bims-tumhet 2021-08-29 papers

bims-tumhet

Biomed News

on Tumor Heterogeneity

Issue of 2021–08–29
eight papers selected by
Sergio Marchini, Humanitas Research

Direct comparisons of bisulfite pyrosequencing versus targeted bisulfite sequencing.
Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management.
PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer.
Utility of Homologous Recombination Deficiency Biomarkers Across Cancer Types.
A nuclear polymorphism at the 8q24 region is associated with improved survival time and chemo-response in high-grade serous ovarian cancer.
Leveraging Genomics, Transcriptomics, and Epigenomics to Understand the Biology and Chemoresistance of Ovarian Cancer.
Clinical Utility of Liquid Biopsy-Based Actionable Mutations Detected via ddPCR.
Immune checkpoint inhibitors in ovarian cancer: where do we stand?

MicroPubl Biol. 2021 ;2021

Direct comparisons of bisulfite pyrosequencing versus targeted bisulfite sequencing.

Dillon E King, A Clare Sparling, Rashmi Joglekar, Joel N Meyer, Susan K Murphy.

DNA methylation is an important epigenetic mechanism involved in proper genome function. Bisulfite pyrosequencing (PSQ) is a commonly used technique to quantify DNA methylation. Although very accurate, bisulfite pyrosequencing can be expensive and time consuming for large-scale quantitative DNA methylation analysis at the single nucleotide level. High throughput DNA methylation sequencing has the potential to address these limitations, but its comparability to other methylation detection methods has not been well studied. We compared QIAseq Targeted Methyl Panel technologies (QMS) and PSQ by analyzing four CpG sites within four genes involved in neurodevelopment. QMS and PSQ had an average 5.6% difference in the detected level of DNA methylation for the same four CpG sites. However, we observed a strong correlation in the levels of methylation across all four CpG sites between the two technologies. These findings demonstrate the comparability of QMS relative to PSQ in the ability to accurately quantify DNA methylation at specific CpG sites.

DOI: https://doi.org/10.17912/micropub.biology.000444
Semin Cancer Biol. 2021 Aug 18. pii: S1044-579X(21)00217-0. [Epub ahead of print]

Platinum-resistant ovarian cancer: From drug resistance mechanisms to liquid biopsy-based biomarkers for disease management.

Mohammad Aslam Khan, Kunwar Somesh Vikramdeo, Sarabjeet Kour Sudan, Seema Singh, Annelise Wilhite, Santanu Dasgupta, Rodney Paul Rocconi, Ajay Pratap Singh.

  Resistance to platinum-based chemotherapy is a major clinical challenge in ovarian cancer, contributing to the high mortality-to-incidence ratio. Management of the platinum-resistant disease has been difficult due to diverse underlying molecular mechanisms. Over the past several years, research has revealed several novel molecular targets that are being explored as biomarkers for treatment planning and monitoring of response. The therapeutic landscape of ovarian cancer is also rapidly evolving, and alternative therapies are becoming available for the recurrent platinum-resistant disease. This review provides a snapshot of platinum resistance mechanisms and discusses liquid-based biomarkers and their potential utility in effective management of platinum-resistant ovarian cancer.

Keywords:  Biomarkers; DNA repair; Epigenetic; Liquid biopsy; Ovarian cancer; Platinum drugs; Platinum resistance

DOI:  https://doi.org/10.1016/j.semcancer.2021.08.005
Int J Mol Sci. 2021 Aug 07. pii: 8506. [Epub ahead of print]22(16):

PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer.

Kristie-Ann Dickson, Tao Xie, Christian Evenhuis, Yue Ma, Deborah J Marsh.

  Several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are now in clinical use for tumours with defects in BReast CAncer genes BRCA1 or BRCA2 that result in deficient homologous recombination repair (HRR). Use of olaparib, niraparib or rucaparib for the treatment of high-grade serous ovarian cancer, including in the maintenance setting, has extended both progression free and overall survival for women with this malignancy. While different PARP inhibitors (PARPis) are mechanistically similar, differences are apparent in their chemical structures, toxicity profiles, PARP trapping abilities and polypharmacological landscapes. We have treated ovarian cancer cell line models of known BRCA status, including the paired cell lines PEO1 and PEO4, and UWB1.289 and UWB1.289+BRCA1, with five PARPis (olaparib, niraparib, rucaparib, talazoparib and veliparib) and observed differences between PARPis in both cell viability and cell survival. A cell line model of acquired resistance to veliparib showed increased resistance to the other four PARPis tested, suggesting that acquired resistance to one PARPi may not be able to be rescued by another. Lastly, as a proof of principle, HRR proficient ovarian cancer cells were sensitised to PARPis by depletion of BRCA1. In the future, guidelines will need to emerge to assist clinicians in matching specific PARPis to specific patients and tumours.

