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Integrative single-cell multiomics analyses dissect molecular signatures of intratumoral heterogeneities and differentiation states of human gastric cancer

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National Science Review 2023年第6期10卷 96-107页

作者： Shuhui Bian Yicheng Wang Yuan Zhou Wendong Wang Limei Guo Lu Wen Wei Fu Xin Zhou Fuchou Tang Biomedical Pioneering Innovation Center School of Life Sciences Department of General Surgery Third Hospital Peking University State Key Laboratory of Reproductive Medicine and Offspring Health Nanjing Medical University Collaborative Innovation Center for Cancer Personalized Medicine Nanjing Medical University Beijing Advanced Innovation Center for Genomics (ICG) Ministry of Education Key Laboratory of Cell Proliferation and Differentiation Department of Pathology Peking University Third Hospital School of Basic Medical Science Peking University Health Science Center Peking University Third Hospital Cancer Center Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary Studies Peking University

Human gastric cancer is a highly lethal disease,but the underlying multiomic mole cular signatures remain largely uncle ar.Here,we performed multi-regional sampling,parallel single-cell multiomics sequencing and integrated analyses of human gastric cancer.We identified common transcrip tomic alterations of gastric cancer cells,such as aberrant down-regulation of genes associated with normal stomach function and up-regulation of KRT7,PI3,S100A4,etc.Surprisingly,aberrant and prevalent up-regulation of genes highly expressed in normal colorectal epithelial cells were also identified in cancer cells,which maybe partially regulated by promoter chromatin accessibility and DNA methylation levels.We reve aled the single-cell DNA methylome landscape of gastric cancer,and identified candidate DNA methylation biomarkers,such as hypermethylated promoters of TMEM240 and HAGLROS,and hypomethylated promoters of TRPM2-AS and HRH1.Additionally,the relationships between genetic lineages,D NA methylation and transcriptomic clusters were systematically revealed at single-cell level.We showed that DNA methylation heterogeneities were mainly among different genetic lineages of cancer cells.Moreover,we found that D NA methylation levels of cancer cells with poorer differentiation states tend to be higher than those of cancer cells with better differentiation states in the primary tumor within the same patient,although still lower than in normal gastric epithelial cells.Cancer cells with poorer differentiation states also prevalently down-regulated MUC1 expression and immune-related pathways,and had poor infiltration of CD 8+T cells.Our study dissected the mole cular signatures of intratumoral heterogeneities and differentiation states of human gastric cancer using integrative single-cell multiomics analyses.

关键词： gastric cancer single-cell multiomics analysis intratumoral heterogeneity tumor differentiation

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Potential unreliability of ALK variant allele frequency in the efficacy prediction of targeted therapy in NSCLC

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Frontiers of Medicine 2023年第3期17卷 493-502页

作者： Wei Rao Yutao Liu Yan Li Lei Guo Tian Qiu Lin Dong Jianming Ying Weihua Li Department of Pathology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of Medical Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China

Anaplastic lymphoma kinase(ALK)is the most common fusion gene involved in non-small cell lung cancer(NSCLC),and remarkable response has been achieved with the use of ALK tyrosine kinase inhibitors(ALK-TKIs).However,the clinical efficacy is highly variable.Pre-existing intratumoral heterogeneity(ITH)has been proven to contribute to the poor treatment response and the resistance to targeted therapies.In this work,we investigated whether the variant allele frequencies(VAFs)of ALK fusions can help assess ITH and predict targeted therapy efficacy.Through the application of next-generation sequencing(NGS),7.2%(326/4548)of patients were detected to be ALK positive.On the basis of the adjusted VAF(adjVAF,VAF normalization for tumor purity)of four different threshold values(adjVAF<50%,40%,30%,or 20%),the association of ALK subclonality with crizotinib efficacy was assessed.Nonetheless,no statistical association was observed between median progression-free survival(PFS)and ALK subclonality assessed by adjVAF,and a poor correlation of adjVAF with PFS was found among the 85 patients who received first-line crizotinib.Results suggest that the ALK VAF determined by hybrid capture-based NGS is probably unreliable for ITH assessment and targeted therapy efficacy prediction in NSCLC.

关键词： ALK fusion next-generation sequencing fluorescence in situ hybridization immunohistochemistry variant allele frequency intratumoral heterogeneity targeted therapy

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Very large hidden genetic diversity in one single tumor:evidence for tumors-in-tumor

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National Science Review 2022年第12期9卷 124-134页

作者： Bingjie Chen Xianrui Wu Yongsen Ruan Yulin Zhang Qichun Cai Luis Zapata Chung-I Wu Ping Lan Haijun Wen State Key Laboratory of Biocontrol School of Life Sciences Sun Yat-sen University GMU-GIBH Joint School of Life Sciences Guangzhou Medical University Evolutionary Genomics and Modelling Lab Centre for Evolution and Cancer The Institute of Cancer Research Department of Colorectal Surgery The Sixth Affiliated Hospital Sun Yat-sen University Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases The Sixth Affiliated Hospital Sun Yat-sen University Cancer Center Clifford HospitalJinan University

