bims-ovdlit 2022-07-17 papers

Issue of 2022–07–17
six papers selected by
Lara Paracchini, Humanitas Research

Ann Oncol. 2022 Jun 09. pii: S0923-7534(22)01721-5. [Epub ahead of print]

ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group.

Circulating tumour DNA (ctDNA) assays conducted on plasma are rapidly developing a strong evidence base for use in patients with cancer. The European Society for Medical Oncology convened an expert working group to review the analytical and clinical validity and utility of ctDNA assays. For patients with advanced cancer, validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, and may be used in routine clinical practice, provided the limitations of the assays are taken into account. Tissue based testing remains the preferred test for many cancer patients, due to limitations of ctDNA assays detecting fusion events and copy number changes, although ctDNA assays may be routinely used when faster results will be clinically important, or when tissue biopsies are not possible or inappropriate. Reflex tumour testing should be considered following a non-informative ctDNA result, due to false negative results with ctDNA testing. In patients treated for early-stage cancers, detection of molecular residual disease (MRD) or molecular relapse (MR), has high evidence of clinical validity in anticipating future relapse in many cancers. MRD/MR detection cannot be recommended in routine clinical practice, as currently there is no evidence for clinical utility in directing treatment. Additional potential applications of ctDNA assays, under research development and not recommended for routine practice, include identifying patients not responding to therapy with early dynamic changes in ctDNA levels, monitoring therapy for the development of resistance mutations prior to clinical progression, and in screening asymptomatic people for cancer. Recommendation for reporting of results, future development of ctDNA assays, and future clinical research are made.

Keywords: Circulating tumour DNA (ctDNA); liquid biopsy; precision medicine

DOI: https://doi.org/10.1016/j.annonc.2022.05.520

Lancet Oncol. 2022 Jul;pii: S1470-2045(22)00408-9. [Epub ahead of print]23 Suppl 1 S9

APC mutations as a predictive marker of endometrial cancer immunotherapy: a retrospective cohort study.

Yiran Li, Yunfeng Song, Jian Huang, Kai Wang.

BACKGROUND: The APC regulator of WNT signalling pathway gene (previously known as adenomatous polyposis coli gene; APC), located on 5q22.2, is a chromatin remodelling-related gene and a typical tumour suppressor. Patients with high expression of PD-L1 or a high tumour mutational burden have been reported to benefit from immunotherapy in endometrial cancer. The objective of this study was to show that APC is a new biomarker target for the diagnosis and treatment of endometrial cancer by analysing the correlation of APC mutations with PD-L1 expression or tumour mutational burden.
METHODS: We did an integrative analysis of a commercially available panel (Burning Rock Biotech, Guangzhou, China) including 520 cancer-related genes on 99 tumour samples from an endometrial cancer cohort in China and DNA-seq data from The Cancer Genome Atlas to identify new gene mutations as endometrial cancer immunotherapy markers. To discover the effect of gene mutations on endometrial cancer, we assessed the correlation between gene mutations and tumour immune microenvironment, and explored the immune microenvironment in endometrial cancer, including tumour mutational burden, PD-L1 expression, and lymphocytic infiltration.
FINDINGS: We found that the relevant mutated genes were related to the chromatin state and generated a discovery set including 12 mutated genes that significantly correlated with PD-L1 expression and tumour mutational burden. We pinpointed the APC gene, which was mutated in 18 (18%) of 99 tumour samples, as a new potential biomarker for immunotherapy. Further analysis showed that tumours with an APC mutation had a high tumour mutational burden, increased expression of PD-L1, and increased lymphocytic infiltration. By assessing the relationship between immunotherapy biomarkers and APC, we verified that APC has inactive mutations (eg, missense mutations, truncating mutations, and a mixture of missense and truncating mutations) in endometrial cancer, which might affect the immune response, including PD-L1 expression, microsatellite instability, and lymphocytic infiltrate. From The Cancer Genome Atlas data, we also found that patients with the APC mutation had longer overall survival.
INTERPRETATION: Our study shows that APC could have an important role in enhancing the response to endometrial cancer treatment, particularly immunotherapy.
FUNDING: The study was supported by the National Natural Science Foundation of China (grant numbers 81472427, 32070583, 81672574, and 81702547), the Shanghai Health System Outstanding Talents Program (grant number 2018YQ23), the Shanghai New Frontier Technology Project (grant number SHDC12015110), and the Shanghai Municipal Medical and Health Discipline Construction Projects (grant number 2017ZZ02015).