Keywords:  BRCA1; BRCA2; PARP inhibitor; homologous recombination repair; niraparib; olaparib; rucaparib; talazoparib; veliparib

DOI:  https://doi.org/10.3390/ijms22168506
JCO Precis Oncol. 2021 Aug;pii: PO.21.00141. [Epub ahead of print]5

Utility of Homologous Recombination Deficiency Biomarkers Across Cancer Types.

Shiro Takamatsu, J B Brown, Ken Yamaguchi, Junzo Hamanishi, Koji Yamanoi, Hisamitsu Takaya, Tomoko Kaneyasu, Seiichi Mori, Masaki Mandai, Noriomi Matsumura.

Homologous recombination DNA repair deficiency (HRD) is associated with sensitivity to platinum and poly (ADP-ribose) polymerase inhibitors in certain cancer types, including breast, ovarian, pancreatic, and prostate. In these cancers, BRCA1/2 alterations and genomic scar signatures are useful indicators for assessing HRD. However, alterations in other homologous recombination repair (HRR)-related genes and their clinical significance in other cancer types have not been adequately and systematically investigated.
METHODS: We obtained data sets of all solid tumors in The Cancer Genome Atlas and Cancer Cell Line Encyclopedia, and comprehensively analyzed HRR pathway gene alterations, their loss-of-heterozygosity status, and per-sample genomic scar scores, that is, the HRD score and mutational signature 3 ratio, DNA methylation profiles, gene expression profiles, somatic TP53 mutations, sex, and clinical or in vitro response to chemical exposure.
RESULTS: Biallelic alterations in HRR genes other than BRCA1/2 were also associated with elevated genomic scar scores. The association between HRR-related gene alterations and genomic scar scores differed significantly by sex and the presence of somatic TP53 mutations. HRD tumors determined by a combination of indices also showed HRD features in gene expression analysis and exhibited significantly higher sensitivity to DNA-damaging agents than non-HRD cases in both clinical samples and cell lines.
CONCLUSION: This study provides evidence for the usefulness of HRD analysis in all cancer types, improves chemotherapy decision making and its efficacy in clinical settings, and represents a substantial advancement in precision oncology.A comprehensive pan-cancer analysis on the clinical significance of homologous recombination deficiency.

DOI: https://doi.org/10.1200/PO.21.00141
Oncol Lett. 2021 Oct;22(4): 733

A nuclear polymorphism at the 8q24 region is associated with improved survival time and chemo-response in high-grade serous ovarian cancer.

Danielle Ikoma, Nicholas Cardillo, Eric Devor, Jesus Gonzalez-Bosquet.

  The 8q24 chromosomal region is strongly associated with an increased risk of ovarian cancer. One single nucleotide polymorphism that is associated with ovarian cancer in this region is rs6983267, located within the long non-coding RNA colon cancer associated transcript 2 (CCAT2). The aim of the present study was to assess the association between rs6983267 and clinical outcomes in patients with high-grade serous ovarian cancer (HGSOC). The present retrospective genetic association study utilized Sanger sequencing to determine the genotype at the rs6983267 locus (GG, GT, TT) in 98 patients with HGSOC. Survival time and chemotherapy responses between patients were compared with the TT genotype and patients with a genotype containing a G allele (GT, GG). Survival analyses were performed using Cox proportional hazard ratio analysis. Association with chemo-response was performed using a logistic regression. The results revealed that patients with HGSOC and the TT genotype at the rs6983267 locus had improved survival time compared with patients with genotypes containing a G allele [hazard ratio=0.59; 95% confidence interval (CI), 0.36-0.97; P=0.039] and were significantly associated with International Federation of Gynecology and Obstetrics stage [odds ratio (OR)=5.34; 95% CI, 1.50-22.62; P=0.014] and positive chemo-response (OR=4.51; 95% CI, 1.40-18.00; P=0.018). In summary, patients with HGSOC and the TT genotype at the rs6983267 locus had improved survival time compared with those with a G allele, despite being associated with more advanced disease; this was possibly due to an improved response to chemotherapy.

