoing preventive salpingo-oophorectomy. Data on patient characteristics, interventions, outcomes, and incidence of STIC were extracted and analysed.
RESULTS: Nine international studies were included in the review, reporting varying incidences of STIC among patients undergoing salpingo-oophorectomy. The overall incidence of STIC in all the women included in the studies was 7.31%, while that in the BRCA-mutated women was approximately 6.08%. Notably, the presence of the TP53 signature was significantly associated with the occurrence of STIC.
CONCLUSIONS: The etiopathogenesis of STIC involves complex interactions between genetic, environmental, and molecular factors. Further research is needed to fully understand its mechanisms and identify additional risk factors beyond BRCA mutations. Establishing a national database of STIC cases could facilitate future research and improve patient outcomes.

Keywords:  BRCA mutations; HGSC; STIC; ovarian cancer; prophylactic surgery

DOI:  https://doi.org/10.3390/diagnostics14222577
Mol Cancer. 2024 Nov 29. 23(1): 265

Cancer liquid biopsies by Oxford Nanopore Technologies sequencing of cell-free DNA: from basic research to clinical applications.

Hua-Qi Si, Peng Wang, Fei Long, Wei Zhong, Yuan-Dong Meng, Yuan Rong, Xiang-Yu Meng, Fu-Bing Wang.

  Liquid biopsies, in particular, analysis of cell-free DNA, are expected to revolutionize the current landscape of cancer diagnostics and treatment. However, the existing methods for cfDNA-based liquid biopsies for cancer have certain limitations, such as fragment interruption and GC bias, which are likely to be resolved by the emerging Oxford Nanopore Technologies (ONT), characterized by long read-length, fast read-times, high throughput, and polymerase chain reaction-free. In this review, we summarized the current literatures regarding the feasibility and applications of cfDNA-based liquid biopsies using ONT for cancer management, a possible game-changer that we believe is promising in detecting multimodal biomarkers and can be applied in a wide range of oncology utilities including early screening, diagnosis, and treatment monitoring.

Keywords:  Cell-free DNA; Diagnosis; Liquid biopsies; Oncology; Oxford Nanopore Technologies; Personalized medicine

DOI:  https://doi.org/10.1186/s12943-024-02178-6
Nat Genet. 2024 Nov 29.

Characterizing the evolutionary dynamics of cancer proliferation in single-cell clones with SPRINTER.

TRACERx Consortium

Proliferation is a key hallmark of cancer, but whether it differs between evolutionarily distinct clones co-existing within a tumor is unknown. We introduce the Single-cell Proliferation Rate Inference in Non-homogeneous Tumors through Evolutionary Routes (SPRINTER) algorithm that uses single-cell whole-genome DNA sequencing data to enable accurate identification and clone assignment of S- and G2-phase cells, as assessed by generating accurate ground truth data. Applied to a newly generated longitudinal, primary-metastasis-matched dataset of 14,994 non-small cell lung cancer cells, SPRINTER revealed widespread clone proliferation heterogeneity, orthogonally supported by Ki-67 staining, nuclei imaging and clinical imaging. We further demonstrated that high-proliferation clones have increased metastatic seeding potential, increased circulating tumor DNA shedding and clone-specific altered replication timing in proliferation- or metastasis-related genes associated with expression changes. Applied to previously generated datasets of 61,914 breast and ovarian cancer cells, SPRINTER revealed increased single-cell rates of different genomic variants and enrichment of proliferation-related gene amplifications in high-proliferation clones.

DOI: https://doi.org/10.1038/s41588-024-01989-z
J Immunother Cancer. 2024 Nov 27. pii: e010069. [Epub ahead of print]12(11):

Genetic and therapeutic heterogeneity shape the baseline and longitudinal immune ecosystem of ovarian clear cell carcinoma.

Siyu Xia, Lihua Chen, Min Yu, Jiana Li, Jiaxin Chen, Fei Xu, Mengdong Ni, Chaohua Liu, Xiaohua Wu, Xiaojun Chen, Jiajia Li.

   BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a rare and chemo-resistant subtype of ovarian cancer. While immunotherapy has demonstrated effectiveness in some OCCC cases, the mechanisms for heterogeneous immunoreactivity and potential combinatory strategies remain unclear.
METHODS: Tumor samples from 13 patients with OCCC underwent single-cell mRNA-seq and TCR-seq to generate 1 40 683 cells transcriptome, while additionally 31 formalin-fixed paraffin-embedded samples were used for immunohistochemistry. Spatial transcriptomics of two OCCC samples and bulk RNA-seq of 58 patients were incorporated for spatial and interpatient level explorations. Serum tumor markers and radiologic images of three patients with OCCC who received combinatory VEGF and PD-1 inhibition were retrospectively analyzed.
RESULTS: OCCC exhibited a dynamic immune architecture shaped by genetic and therapeutic pressure. ARID1A mutation linked to baseline immune activation, correlated with an enrichment of neoantigen-reactive CXCL13+ CTLA4+ CD8+ T cells (p<0.001) and enhanced FASLG-FAS interactions. Recurrent OCCC was fibrotic, angiogenic, and immunosuppressive, exhibiting metabolic reprogramming towards activated activity in fatty acid metabolism. High CD36 (log-rank p=0.012, HR: 4.515) and CD47 expression (log-rank p=0.037, HR: 3.246) indicated worse progression-free survival. Treatment with bevacizumab increased intratumoral T cell infiltration and activated T cell interferon-γ signaling. Retrospective analysis of clinical cases revealed that combination therapy with anti-VEGF (vascular endothelial growth factor) and anti-PD-1 agents exerted clinical benefits in patients with OCCC with persistent, recurrent, and metastatic disease.
CONCLUSIONS: ARID1A mutation correlated with OCCC baseline immune activation. Stromal reconstruction and tumor metabolic reprogramming functioned as key processes of OCCC dynamic progression. VEGF inhibition remodeled OCCC stroma, restored T cell function and potentiated immunotherapy. CD36 and CD47 might be potential therapeutic targets for recurrent OCCC.

Keywords:  combination therapy; escape/evasion; immunotherapy; ovarian cancer; tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2024-010069
Biochim Biophys Acta Rev Cancer. 2024 Nov 22. pii: S0304-419X(24)00155-0. [Epub ahead of print] 189224

Biomarkers in high grade serous ovarian cancer.

Mark Bates, Bashir M Mohamed, Faye Lewis, Sharon O'Toole, John J O'Leary.

  High-grade serous ovarian cancer (HGSC) is the most common subtype of ovarian cancer. HGSC patients typically present with advanced disease, which is often resistant to chemotherapy and recurs despite initial responses to therapy, resulting in the poor prognosis associated with this disease. There is a need to utilise biomarkers to manage the various aspects of HGSC patient care. In this review we discuss the current state of biomarkers in HGSC, focusing on the various available immunohistochemical (IHC) and blood-based biomarkers, which have been examined for their diagnostic, prognostic and theranostic potential in HGSC. These include various routine clinical IHC biomarkers such as p53, WT1, keratins, PAX8, Ki67 and p16 and clinical blood-borne markers and algorithms such as CA125, HE4, ROMA, RMI, ROCA, and others. We also discuss various components of the liquid biopsy as well as a number of novel IHC biomarkers and non-routine blood-borne biomarkers, which have been examined in various ovarian cancer studies. We also discuss the future of ovarian cancer biomarker research and highlight some of the challenges currently facing the field.

Keywords:  Biomarkers; Diagnostics; Inflammation; Liquid biopsy; Ovarian cancer; Prognostics; Senescence; Theranostics

DOI:  https://doi.org/10.1016/j.bbcan.2024.189224
Metabolites. 2024 Nov 07. pii: 600. [Epub ahead of print]14(11):

Metabolomics of Papanicolaou Tests for the Discovery of Ovarian Cancer Biomarkers.

Samyukta Sah, Elisabeth M Schwiebert, Samuel G Moore, Ying Liu, David A Gaul, Kristin L M Boylan, Amy P N Skubitz, Facundo M Fernández.