DOI: https://doi.org/10.1016/S1470-2045(22)00408-9

Precis Clin Med. 2022 Mar;5(1): pbac002

Recent advances in single-cell sequencing technologies.

Lu Wen, Fuchou Tang.

Single-cell omics sequencing was first achieved for the transcriptome in 2009, which was followed by fast development of technologies for profiling the genome, DNA methylome, 3D genome architecture, chromatin accessibility, histone modifications, etc., in an individual cell. In this review we mainly focus on the recent progress in four topics in the single-cell omics field: single-cell epigenome sequencing, single-cell genome sequencing for lineage tracing, spatially resolved single-cell transcriptomics and third-generation sequencing platform-based single-cell omics sequencing. We also discuss the potential applications and future directions of these single-cell omics sequencing technologies for different biomedical systems, especially for the human stem cell field.

Keywords: epigenome sequencing; genome sequencing; human stem cell; lineage tracing; single-cell omics; third-generation sequencing

DOI: https://doi.org/10.1093/pcmedi/pbac002

Lancet Oncol. 2022 Jul;pii: S1470-2045(22)00414-4. [Epub ahead of print]23 Suppl 1 S15

Early detection of hepatocellular carcinoma with methylation and fragmentation signatures of circulating tumour DNA: a prospective, multicentre, case-control, observational study.

Xinrong Yang, Jian Zhou, Jia Fan, De-Zhen Guo, Ao Huang, Chengcheng Ma, Minjie Xu, Wei Li, Zhixi Su.

BACKGROUND: Hepatocellular carcinoma is one of the deadliest cancers worldwide. Early detection has been shown to enable more effective treatments, thus decreasing morbidity and mortality. Non-invasive cancer detection via circulating tumour DNA (ctDNA) has emerged as a promising approach to monitor the molecular changes in liver tumour cells. We aimed to use ctDNA methylation and fragmentation signals to develop a blood-based assay for hepatocellular carcinoma early detection, named HcSeer.
METHODS: A targeted methylation sequencing panel was designed to integrate 1601 liver cancer-informative methylation markers, on the basis of in-house data and data from the public databases The Cancer Genome Atlas and Gene Expression Omnibus. Various methylation features were constructed from methylation sequencing data, including methylation haplotype load and methylated haplotype fraction. Low-pass whole-genome sequencing data from plasma samples were also analysed at a mean sequencing depth of 10×. Fragmentomic features, such as end motif, breakpoint motif, fragmentation size ratio, and copy number variation, were extracted from whole-genome sequencing data. A two-step deep neural network model was built to classify cancer and healthy samples with selected features of both types. The robustness of entire approach was verified with a 3× cross-validation by randomly splitting samples into training set and test set at a 2:1 ratio.
FINDINGS: In the discovery phase, a case-control study was designed to develop the HcSeer assay for the early detection of hepatocellular carcinoma. A total of 401 participants were recruited (200 healthy individuals and 201 patients with hepatocellular carcinoma). Most patients with cancer were at early stages standardised by Chinese liver cancer staging (109 [54%] at stage I and 25 [12%] at stage II). The classification model of HcSeer assay was built and cross-validated to achieve an average area under the curve of 0·99 (sensitivity 94% [189 of 201; 95% CI 90-97%] and specificity 96% [192 of 200; 92-98%]). The detection accuracy was observed to increase with cancer stages, with 91% (99 of 109; 95% CI 83-95%) sensitivity for stage I, 96% (24 of 25; 77-100%) for stage II, 98% (43 of 44; 86-100%) for stage III, and 100% (23 of 23, 84-100%) for stage IV. The validation cohort is ongoing, with the aim of reaching 510 plasma samples from multiple centres, including a full spectrum of liver diseases and age-matched healthy controls. The validation phase is expected to be completed in June, 2022.
INTERPRETATION: We have developed the HcSeer assay to combine the signatures of DNA methylation and genome-wide fragmentome. In a case-control study, we showed its feasibility to detect early-stage hepatocellular carcinoma with high accuracy. We propose it as a potential aid for non-invasive diagnostics of hepatocellular carcinoma. The performance of the assay is being validated in an independent sample set collected through a multicentre study, which was approved by the Ethical Committee of Zhongshan Hospital affiliated to Fudan University (number B2020-299R).
FUNDING: This study was supported by the National Key Research and Development Program of China (grant number 2019YFC1315800).

