Publications by authors named "Yanfang Guan"

90 Publications

Lung cancer-associated T cell repertoire as potential biomarker for early detection of stage I lung cancer.

Lung Cancer 2021 Sep 28;162:16-22. Epub 2021 Sep 28.

Department of Respiratory Medicine, National Key Clinical Specialty, Branch of National Clinical Research Center for Respiratory Disease, Xiangya Hospital, Central South University, China; Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, China; Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, China; National Clinical Research Center for Geriatric Disorders, Changsha, China. Electronic address:

Background: Early detection of lung cancer in asymptomatic patients remains challenging, especially for stage I. Considering the substantial interaction with tumor immunogenicity, we hypothesized that lung cancer-associated TCR (LC-aTCR) may serve as potential biomarker in early detection of stage I lung cancer.

Methods: Individuals who received low-dose computed tomography (LDCT) screening were enrolled in the study. Surgical tissues and peripheral blood specimens were collected and performed with DNA-based T cell repertoire (TCR) sequencing. The motif-based algorithm was used to deconstruct specific lung cancer-associated TCRs (LC-aTCRs).

Results: A total of 146 individuals participating in the real-world LDCT screening project were enrolled in this study, including 52 patients with pathologically-confirmed stage I lung cancer and 94 non-cancer controls. We developed a motif-based algorithm to define 80 LC-aTCRs in the training cohort. Moreover, in the validation cohort, high sensitivity and specificity was showed in stage I lung cancer with 72% and 91% respectively, and the AUC of the ROC curve was 0.91 (95% CI: 0.85 ∼ 0.96).

Conclusion: This work provides inspiration for stage I lung cancer detection by using blood TCR profiling data. The combination of TCR-based assay and routine screening deserves further testing in larger cohorts.
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http://dx.doi.org/10.1016/j.lungcan.2021.09.017DOI Listing
September 2021

Genomic comparison between cerebrospinal fluid and primary tumor revealed the genetic events associated with brain metastasis in lung adenocarcinoma.

Cell Death Dis 2021 10 12;12(10):935. Epub 2021 Oct 12.

Department of Neurosurgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Hunan Province, Changsha, 410013, China.

Lung adenocarcinoma (LUAD) is most common pathological type of lung cancer. LUAD with brain metastases (BMs) usually have poor prognosis. To identify the potential genetic factors associated with BM, a genomic comparison for BM cerebrospinal fluid (CSF) and primary lung tumor samples obtained from 1082 early- and late-stage LUAD patients was performed. We found that single nucleotide variation (SNV) of EGFR was highly enriched in CSF (87% of samples). Compared with the other primary lung tissues, copy number gain of EGFR (27%), CDK4 (11%), PMS2 (11%), MET (10%), IL7R (8%), RICTOR (7%), FLT4 (5%), and FGFR4 (4%), and copy number loss of CDKN2A (28%) and CDKN2B (18%) were remarkably more frequent in CSF samples. CSF had significantly lower tumor mutation burden (TMB) level but more abundant copy number variant. It was also found that the relationships among co-occurrent and mutually exclusive genes were dynamically changing with LUAD development. Additionally, CSF (97% of samples) harbored more abundant targeted drugs related driver and fusion genes. The signature 15 associated with defective DNA mismatch repair (dMMR) was only identified in the CSF group. Cancer associated pathway analysis further revealed that ErbB (95%) and cell cycle (84%) were unique pathways in CSF samples. The tumor evolution analysis showed that CSF carried significantly fewer clusters, but subclonal proportion of EGFR was remarkably increased with tumor progression. Collectively, CSF sequencing showed unique genomic characteristics and the intense copy number instability associated with cell cycle disorder and dMMR might be the crucial genetic factors in BM of LUAD.
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http://dx.doi.org/10.1038/s41419-021-04223-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511004PMC
October 2021

Construction and Validation of a Platinum Sensitivity Predictive Model With Multiple Genomic Variations for Epithelial Ovarian Cancer.

Front Oncol 2021 16;11:725264. Epub 2021 Sep 16.

Department of Gynecologic Oncology, Peking University Cancer Hospital & Institute, Beijing, China.