Keywords:  chromosome 8q24; colon cancer associated transcript 2; high-grade serous ovarian cancer; long non-coding RNA; rs6983267 single nucleotide polymorphism

DOI:  https://doi.org/10.3892/ol.2021.12994
Cancers (Basel). 2021 Aug 10. pii: 4029. [Epub ahead of print]13(16):

Leveraging Genomics, Transcriptomics, and Epigenomics to Understand the Biology and Chemoresistance of Ovarian Cancer.

Sandra Muñoz-Galván, Amancio Carnero.

  Ovarian cancer is a major cause of fatality due to a gynecological malignancy. This lethality is largely due to the unspecific clinical manifestations of ovarian cancer, which lead to late detection and to high resistance to conventional therapies based on platinum. In recent years, we have advanced our understanding of the mechanisms provoking tumor relapse, and the advent of so-called omics technologies has provided exceptional tools to evaluate molecular mechanisms leading to therapy resistance in ovarian cancer. Here, we review the contribution of genomics, transcriptomics, and epigenomics techniques to our knowledge about the biology and molecular features of ovarian cancers, with a focus on therapy resistance. The use of these technologies to identify molecular markers and mechanisms leading to chemoresistance in these tumors is discussed, as well as potential further applications.

Keywords:  chemoresistance; epigenomics; genomics; ovarian cancer; transcriptomic

DOI:  https://doi.org/10.3390/cancers13164029
Biomedicines. 2021 Jul 28. pii: 906. [Epub ahead of print]9(8):

Clinical Utility of Liquid Biopsy-Based Actionable Mutations Detected via ddPCR.

Irina Palacín-Aliana, Noemí García-Romero, Adrià Asensi-Puig, Josefa Carrión-Navarro, Víctor González-Rumayor, Ángel Ayuso-Sacido.

  Cancer is one of the leading causes of death worldwide and remains a major public health challenge. The introduction of more sensitive and powerful technologies has permitted the appearance of new tumor-specific molecular aberrations with a significant cancer management improvement. Therefore, molecular pathology profiling has become fundamental not only to guide tumor diagnosis and prognosis but also to assist with therapeutic decisions in daily practice. Although tumor biopsies continue to be mandatory in cancer diagnosis and classification, several studies have demonstrated that liquid biopsies could be used as a potential tool for the detection of cancer-specific biomarkers. One of the main advantages is that circulating free DNA (cfDNA) provides information about intra-tumoral heterogeneity, reflecting dynamic changes in tumor burden. This minimally invasive tool has become an accurate and reliable instrument for monitoring cancer genetics. However, implementing liquid biopsies across the clinical practice is still ongoing. The main challenge is to detect genomic alterations at low allele fractions. Droplet digital PCR (ddPCR) is a powerful approach that can overcome this issue due to its high sensitivity and specificity. Here we explore the real-world clinical utility of the liquid biopsy ddPCR assays in the most diagnosed cancer subtypes.

Keywords:  breast cancer; cancer biomarkers; colorectal cancer; ddPCR; liquid biopsy; lung cancer; pancreatic cancer

DOI:  https://doi.org/10.3390/biomedicines9080906
Ther Adv Med Oncol. 2021 ;13 17588359211039899

Immune checkpoint inhibitors in ovarian cancer: where do we stand?

Alexandra Leary, David Tan, Jonathan Ledermann.

  Numerous retrospective studies have demonstrated that the density of intra-tumoral immune cell infiltration is prognostic in epithelial ovarian cancer (OC). These observations together with reports of programmed death ligand-1 (PD-L1) expression in advanced OC provided the rationale for investigating the benefit of programmed death-1 (PD1) or PD-L1 inhibition in OC. Unfortunately clinical trials to date evaluating PD1/PD-L1 inhibition in patients with relapsed OC have been disappointing. In this review we will discuss early results from single agent PD1/PD-L1 inhibitors and the strategies to enhance benefit from immune-oncology agents in OC, including proposing anti-PD-L1 in combination with other agents (cytotoxics, anti-angiogenics, poly(ADP-ribose) polymerase. (PARP) inhibitors, targeted therapies or other immunotherapies), as well as evaluating these agents earlier in the disease course, or in biomarker selected patients.

Keywords:  PARP inhibitors; anti-angiogenic; combinations; immune checkpoint inhibitors; ovarian cancer; predictive biomarkers

DOI:  https://doi.org/10.1177/17588359211039899