bims-tumhet 2023-05-14 papers

Issue of 2023–05–14
seven papers selected by
Sergio Marchini, Humanitas Research

Elife. 2023 May 11. pii: e83867. [Epub ahead of print]12

High-grade serous ovarian carcinoma organoids as models of chromosomal instability.

Maria Vias, Lena Morrill Gavarró, Carolin M Sauer, Deborah A Sanders, Anna M Piskorz, Dominique-Laurent Couturier, Stéphane Ballereau, Bárbara Hernando, Michael P Schneider, James Hall, Filipe Correia-Martins, Florian Markowetz, Geoff Macintyre, James D Brenton.

High-grade serous ovarian carcinoma (HGSOC) is the most genomically complex cancer, characterized by ubiquitous TP53 mutation, profound chromosomal instability, and heterogeneity. The mutational processes driving chromosomal instability in HGSOC can be distinguished by specific copy number signatures. To develop clinically relevant models of these mutational processes we derived 15 continuous HGSOC patient-derived organoids (PDOs) and characterized them using bulk transcriptomic, bulk genomic, single-cell genomic, and drug sensitivity assays. We show that HGSOC PDOs comprise communities of different clonal populations and represent models of different causes of chromosomal instability including homologous recombination deficiency, chromothripsis, tandem-duplicator phenotype, and whole genome duplication. We also show that these PDOs can be used as exploratory tools to study transcriptional effects of copy number alterations as well as compound-sensitivity tests. In summary, HGSOC PDO cultures provide validated genomic models for studies of specific mutational processes and precision therapeutics.

Keywords: cancer biology; chromosomal instability; genetics; genomics; high-grade serous ovarian cancer; human; organoids

DOI: https://doi.org/10.7554/eLife.83867

Curr Opin Pharmacol. 2023 May 04. pii: S1471-4892(23)00034-6. [Epub ahead of print]70 102381

Targeting DNA damage repair precision medicine strategies in cancer.

Juliette Brownlie, Sanat Kulkarni, Mashael Algethami, Jennie N Jeyapalan, Nigel P Mongan, Emad A Rakha, Srinivasan Madhusudan.

DNA repair targeted therapeutics is a promising precision medicine strategy in cancer. The development and clinical use of PARP inhibitors has transformed lives for many patients with BRCA germline deficient breast and ovarian cancer as well as platinum sensitive epithelial ovarian cancers. However, lessons learnt from the clinical use of PARP inhibitors also confirm that not all patients respond either due to intrinsic or acquired resistance. Therefore, the search for additional synthetic lethality approaches is an active area of translational and clinical research. Here, we review the current clinical state of PARP inhibitors and other evolving DNA repair targets including ATM, ATR, WEE1 inhibitors and others in cancer.

DOI: https://doi.org/10.1016/j.coph.2023.102381

J Natl Cancer Inst. 2023 May 11. pii: djad080. [Epub ahead of print]

Copy number aberrations in ctDNA enables prognosis prediction and molecular characterization of breast cancer.

BACKGROUNDS: Low-pass whole-genome sequencing (LP-WGS)-based circulating tumor DNA (ctDNA) analysis is a versatile tool for somatic copy number aberration (CNA) detection, and this study aims to explore its clinical implication in breast cancer.
METHODS: We analyzed LP-WGS ctDNA data from 207 metastatic breast cancer (MBC) patients to explore prognostic value of ctDNA CNA burden, and validated it in 465 stage II-III triple-negative breast cancer (TNBC) patients who received neoadjuvant chemotherapy in phase III PEARLY trial (NCT02441933). The clinical implication of locus-level LP-WGS ctDNA profiling was further evaluated.
RESULTS: We found that a high baseline ctDNA CNA burden predicts poor overall survival and progression-free survival of MBC patients. The post-hoc analysis of PEARLY trial showed that a high baseline ctDNA CNA burden predicted poor disease-free survival independent from pathologic complete response (pCR), validating its robust prognostic significance. The 24-month disease-free survival rate was 96.9% and 55.9% in pCR (+)/Low I-score and non-pCR/High I-score patients, respectively. The locus-level ctDNA CNA profile classified MBC patients into five molecular clusters and revealed targetable oncogenic CNAs. LP-WGS ctDNA and in vitro analysis identified the BCL6 amplification as a resistance factor for CDK4/6 inhibitors. We estimated ctDNA-based homologous recombination deficiency (HRD) status of patients by shallowHRD algorithm, which was highest in the TNBC and correlated with platinum-based chemotherapy response.
CONCLUSIONS: These results demonstrate LP-WGS ctDNA CNA analysis as an essential tool for prognosis prediction and molecular profiling. Particularly, ctDNA CNA burden can serve as a useful determinant for escalating or de-escalating (neo)adjuvant strategy in TNBC patients.

Keywords: LP-WGS ctDNA analysis; breast cancer; copy number aberrations; molecular profiling; prognosis

DOI: https://doi.org/10.1093/jnci/djad080

Nat Rev Genet. 2023 May 09.