Platinum-based chemotherapy is still the standard of care after cytoreductive surgery in the first-line treatment for epithelial ovarian cancer. This study aims to integrate novel biomarkers for predicting platinum sensitivity in EOC after initial cytoreductive surgery precisely. To this end, 60 patients were recruited from September 2014 to October 2019. Based on the duration of progress-free survival, 44 and 16 patients were assigned to platinum-sensitive and platinum-resistant group, respectively. Next generation sequencing was performed to dissect the genomic features of ovarian tumors obtained from surgery. Multiple genomic variations were compared between two groups, including single-nucleotide variant, single base or indel signature, loss of heterozygosity (LOH), whole-genome duplication (WGD), and others. The results demonstrated that patients with characteristics including positive SBS10a signature (p < 0.05), or LOH (p < 0.01), or negative WGD (p < 0.01) were significantly enriched in platinum-sensitive group. Consistently, patients with positive SBS10a signature (15.8 10.1 months, p < 0.05), or LOH (16.5 9.2 months, p < 0.05), or negative WGD (16.5 9.1 months, p < 0.05) have significantly longer PFS than those without these genetic features. By integrating these three biomarkers, a lasso regression model was employed to train and test for all patients, with the AUC value 0.864 in platinum sensitivity prediction. Notably, 388 ovarian cancer patients from TCGA dataset were leveraged as independent validation cohort with AUC value 0.808, suggesting the favorable performance and reliability of this model.
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http://dx.doi.org/10.3389/fonc.2021.725264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481766PMC
September 2021

Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer.

Nat Commun 2021 09 14;12(1):5431. Epub 2021 Sep 14.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment.
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http://dx.doi.org/10.1038/s41467-021-25787-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440529PMC
September 2021

Multiomics Analysis Reveals Distinct Immunogenomic Features of Lung Cancer with Ground-Glass Opacity.

Am J Respir Crit Care Med 2021 11;204(10):1180-1192

Department of Thoracic Surgery and.

Ground-glass opacity (GGO)-associated lung cancers are common and radiologically distinct clinical entities known to have an indolent clinical course and superior survival, implying a unique underlying biology. However, the molecular and immune characteristics of GGO-associated lung nodules have not been systemically studied. To provide mechanistic insights for the treatment of these radiologically distinct clinical entities. We initiated a prospective cohort study to collect and characterize pulmonary nodules with GGO components (nonsolid and part-solid nodules) or without GGO components, as precisely quantified by using three-dimensional image reconstruction to delineate the molecular and immune features associated with GGO. Multiomics assessment conducted by using targeted gene panel sequencing, RNA sequencing, TCR (T-cell receptor) sequencing, and circulating tumor DNA detection was performed. GGO-associated lung cancers exhibited a lower tumor mutation burden than solid nodules. Transcriptomic analysis revealed a less active immune environment in GGO components and immune pathways, decreased expression of immune activation markers, and less infiltration of most immune-cell subsets, which was confirmed by using multiplex immunofluorescence. Furthermore, T-cell repertoire sequencing revealed lower T-cell expansion in GGO-associated lung cancers. HLA loss of heterozygosity was significantly less common in lung adenocarcinomas with GGO components than in those without. Circulating tumor DNA analysis suggested that the release of tumor DNA to the peripheral blood was correlated with the tumor size of non-GGO components. Compared with lung cancers presenting with solid lung nodules, GGO-associated lung cancers are characterized by a less active metabolism and a less active immune microenvironment, which may be the mechanisms underlying their indolent clinical course. Clinical trial registered with www.clinicaltrials.gov (NCT03320044).
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http://dx.doi.org/10.1164/rccm.202101-0119OCDOI Listing
November 2021

RBM10 Deficiency Is Associated With Increased Immune Activity in Lung Adenocarcinoma.

Front Oncol 2021 21;11:677826. Epub 2021 Jul 21.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Surgery II, Peking University Cancer Hospital & Institute, Beijing, China.

