bims-tumhet 2022-01-09 papers

Issue of 2022–01–09
six papers selected by
Sergio Marchini, Humanitas Research

Front Oncol. 2021 ;11 754524

Perspectives on PARP Inhibitor Combinations for Ovarian Cancer.

Renata Colombo Bonadio, Maria Del Pilar Estevez-Diz.

Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors' efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.

Keywords: DNA repair; PARP inhibitor; combinations; homologous recombination; ovarian cancer

DOI: https://doi.org/10.3389/fonc.2021.754524

BMC Cancer. 2022 Jan 03. 22(1): 13

Landscape of homologous recombination deficiencies in solid tumours: analyses of two independent genomic datasets.

Zhongwu Lai, Matthew Brosnan, Ethan S Sokol, Mingchao Xie, Jonathan R Dry, Elizabeth A Harrington, J Carl Barrett, Darren Hodgson.

BACKGROUND: DNA repair deficiencies are characteristic of cancer and homologous recombination deficiency (HRD) is the most common. HRD sensitizes tumour cells to PARP inhibitors so it is important to understand the landscape of HRD across different solid tumour types.
METHODS: Germline and somatic BRCA mutations in breast and ovarian cancers were evaluated using sequencing data from The Cancer Genome Atlas (TCGA) database. Secondly, a larger independent genomic dataset was analysed to validate the TCGA results and determine the frequency of germline and somatic mutations across 15 different candidate homologous recombination repair (HRR) genes, and their relationship with the genetic events of bi-allelic loss, loss of heterozygosity (LOH) and tumour mutation burden (TMB).
RESULTS: Approximately one-third of breast and ovarian cancer BRCA mutations were somatic. These showed a similar degree of bi-allelic loss and clinical outcomes to germline mutations, identifying potentially 50% more patients that may benefit from precision treatments. HRR mutations were present in sizable proportions in all tumour types analysed and were associated with high TMB and LOH scores. We also identified numerous BRCA reversion mutations across all tumour types.
CONCLUSIONS: Our results will facilitate future research into the efficacy of precision oncology treatments, including PARP and immune checkpoint inhibitors.

Keywords: Breast; Genomic loss of heterozygosity; Germline; Homologous recombination deficiency; Homologous recombination repair; Immune checkpoint inhibitors; Loss of function; Ovarian; PARP inhibitors; Somatic; cancer

DOI: https://doi.org/10.1186/s12885-021-09082-y

Front Oncol. 2021 ;11 772604

Inferring Homologous Recombination Deficiency of Ovarian Cancer From the Landscape of Copy Number Variation at Subchromosomal and Genetic Resolutions.

Meng Zhang, Si-Cong Ma, Jia-Le Tan, Jian Wang, Xue Bai, Zhong-Yi Dong, Qing-Xue Zhang.

Background: Homologous recombination deficiency (HRD) is characterized by overall genomic instability and has emerged as an indispensable therapeutic target across various tumor types, particularly in ovarian cancer (OV). Unfortunately, current detection assays are far from perfect for identifying every HRD patient. The purpose of this study was to infer HRD from the landscape of copy number variation (CNV).
Methods: Genome-wide CNV landscape was measured in OV patients from the Australian Ovarian Cancer Study (AOCS) clinical cohort and >10,000 patients across 33 tumor types from The Cancer Genome Atlas (TCGA). HRD-predictive CNVs at subchromosomal resolution were identified through exploratory analysis depicting the CNV landscape of HRD versus non-HRD OV patients and independently validated using TCGA and AOCS cohorts. Gene-level CNVs were further analyzed to explore their potential predictive significance for HRD across tumor types at genetic resolution.
Results: At subchromosomal resolution, 8q24.2 amplification and 5q13.2 deletion were predominantly witnessed in HRD patients (both p < 0.0001), whereas 19q12 amplification occurred mainly in non-HRD patients (p < 0.0001), compared with their corresponding counterparts within TCGA-OV. The predictive significance of 8q24.2 amplification (p < 0.0001), 5q13.2 deletion (p = 0.0056), and 19q12 amplification (p = 0.0034) was externally validated within AOCS. Remarkably, pan-cancer analysis confirmed a cross-tumor predictive role of 8q24.2 amplification for HRD (p < 0.0001). Further analysis of CNV in 8q24.2 at genetic resolution revealed that amplifications of the oncogenes, MYC (p = 0.0001) and NDRG1 (p = 0.0004), located on this fragment were also associated with HRD in a pan-cancer manner.
Conclusions: The CNV landscape serves as a generalized predictor of HRD in cancer patients not limited to OV. The detection of CNV at subchromosomal or genetic resolution could aid in the personalized treatment of HRD patients.