Despite the concern of within-tumor genetic diversity,this diversity is in fact limited by the kinship among cells in the tumor.Indeed,genomic studies have amply supported the ’Nowell dogma’ whereby cells of the same tumor descend from a single progenitor cell.In parallel,genomic data also suggest that the diversity could be> 10-fold larger if tumor cells are of multiple origins.We develop an evolutionary hypothesis that a single tumor may often harbor multiple cell clones of independent origins,but only one would be large enough to be detected.To test the hypothesis,we search for independent tumors within a larger one(or tumors-in-tumor).Very high density sampling was done on two cases of colon tumors.Case 1 indeed has 13 independent clones of disparate sizes,many having heavy mutation burdens and potentially highly tumorigenic.In Case 2,despite a very intensive search,only two small independent clones could be found.The two cases show very similar movements and metastasis of the dominant clone.Cells initially move actively in the expanding tumor but become nearly immobile in late stages.In conclusion,tumors-in-tumor are plausible but could be very demanding to find.Despite their small sizes,they can enhance the within-tumor diversity by orders of magnitude.Such increases may contribute to the missing genetic diversity associated with the resistance to cancer therapy.

关键词： intratumoral heterogeneity tumor origins cancer evolution tumors-in-tumor

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Mechanisms of acquired resistance of BRCA1/2-driven tumors to platinum compounds and PARP inhibitors

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World Journal of Clinical Oncology 2021年第7期12卷 544-556页

作者： Evgeny Imyanitov Anna Sokolenko Department of Tumor Growth Biology N.N.Petrov Institute of OncologySaint-Petersburg 197758Russia Department of Medical Genetics St.-Petersburg Pediatric Medical UniversitySaint-Petersburg 194100Russia Department of Oncology I.I.Mechnikov North-Western Medical UniversitySaint-Petersburg 191015Russia

Molecular pathogenesis of tumors arising in BRCA1/2 germ-line mutation carriers usually includes somatic inactivation of the remaining allele of the involved gene.Consequently,BRCA1/2-driven cancers are sensitive to platinum-based therapy and poly(ADP-ribose)polymerase inhibitors(PARPi).Long-term exposure to these drugs may result in the emergence of secondary BRCA1/2 mutations,which restore the open-reading frame of the affected allele.This platinum/PARPi crossresistance mechanism applies both for BRCA1 and BRCA2 genes and has been repeatedly validated in various laboratory models and multiple clinical studies.There are some other routes associated with the partial rescue of BRCA1/2 function or the development of BRCA1/2-independent pathways for genomic maintenance;however,their actual clinical relevance remains to be established.In addition,studies on the short-term neoadjuvant therapy for ovarian cancer revealed that even chemonaive BRCA1-driven tumors contain a small proportion of BRCA1-proficient cells.These pre-existing cells with retained BRCA1 heterozygosity rapidly repopulate the tumor mass during platinum exposure,but become outcompeted by BRCA1-deficient cells during therapy holidays.Understanding of the platinum/PARPi resistance pathways has led to the development of novel therapeutic approaches,which aim to improve the management of BRCA1/2-related cancers and are currently undergoing preclinical and clinical evaluation.

关键词： BRCA1/2 mutations Platinum-based therapy Poly(ADP-ribose)polymerase inhibitors Drug resistance Secondary mutations intratumoral heterogeneity Neoadjuvant therapy

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Unmasking tumor heterogeneity and clonal evolution by single-cell analysis

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Journal of Cancer Metastasis and Treatment 2018年第1期4卷 548-566页

作者： Xiaoshan Shi Papia Chakraborty Amitabha Chaudhuri MedGenome Inc. Foster CityCalifornia 94404USA

The intratumoral heterogeneity orchestrated by the tumor intrinsic and extrinsic mechanisms enable cancers to persist and spread notwithstanding the use of aggressive interventional therapies.The heterogeneity is revealed at multiple levels-at the level of individual tumor cells,in the cellular composition of tumor infiltrates and in the chemical microenvironment in which the cells reside.Deconvoluting the complex nature of the cell types present in the tumor,along with the homo and heterotypic interactions between different cell types can produce novel insights of biological and clinical relevance.However,most techniques analyze tumors at a gross level missing key inter-cell-type genotypic and phenotypic differences.The advent of single-cell sequencing has given an unprecedented opportunity to analyze the tumor at a resolution that not only captures the diversity of the cellular composition of a tumor but also provides information on the genetic,epigenetic and functional states of different cell types.In this review,we summarize the genesis of tumor heterogeneity,its impact on tumor growth and progression and their clinical consequences.We present an overview of the currently available platforms for isolation and sequencing of single tumor cells and provide evidence of its utility in precision medicine and personalized therapy.

关键词： intratumoral heterogeneity single-cell sequencing clonal evolution circulating tumor cells drug resistance

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