Introduction: RBM10 is one of the frequently mutated genes in lung adenocarcinoma (LUAD). Previous studies have confirmed that RBM10 could suppress the disease progression and cell proliferation in LUAD, but its loss-of-function mutations are more frequent in early-stage disease and decrease with the advancement of the clinical stage. This is contradictory to its role of tumor suppressor. Here, we conducted a systematic analysis to elucidate whether there was other potential biological significance of RBM10 deficiency during the progression of LUAD.

Materials And Methods: The whole exome sequencing data of 39 tumor samples from early-stage LUADs (GGN cohort) and genomic and transcriptome data of the Cancer Genome Atlas (TCGA) LUAD cohort (TCGA_LUAD cohort) and a Chinese LUAD cohort (CHOICE_ADC cohort) were first obtained. Systematic bioinformatic analyses were then conducted to determine gene expression signature, immune infiltration levels and predicted immunotherapy response. Immunohistochemistry (IHC) was also conducted to validate the result of immune infiltration.

Results: The mutation rate of RBM10 was significantly higher in the GGN cohort than that in the TCGA_LUAD and CHOICE_ADC cohorts. In both TCGA_LUAD and CHOICE_ADC cohorts, multiple immune related pathways were markedly enriched in RBM10 deficient group. Further analyses showed that tumors with RBM10 mutations displayed higher TMB, and LUADs with RBM10 deficiency also showed higher HLA expression levels, including many HLA class I and II molecules. Additionally, many immune cells, including myeloid dendritic cells, macrophages, neutrophils and CD8+T cells, showed higher infiltration levels in LUADs with RBM10 deficiency. Finally, some immune checkpoint molecules, such as PD-L1 and TIM-3, were highly expressed in RBM10 deficient population and the predicted immunotherapy response was calculated through TIDE algorithm, showing that IFNG expression, MSI score and CD8 expression were higher in RBM10 deficient group, while MDSC and M2 macrophage were lower in RBM10 deficient group.

Conclusion: Our study demonstrates that RBM10 deficient LUADs show higher HLA expression and immune cell infiltration, and some immune checkpoint molecules are also highly expressed. In brief, RBM10 deficiency could enhance anti-tumor immunity in LUAD.
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http://dx.doi.org/10.3389/fonc.2021.677826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336464PMC
July 2021

An epigenomic landscape of cervical intraepithelial neoplasia and cervical cancer using single-base resolution methylome and hydroxymethylome.

Clin Transl Med 2021 07;11(7):e498

Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Centre for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.

Background: Cervical cancer (CC) is the second leading cause of cancer death among women worldwide. Epigenetic regulation of gene expression through DNA methylation and hydroxymethylation plays a pivotal role during tumorigenesis. In this study, to analyze the epigenomic landscape and identify potential biomarkers for CCs, we selected a series of samples from normal to cervical intra-epithelial neoplasia (CINs) to CCs and performed an integrative analysis of whole-genome bisulfite sequencing (WGBS-seq), oxidative WGBS, RNA-seq, and external histone modifications profiling data.

Results: In the development and progression of CC, there were genome-wide hypo-methylation and hypo-hydroxymethylation, accompanied by local hyper-methylation and hyper-hydroxymethylation. Hydroxymethylation prefers to distribute in the CpG islands and CpG shores, as displayed a trend of gradual decline from health to CIN2, while a trend of increase from CIN3 to CC. The differentially methylated and hydroxymethylated region-associated genes both enriched in Hippo and other cancer-related signaling pathways that drive cervical carcinogenesis. Furthermore, we identified eight novel differentially methylated/hydroxymethylated-associated genes (DES, MAL, MTIF2, PIP5K1A, RPS6KA6, ANGEL2, MPP, and PAPSS2) significantly correlated with the overall survival of CC. In addition, no any correlation was observed between methylation or hydroxymethylation levels and somatic copy number variations in CINs and CCs.

Conclusion: Our current study systematically delineates the map of methylome and hydroxymethylome from CINs to CC, and some differentially methylated/hydroxymethylated-associated genes can be used as the potential epigenetic biomarkers in CC prognosis.
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http://dx.doi.org/10.1002/ctm2.498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288011PMC
July 2021

The prevalence of HLA-I LOH in Chinese pan-cancer patients and genomic features of patients harboring HLA-I LOH.