  Background: Ovarian cancer (OC) remains one of the most lethal cancers among women due to most cases going undiagnosed until later stages. The early detection and treatment of this malignancy provides the best prognosis, but the lack of an accurate and sensitive screening tool combined with ambiguous symptoms hinders these diagnoses. In contrast, screening for cervical cancer via Papanicolaou (Pap) tests is a widespread practice that greatly reduces the cancer's mortality rates. Interestingly, previous studies show evidence of OC cells in Pap tests, suggesting that proteins, and potentially lipids, shed from ovarian tumors end up in the cervix. The goal of this study is to evaluate the practicality of using Pap tests as biospecimens for OC-screening-related metabolomics. Methods: To evaluate the effectiveness of using residual Pap test samples as biospecimens for potential metabolomics work, 29 Pap test samples, collected from women over the age of 50 with normal cytology and no visible blood contamination, were first obtained from the University of Minnesota, with IRB approval. These samples were centrifuged to recover the cell pellets from the supernatants. The cell pellets underwent a biphasic extraction, followed by an RP-LC-MS analysis, while the supernatants underwent two separate extractions and analyses, including RP-LC-MS and HILIC-LC-MS. Non-targeted features were detected in the range of 220-1000 m/z to determine the sensitivity and scope of the various extraction and analytical workflows, as well as evaluating residual Pap test samples as viable metabolomics biospecimens. Results: The biphasic extraction and subsequent RP-LC-MS analysis of the isolated cell pellets from all 29 samples yielded informative, exploratory data, highlighting the potential of using residual Pap test samples as biospecimens for metabolomics, specifically lipidomics, studies. Each sample was analyzed in both the positive and negative ion mode, yielding the detection of 7318 in the positive ion mode and 3733 in the negative ion mode. Using multiple reference libraries, 22.85% and 36.19% of these features were annotated in the positive and negative ion mode, respectively. Among these detected features, 453 unique lipids, representative of 20 different lipid subclasses, were annotated in all 29 samples. Of the various lipid subclasses represented from the detected lipids, ceramides, triacylglycerols, hexosylceramides, and phosphatidylcholines contributed to over half (53.3%) of the detected lipids at 16.2%, 13.0%, 12.8%, and 11.3%, respectively. Conclusions: The detection of these 453 common lipids across all patients establishes a relative lipidome baseline for women over the age of 50 with normal cervical cytology. This exploratory study is the first investigation to utilize residual Pap test samples as biospecimens in a metabolomics/lipidomics workflow.

Keywords:  Papanicolaou (Pap) tests; liquid chromatography (LC); mass spectrometry (MS); ovarian cancer (OC)

DOI:  https://doi.org/10.3390/metabo14110600
Cancers (Basel). 2024 Nov 05. pii: 3725. [Epub ahead of print]16(22):

LINE-1 cfDNA Methylation as an Emerging Biomarker in Solid Cancers.

Ugur Gezer, Emre Özgür, Ebru E Yörüker, Eleni Polatoglou, Stefan Holdenrieder, Abel Bronkhorst.

  Epigenetic dysregulation is a hallmark of many human malignancies, with DNA methylation being a primary mechanism influencing gene expression and maintaining genomic stability. Genome-wide hypomethylation, characteristic of many cancers, is partly attributed to the demethylation of repetitive elements, including LINE-1, a prevalent non-LTR retrotransposon. The methylation status of LINE-1 is closely associated with overall genomic methylation levels in tumors. cfDNA comprises extracellular DNA fragments found in bodily fluids such as plasma, serum, and urine, offering a dynamic snapshot of the genetic and epigenetic landscape of tumors. This real-time sampling provides a minimally invasive avenue for cancer diagnostics, prognostics, and monitoring. The methylation status of LINE-1 in cfDNA has emerged as a promising biomarker, with several studies highlighting its potential in diagnosing and predicting outcomes in cancer patients. Recent research also suggests that cfDNA-based LINE-1 methylation analysis could serve as a valuable tool in evaluating the efficacy of cancer therapies, including immunotherapy. The growing clinical significance of cfDNA calls for a closer examination of its components, particularly repetitive elements like LINE-1. Despite their importance, the role of LINE-1 elements in cfDNA has not been thoroughly gauged. We aim to address this gap by reviewing the current literature on LINE-1 cfDNA assays, focusing on their potential applications in diagnostics and disease monitoring.

Keywords:  biomarkers; cfDNA; clinical oncology; ctDNA; liquid biopsy

DOI:  https://doi.org/10.3390/cancers16223725