Beyond assembly: the increasing flexibility of single-molecule sequencing technology.

Paul W Hook, Winston Timp.

The maturation of high-throughput short-read sequencing technology over the past two decades has shaped the way genomes are studied. Recently, single-molecule, long-read sequencing has emerged as an essential tool in deciphering genome structure and function, including filling gaps in the human reference genome, measuring the epigenome and characterizing splicing variants in the transcriptome. With recent technological developments, these single-molecule technologies have moved beyond genome assembly and are being used in a variety of ways, including to selectively sequence specific loci with long reads, measure chromatin state and protein-DNA binding in order to investigate the dynamics of gene regulation, and rapidly determine copy number variation. These increasingly flexible uses of single-molecule technologies highlight a young and fast-moving part of the field that is leading to a more accessible era of nucleic acid sequencing.

DOI: https://doi.org/10.1038/s41576-023-00600-1

Nat Genet. 2023 May;55(5): 820-831

Genetic immune escape landscape in primary and metastatic cancer.

Francisco Martínez-Jiménez, Peter Priestley, Charles Shale, Jonathan Baber, Erik Rozemuller, Edwin Cuppen.

Studies have characterized the immune escape landscape across primary tumors. However, whether late-stage metastatic tumors present differences in genetic immune escape (GIE) prevalence and dynamics remains unclear. We performed a pan-cancer characterization of GIE prevalence across six immune escape pathways in 6,319 uniformly processed tumor samples. To address the complexity of the HLA-I locus in the germline and in tumors, we developed LILAC, an open-source integrative framework. One in four tumors harbors GIE alterations, with high mechanistic and frequency variability across cancer types. GIE prevalence is generally consistent between primary and metastatic tumors. We reveal that GIE alterations are selected for in tumor evolution and focal loss of heterozygosity of HLA-I tends to eliminate the HLA allele, presenting the largest neoepitope repertoire. Finally, high mutational burden tumors showed a tendency toward focal loss of heterozygosity of HLA-I as the immune evasion mechanism, whereas, in hypermutated tumors, other immune evasion strategies prevail.

DOI: https://doi.org/10.1038/s41588-023-01367-1

Am J Clin Pathol. 2023 May 11. pii: aqad046. [Epub ahead of print]

Diagnostic utility of DNA integrity number as an indicator of sufficient DNA quality in next-generation sequencing-based genomic profiling.

Kaho Hiramatsu, Chiaki Matsuda, Katsuhiro Masago, Kazuhiro Toriyama, Eiichi Sasaki, Yasuko Fujita, Masataka Haneda, Hiromichi Ebi, Noriko Shibata, Waki Hosoda.

OBJECTIVES: DNA integrity number (DIN) is a metric for assessing DNA degradation, calculated based on electrophoresis using the Agilent TapeStation System. The utility of DIN as a diagnostic indicator of sufficient DNA quality in clinical next-generation sequencing (NGS) has not been well described.
METHODS: We evaluated the DINs of 166 tumor formalin-fixed, paraffin-embedded (FFPE) tissue samples submitted for 124-gene panel sequencing. We also investigated a new metric on the electropherogram that could improve the predictive accuracy of the DIN.
RESULTS: A DIN cutoff of 2.5 discriminated samples with successful analysis (n = 143) from samples with failed analysis (n = 23), with a sensitivity of 0.84 and a specificity of 0.78 (area under the curve [AUC] = 0.88). The DIN was positively correlated with the mean coverage (r = 0.72, P < .0001) but could not discriminate success from failure when the DIN was below 2.5 (negative predictive value, 0.44). We introduced a new metric, the peak/base ratio, that distinguished success from failure with higher accuracy than the DIN (cutoff = 1.6; sensitivity = 0.98, specificity = 0.83, and AUC =0.96).
CONCLUSIONS: To predict successful NGS, the DNA quality of FFPE tissue can be easily and reliably assessed using the DIN and peak/base ratio.

Keywords: DNA degradation; DNA integrity number (DIN); electrophoresis; formalin-fixed; next-generation sequencing (NGS); paraffin-embedded tissue; peak/base ratio

DOI: https://doi.org/10.1093/ajcp/aqad046

Epigenetics Chromatin. 2023 May 11. 16(1): 17

Loss of CpG island immunity to DNA methylation induced by mutation.

Bernhard Horsthemke, Adrian Bird.

The inheritance of acquired traits in mammals is a highly controversial topic in biology. Recently, Takahashi et al. (Cell 186:715-731, 2023) have reported that insertion of CpG-free DNA into a CpG island (CGI) can induce DNA methylation of the CGI and that this aberrant methylation pattern can be transmitted across generations, even after removal of the foreign DNA. These results were interpreted as evidence for transgenerational inheritance of acquired DNA methylation patterns. Here, we discuss several interpretational issues raised by this study and consider alternative explanations.

Keywords: Acquired characters; CpG island; DNA methylation; Epigenetics; Mutation; Transgenerational inheritance

DOI: https://doi.org/10.1186/s13072-023-00488-5