Hum Mutat 2021 Oct 20;42(10):1254-1264. Epub 2021 Jul 20.

Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.

HLA-I LOH may facilitate immune evasion. However, large population studies on the prevalence of HLA-I LOH across different cancer types and in relation to mutational profiles are lacking, in particular, in the Chinese population. In this study, analysis was performed in 1504 advanced pan-cancer patients and 134 early-stage non-small-cell lung cancer patients using a 1021-gene panel. The consistency between the 1021-gene panel and whole-exome sequencing was evaluated in 45 samples, where concordant results were obtained in 95.6% (43/45) of the samples. Analytical results revealed that the prevalence of HLA-I LOH in tumor tissue presents considerable differences across cancer types. HLA-I LOH was relevant to genomic instability, reflected in higher tumor mutation burden level. HLA-I LOH occurs more frequently in MSS samples than in MSI-H samples. The alteration frequencies of p53 pathway, RTK/RAS pathway, Notch pathway, Hippo pathway, and Nrf2 pathway in HLA-I LOH group were significantly higher than that in HLA-I stable group (p < .0001, p < .0001, p = .032, p = .013, p = .003, respectively). In DNA damage response pathways, alterations in the checkpoint factor pathway and Fanconi anemia pathway are enriched in HLA-I LOH group (p < .0001, p = .023, respectively). Besides, HLA-I LOH was accompanied by higher mutation rates of several tumor suppressors, including TP53 and LRP1B. These results may shed light on follow-up tumor immunology research.
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http://dx.doi.org/10.1002/humu.24255DOI Listing
October 2021

The molecular tumor burden index as a response evaluation criterion in breast cancer.

Signal Transduct Target Ther 2021 07 7;6(1):251. Epub 2021 Jul 7.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Circulating tumor DNA (ctDNA) is a potential biomarker of prognosis and therapeutic response. We conducted this study to explore the role of the molecular tumor burden index (mTBI) in ctDNA as a therapeutic response and prognostic biomarker in a larger cohort prospective phase III randomized multicenter study. We collected 291 plasma samples from 125 metastatic breast cancer patients from the CAMELLIA study (NCT01917279). Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA from the plasma samples. The pretreatment mTBI value was correlated with tumor burden (P = 0.025). Patients with high-level pretreatment mTBI had shorter overall survival than patients with low-level pretreatment mTBI, and the median overall survival was 40.9 months and 68.4 months, respectively (P = 0.011). Patients with mTBI decrease to less than 0.02% at the first tumor evaluation had longer progression-free survival and overall survival (P < 0.001 and P = 0.007, respectively). The mTBI has good sensitivity to identify complete response/partial response and progressive disease based on computed tomography scans (88.5% and 87.5%, respectively). The patients classified as molecular responders had longer progression-free survival and overall survival than the nonmolecular responders in the overall cohort (P < 0.001 and P = 0.036, respectively), as well as in the cohort in which computed tomography scans were defined as representing stable disease (P = 0.027 and P = 0.015, respectively). The mTBI in ctDNA detected in liquid biopsies is a potential biomarker of therapeutic response and prognosis in patients with metastatic breast cancer.
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http://dx.doi.org/10.1038/s41392-021-00662-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260637PMC
July 2021

Weighting tumor-specific TCR repertoires as a classifier to stratify the immunotherapy delivery in non-small cell lung cancers.

Sci Adv 2021 May 19;7(21). Epub 2021 May 19.

