bims-ovdlit 2021-05-30 papers

Clin Transl Med. 2021 May;11(5): e399

Identification of biomarkers complementary to homologous recombination deficiency for improving the clinical outcome of ovarian serous cystadenocarcinoma.

Zhiwen Shi, Qingguo Zhao, Bin Lv, Xinyu Qu, Xiao Han, Hongyan Wang, Junjun Qiu, Keqin Hua.

Ovarian cancer patients with homologous recombination deficiency (HRD) tumors would benefit from PARP inhibitor (PARPi) therapy. However, patients with HRD tumors account for less than 50% of the whole cohort, so new biomarkers still need to be developed. Based on the data from the SNP array and somatic mutation profiles in the ovarian cancer genome, we found that high frequency of actionable mutations existed in patients with non-HRD tumors. Through transcriptome analysis, we identified that a downstream target of the cGAS-STING pathway, CXCL11, was upregulated in HRD tumors and could be used as a predictor of survival outcome. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that CXCL11 expression signature was closely correlated with cytotoxic cells, neoantigen load and immune checkpoint blockade (ICB). Clinical trial data confirmed that the expression of CXCL11 could be used as a biomarker for anti-PD-1/PD-L1 therapy. Finally, in vivo and in vitro experiments showed that cancer cells with PARPi treatment increased the expression of CXCL11. Collectively, our study not only provides biomarkers of ovarian cancer complementary to the HRD score but also introduces a potential new perspective for identifying prognostic biomarkers of immunotherapy.

Keywords: CXCL11; HRD; PARPi; TIME; cGAS-STING; ovarian cancer

DOI: https://doi.org/10.1002/ctm2.399

Nat Commun. 2021 May 28. 12(1): 3230

Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden.

Sequencing of cell-free DNA in the blood of cancer patients (liquid biopsy) provides attractive opportunities for early diagnosis, assessment of treatment response, and minimally invasive disease monitoring. To unlock liquid biopsy analysis for pediatric tumors with few genetic aberrations, we introduce an integrated genetic/epigenetic analysis method and demonstrate its utility on 241 deep whole-genome sequencing profiles of 95 patients with Ewing sarcoma and 31 patients with other pediatric sarcomas. Our method achieves sensitive detection and classification of circulating tumor DNA in peripheral blood independent of any genetic alterations. Moreover, we benchmark different metrics for cell-free DNA fragmentation analysis, and we introduce the LIQUORICE algorithm for detecting circulating tumor DNA based on cancer-specific chromatin signatures. Finally, we combine several fragmentation-based metrics into an integrated machine learning classifier for liquid biopsy analysis that exploits widespread epigenetic deregulation and is tailored to cancers with low mutation rates. Clinical associations highlight the potential value of cfDNA fragmentation patterns as prognostic biomarkers in Ewing sarcoma. In summary, our study provides a comprehensive analysis of circulating tumor DNA beyond recurrent genetic aberrations, and it renders the benefits of liquid biopsy more readily accessible for childhood cancers.

DOI: https://doi.org/10.1038/s41467-021-23445-w

J Obstet Gynaecol Res. 2021 May 25.

Precision medicine for hereditary tumors in gynecologic malignancies.

Masayuki Sekine, Takayuki Enomoto.

Genomic medicine for gynecologic tumors is characterized by hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). Poly ADP-ribose polymerase (PARP) inhibitor, olaparib, and the immune checkpoint inhibitor, pembrolizumab, which are drugs that show sensitivity to each hereditary tumor, have begun to spread in clinical practice for gynecologic malignancies. In clinical use, platinum sensitivity is used as a clinical surrogate marker for olaparib sensitivity, and microsatellite instability is used as a biological surrogate marker for pembrolizumab sensitivity. BRCA genetic testing and microsatellite instability test have been used as companion diagnostics before starting olaparib and pembrolizumab treatment, respectively. Homologous recombination deficiency test could be used for companion diagnostic of olaparib combination with bevacizumab in first-line maintenance treatment and niraparib without re-administration of platinum agents in the treatment of recurrence. The approval of the three drugs has been changing the treatment of gynecologic malignancies. Furthermore, preventive medical care has been covered by insurance since April 2020 for breast and/or ovarian cancer patients with germline BRCA1/2 mutation in Japan. This review article outlines the current status and future prospects of precision medicine for gynecologic hereditary tumors focusing on HBOC and LS.

Keywords: Hereditary Tumor; Hereditary breast and ovarian cancer; Lynch syndrome; PARP inhibitor; Risk-reducing surgery

DOI: https://doi.org/10.1111/jog.14861

Nat Commun. 2021 May 24. 12(1): 3032

Detecting and phasing minor single-nucleotide variants from long-read sequencing data.

Zhixing Feng, Jose C Clemente, Brandon Wong, Eric E Schadt.

Cellular genetic heterogeneity is common in many biological conditions including cancer, microbiome, and co-infection of multiple pathogens. Detecting and phasing minor variants play an instrumental role in deciphering cellular genetic heterogeneity, but they are still difficult tasks because of technological limitations. Recently, long-read sequencing technologies, including those by Pacific Biosciences and Oxford Nanopore, provide an opportunity to tackle these challenges. However, high error rates make it difficult to take full advantage of these technologies. To fill this gap, we introduce iGDA, an open-source tool that can accurately detect and phase minor single-nucleotide variants (SNVs), whose frequencies are as low as 0.2%, from raw long-read sequencing data. We also demonstrate that iGDA can accurately reconstruct haplotypes in closely related strains of the same species (divergence ≥0.011%) from long-read metagenomic data.

DOI: https://doi.org/10.1038/s41467-021-23289-4

Cell Rep. 2021 May 25. pii: S2211-1247(21)00507-6. [Epub ahead of print]35(8): 109165

Characterizing the tumor microenvironment of metastatic ovarian cancer by single-cell transcriptomics.

Susan Olalekan, Bingqing Xie, Rebecca Back, Heather Eckart, Anindita Basu.

Understanding the cellular composition of the tumor microenvironment and the interactions of the cells is essential to the development of successful immunotherapies in cancer. We perform single-cell RNA sequencing (scRNA-seq) of 9,885 cells isolated from the omentum in 6 patients with ovarian cancer and identify 9 major cell types, including cancer, stromal, and immune cells. Transcriptional analysis of immune cells stratifies our patient samples into 2 groups: (1) high T cell infiltration (high Tinf) and (2) low T cell infiltration (low Tinf). TOX-expressing resident memory CD8+ T (CD8+ Trm) and granulysin-expressing CD4+ T cell clusters are enriched in the high Tinf group. Concurrently, we find unique plasmablast and plasma B cell clusters, and finally, NR1H2+IRF8+ and CD274+ macrophage clusters, suggesting an anti-tumor response in the high Tinf group. Our scRNA-seq study of metastatic tumor samples provides important insights in elucidating the immune response within ovarian tumors.

Keywords: human cancer; immune cells; metastasis; ovarian cancer; scRNA-seq; solid tumor; transcriptomics

DOI: https://doi.org/10.1016/j.celrep.2021.109165

Nat Commun. 2021 May 27. 12(1): 3199

Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer.

In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer's mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.

DOI: https://doi.org/10.1038/s41467-021-23394-4