Keywords: biomarker; chromosome; copy number variation; homologous recombination deficiency; ovarian cancer

DOI: https://doi.org/10.3389/fonc.2021.772604

Mol Oncol. 2022 Jan 02.

Genome-wide DNA methylation profiling and identification of potential pan-cancer and tumor-specific biomarkers.

Joe Ibrahim, Ken Op de Beeck, Erik Fransen, Marc Peeters, Guy Van Camp.

DNA methylation alterations have already been linked to cancer, and their usefulness for therapy and diagnosis has encouraged research into the human epigenome. Several biomarker studies have focused on identifying cancer types individually, yet common cancer and multi-cancer markers are still underexplored. We used The Cancer Genome Atlas (TCGA) to investigate genome-wide methylation profiles of 14 different cancer types and developed a three-step computational approach to select candidate biomarker CpG sites. In total, 1,991 pan-cancer and between 75 and 1,803 cancer-specific differentially methylated CpG sites were discovered. Differentially methylated blocks and regions were also discovered for the first time on such a large-scale. Through a three-step computational approach, a combination of four pan-cancer CpG markers was identified from these sites and externally validated (AUC = 0.90), maintaining comparable performance across tumor stages. Additionally, 20 tumor-specific CpG markers were identified and made up the final type-specific prediction model, which could accurately differentiate tumor types (AUC = 0.87-0.99). Our study highlights the power of the methylome as a rich source of cancer biomarkers, and the signatures we identified provide a new resource for understanding cancer mechanisms on the wider genomic scale with strong applicability in the context of new minimally invasive cancer detection assays.

Keywords: Biomarker; Cancer; Genome-wide analysis; Methylation; Pan-cancer; Tumor-specific

DOI: https://doi.org/10.1002/1878-0261.13176

PLoS One. 2022 ;17(1): e0262272

Detection of MDM2 amplification by shallow whole genome sequencing of cell-free DNA of patients with dedifferentiated liposarcoma.

Joanna Przybyl, Lien Spans, Kristen Ganjoo, Nam Bui, David Mohler, Jeffrey Norton, George Poultsides, Maria Debiec-Rychter, Matt van de Rijn.

High-level amplification of MDM2 and other genes in the 12q13-15 locus is a hallmark genetic feature of well-differentiated and dedifferentiated liposarcomas (WDLPS and DDLPS, respectively). Detection of this genomic aberration in plasma cell-free DNA may be a clinically useful assay for non-invasive distinction between these liposarcomas and other retroperitoneal tumors in differential diagnosis, and might be useful for the early detection of disease recurrence. In this study, we performed shallow whole genome sequencing of cell-free DNA extracted from 10 plasma samples from 3 patients with DDLPS and 1 patient with WDLPS. In addition, we studied 31 plasma samples from 11 patients with other types of soft tissue tumors. We detected MDM2 amplification in cell-free DNA of 2 of 3 patients with DDLPS. By applying a genome-wide approach to the analysis of cell-free DNA, we also detected amplification of other genes that are known to be recurrently affected in DDLPS. Based on the analysis of one patient with DDLPS with longitudinal plasma samples available, we show that tracking MDM2 amplification in cell-free DNA may be potentially useful for evaluation of response to treatment. The patient with WDLPS and patients with other soft tissue tumors in differential diagnosis were negative for the MDM2 amplification in cell-free DNA. In summary, we demonstrate the feasibility of detecting amplification of MDM2 and other DDLPS-associated genes in plasma cell-free DNA using technology that is already routinely applied for other clinical indications. Our results may have clinical implications for improved diagnosis and surveillance of patients with retroperitoneal tumors.

DOI: https://doi.org/10.1371/journal.pone.0262272