State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Analysis of T cell receptor (TCR) repertoires may contribute to better understanding of the response to immunotherapy. By deep sequencing of the TCR β chain complementarity-determining regions in the paired biopsies and peripheral blood specimens of 31 patients with non-small cell lung cancer (NSCLC) treated with anti-programmed death 1 (PD-1) or PD-ligand 1 (PD-L1) therapy, we developed a previously unidentified index, the TCR-based immunotherapy response index (TIR index), that estimated the degree of overlap of the TCR repertoire between tumor-infiltrating lymphocytes and circulating PD-1CD8T cells (shared TCR clones). This index correlated with response and survival outcomes of anti-PD-(L)1 treatment. All the TCR sequences of neoantigen-stimulated T cells were included in the shared TCR clones, indicating that TCR clones involved in TIR index estimation represented tumor-specific T cells. Therefore, the TIR index is a feasible approach for assessing tumor-specific TCR and stratifying patients with NSCLC for anti-PD-(L)1 therapy.
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http://dx.doi.org/10.1126/sciadv.abd6971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133747PMC
May 2021

Serial circulating tumor DNA identification associated with the efficacy and prognosis of neoadjuvant chemotherapy in breast cancer.

Breast Cancer Res Treat 2021 Aug 18;188(3):661-673. Epub 2021 May 18.

Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifu Garden, Dongcheng District, Beijing, 100010, China.

Background: Circulating tumor DNA (ctDNA) provides a promising noninvasive alternative to evaluate the efficacy of neoadjuvant chemotherapy (NCT) in breast cancer.

Methods: Herein, we collected 63 tissue (aspiration biopsies and resected tissues) and 206 blood samples (baseline, during chemotherapy (Chemo), after chemotherapy (Post-Chemo), after operation (Post-Op), during follow-up) from 32 patients, and preformed targeted deep sequencing with a customed 1021-gene panel.

Results: As the results, TP53 (43.8%) and PIK3CA (40.6%) were the most common mutant genes in the primary tumors. At least one tumor-derived mutation was detected in the following number of blood samples: 21, baseline; 3, Chemo; 9, Post-Chemo; and 5, Post-Op. Four patients with pathologic complete response had no tissue mutation in Chemo and Post-Chemo blood. Compared to patients with mutation-positive Chemo or Post-Chemo blood, the counterparts showed a superior primary tumor decrease (median, 86.5% versus 54.6%) and lymph involvement (median, 1 versus 3.5). All five patients with mutation-positive Post-Op developed distant metastases during follow-up, and the sensitivity of detecting clinically relapsed patients was 71.4% (5/7). The median DFS was 9.8 months for patients with mutation-positive Post-Op but not reached for the others (HR 23.53; 95% CI, 1.904-290.9; p < 0.0001).

Conclusions: Our study shows that sequential monitoring of blood ctDNA was an effective method for evaluating NCT efficacy and patient recurrence. Integrating ctDNA profiling into the management of LABC patients might improve clinical outcome.

Trial Registration: This prospective study recruited LABC patients at Peking Union Medical College Hospital (ClinicalTrials.gov Identifier: NCT02797652).
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http://dx.doi.org/10.1007/s10549-021-06247-yDOI Listing
August 2021

Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC.

Front Oncol 2021 22;11:659321. Epub 2021 Apr 22.

Cancer Center, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China.

Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2-0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31-0.96; Cohort 3: 21 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18-1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.
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http://dx.doi.org/10.3389/fonc.2021.659321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100434PMC
April 2021

Circulating tumor DNA by high-throughput sequencing of T cell receptor monitored treatment response and predicted treatment failure in T cell lymphomas.

Int J Lab Hematol 2021 Oct 18;43(5):1041-1049. Epub 2021 Mar 18.

Department of Hematology, Peking Union Medical College Hospital, Beijing, China.

Introduction: Next-generation sequencing (NGS)-based circulating tumor DNA (ctDNA) detection is a promising monitoring tool for lymphoid malignancies. Studies for T cell lymphoma are limited.

Methods: We explored whether this technology is applicable to T cell lymphoma with different subtypes and assessed its performance in clinical settings.

Results: Thirty tumor and 74 blood samples were analyzed in our study. Malignant clone was identified in 23 of the 30 (76.7%) tumor samples through high-throughput sequencing (HTS) combined with PCR. We detected the same tumor clone in plasma in 18out of the 23 (78.3%) patients. Circulating tumor DNA fraction correlated with lactate dehydrogenase (LDH) (r = .52, P = .017), high level of ctDNA predicted treatment failure (P = .0003) and there was a trend patients with high ctDNA burden would have poorer PFS Furthermore, ctDNA changed in concordance with clinical outcome and was more sensitive than PET/CT. Also, recurrence of ctDNA was an important clue for relapse.