DOI: https://doi.org/10.1016/S1470-2045(22)00414-4

Mol Oncol. 2022 Jul 14.

DNA repair as a shared hallmark in cancer and ageing.

Thomas L Clarke, Raul Mostoslavsky.

Increasing evidence demonstrates that DNA damage and genome instability play a crucial role in ageing. Mammalian cells have developed a wide range of complex and well-orchestrated DNA repair pathways to respond to and resolve the many different types of DNA lesions that occur from exogenous and endogenous sources. Defects in these repair pathways lead to accelerated or premature ageing syndromes and increase the likelihood of cancer development. Understanding the fundamental mechanisms of DNA repair will help develop novel strategies to treat ageing-related diseases. Here, we revisit the processes involved in DNA damage repair and how these can contribute to diseases, including aging and cancer. We also review recent mechanistic insights into DNA repair and discuss how these insights are being used to develop novel therapeutic strategies for treating human disease. We discuss the use of PARP inhibitors in the clinic for the treatment of breast and ovarian cancer and the challenges associated with acquired drug resistance. Finally, we discuss how DNA repair pathway-targeted therapeutics are moving beyond PARP inhibition in the search for ever more innovative and efficacious cancer therapies.

Keywords: DNA damage; ageing; cancer; genome instability; therapeutics

DOI: https://doi.org/10.1002/1878-0261.13285

Nat Genet. 2022 Jul;54(7): 996-1012

Functional landscapes of POLE and POLD1 mutations in checkpoint blockade-dependent antitumor immunity.

Defects in pathways governing genomic fidelity have been linked to improved response to immune checkpoint blockade therapy (ICB). Pathogenic POLE/POLD1 mutations can cause hypermutation, yet how diverse mutations in POLE/POLD1 influence antitumor immunity following ICB is unclear. Here, we comprehensively determined the effect of POLE/POLD1 mutations in ICB and elucidated the mechanistic impact of these mutations on tumor immunity. Murine syngeneic tumors harboring Pole/Pold1 functional mutations displayed enhanced antitumor immunity and were sensitive to ICB. Patients with POLE/POLD1 mutated tumors harboring telltale mutational signatures respond better to ICB than patients harboring wild-type or signature-negative tumors. A mutant POLE/D1 function-associated signature-based model outperformed several traditional approaches for identifying POLE/POLD1 mutated patients that benefit from ICB. Strikingly, the spectrum of mutational signatures correlates with the biochemical features of neoantigens. Alterations that cause POLE/POLD1 function-associated signatures generate T cell receptor (TCR)-contact residues with increased hydrophobicity, potentially facilitating T cell recognition. Altogether, the functional landscapes of POLE/POLD1 mutations shape immunotherapy efficacy.

DOI: https://doi.org/10.1038/s41588-022-01108-w