Conclusion: In conclusion, our study indicated that ctDNA monitoring was suitable for T cell lymphoma. High level of pretreatment ctDNA was a poor prognosis factor and changes of ctDNA correlated well with clinical courses and was sensitive to find early relapse.
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http://dx.doi.org/10.1111/ijlh.13498DOI Listing
October 2021

DNA damage response as a prognostic indicator in metastatic breast cancer via mutational analysis.

Ann Transl Med 2021 Feb;9(3):220

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Background: High tumor heterogeneity contributes to breast cancer recurrence and metastasis. However, the lack of indicators to serve as precise and reliable means of predicting breast cancer prognosis has yet to be addressed. This study aims to reveal the prognostic relevance of mutations in metastatic breast cancer (MBC) by large-scale circulating tumor DNA (ctDNA) analysis in China.

Methods: We performed ctDNA panel-captured sequencing of 958 blood samples from MBC patients including 494 hormone receptor (HR)-positive cases, 130 human epidermal growth factor receptor 2-positive cases, and 177 triple-negative breast cancer (TNBC) cases. The somatic mutations and potential targets were assessed. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method.

Results: In 801 of the 958 MBC blood samples, 663 mutated genes and 5,829 nonsynonymous alterations were identified. Mutated genes of the highest frequency were tumor protein p53 (, 54%), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (, 41%), estrogen receptor 1 (, 12%), myeloid/lymphoid or mixed-lineage leukemia protein 3 (, 11%), DNA (cytosine-5)-methyltransferase 3A (, 10%), erb-b2 receptor tyrosine kinase 2 (, 10%), GATA binding protein 3 (, 8%), FAT atypical cadherin 1 (, 7%), phosphatase and tensin homolog (, 6%), and mitogen-activated protein kinase kinase kinase 1 (, 6%). Enriched mutations and driver genes in MBC varied across stages and in multiple subtypes. Moreover, , , or coexisting / mutations in MBC were remarkably related with shorter PFS. Mutated DNA damage response (DDR) genes were significantly associated with tumor mutation burden and mutant-allele tumor heterogeneity score, as well as with worse clinical outcome.

Conclusions: Our findings indicate that the mutations of , , , and in particular, DDR genes, in MBC might be relevant indicators of unfavorable prognosis in MBC.
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http://dx.doi.org/10.21037/atm-20-2137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940884PMC
February 2021

Author Correction: Pan-cancer circulating tumor DNA detection in over 10,000 Chinese patients.

Nat Commun 2021 Feb 10;12(1):1048. Epub 2021 Feb 10.

Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100089, P. R. China.

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http://dx.doi.org/10.1038/s41467-021-21285-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876110PMC
February 2021

Genomic profiles and tumor immune microenvironment of primary lung carcinoma and brain oligo-metastasis.

Cell Death Dis 2021 01 21;12(1):106. Epub 2021 Jan 21.

Department of Radiotherapy, The Cancer Hospital of the University of Chinese Academy of Science (Zhejiang Cancer Hospital), Hangzhou, Zhejiang, 310022, China.

Brain metastasis (BM) is a common malignant event in lung cancer. Here, we recruited 33 lung cancer patients with brain oligo-metastasis to explore the genomic features and tumor immune microenvironment (TIME) of the lung and BM independently. For genomic profiling, targeted sequencing was performed. We found that high-frequent ZFHX3 occurred in the lung (40%) and brain tumor (28%), which might relate to brain metastasis event; the vast majority of patients had lesions-shared mutations in primary tumor and BM, confirming the common clonal events; and EGFR was the most frequently clonal gene in both lung and BM, indicating its driver capability. To characterize TIME status, we also sequenced the T cell receptor (TCR) repertoires and performed immunohistochemistry (IHC) on CD8+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression in 28 patients who had paired samples. Through the comparison, the TCR clonality of BM was higher than lung tumor, indicating the distinct pattern of the stronger oligoclonal T cell expansion in BM; the primary tumor had a higher TMB than oligo-BM (13.9 vs 8.7 mutations, p = 0.019); CD8 + TILs of BM were significantly lower than lung tumor (10% vs 30%, p = 0.015), revealing the lower level of cytotoxic T cell infiltration; BM showed statistically equivalent level of PD-L1 compared with lung tumor (p = 0.722). We further investigated the potential biomarkers associated with overall survival (OS) after brain surgery. We found that higher TCR clonality was related to prolonged OS in EGFR-treated patients (HR 0.175, p < 0.001) but the worse outcomes in non-EGFR-treated (HR 2.623, p = 0.034). More CD8+ TILs were an independently positive indicator for OS, in EGFR-treated (HR 0.160, p = 0.001) and non-EGFR-treated patients (HR 0.308, p = 0.009). These findings provide a meaningful molecular and clinical understanding of lung carcinoma and brain oligo-metastasis.
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http://dx.doi.org/10.1038/s41419-021-03410-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820277PMC
January 2021

Pan-cancer circulating tumor DNA detection in over 10,000 Chinese patients.

Nat Commun 2021 01 4;12(1):11. Epub 2021 Jan 4.

Health Management Institute, The Second Medical Center & National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100089, P. R. China.

Circulating tumor DNA (ctDNA) provides a noninvasive approach to elucidate a patient's genomic landscape and actionable information. Here, we design a ctDNA-based study of over 10,000 pan-cancer Chinese patients. Using parallel sequencing between plasma and white blood cells, 14% of plasma cell-free DNA samples contain clonal hematopoiesis (CH) variants, for which detectability increases with age. After eliminating CH variants, ctDNA is detected in 73.5% of plasma samples, with small cell lung cancer (91.1%) and prostate cancer (87.9%) showing the highest detectability. The landscape of putative driver genes revealed by ctDNA profiling is similar to that in a tissue-based database (R = 0.87, p < 0.001) but also shows some discrepancies, such as higher EGFR (44.8% versus 25.2%) and lower KRAS (6.8% versus 27.2%) frequencies in non-small cell lung cancer, and a higher TP53 frequency in hepatocellular carcinoma (53.1% versus 28.6%). Up to 41.2% of plasma samples harbor drug-sensitive alterations. These findings may be helpful for identifying therapeutic targets and combined treatment strategies.
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http://dx.doi.org/10.1038/s41467-020-20162-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782482PMC
January 2021

Genomic origin and intratumor heterogeneity revealed by sequencing on carcinomatous and sarcomatous components of pulmonary sarcomatoid carcinoma.

Oncogene 2021 01 3;40(4):821-832. Epub 2020 Dec 3.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.

Pulmonary sarcomatoid carcinoma (PSC) contains carcinomatous component (CaC) and sarcomatous component (SaC). Herein, we explored the genomic origin and intratumor heterogeneity (ITH) of PSC. We collected 31 resected PSC tumors and obtained CaC and SaC by laser capture microdissection for next-generation sequencing. The majority of PSCs (97%) had component-shared alterations. Driver mutations in EGFR, KRAS, MET, PIK3CA, and EML4-ALK fusion were mostly component-shared. Twenty-seven (87%) PSCs had component-private alterations. Compared with pure lung adenocarcinoma (LUAD), adenocarcinoma component of PSC showed lower EGFR incidence. Compared with other typical sarcomas, numerous genes of SaC exhibited significant differences. CaC and SaC had equivalent and proportional tumor mutation burden (TMB), as well as PD-L1 level. Compared with LUAD, SaC had significant higher TMB and more patients with high PD-L1 expression (tumor proportion score ≥50%). PSC with lower proportion of component-shared alterations (trunk-ratio) had a prolonged disease-free survival (DFS), regardless of the influence of clinical factors. We conclude that most PSCs originate from a monoclone accompanied by genomic ITH which is a potential independent prognostic factor, and more proportion of PSCs may be beneficial from immune checkpoint inhibitors.
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http://dx.doi.org/10.1038/s41388-020-01573-9DOI Listing
January 2021

Circulating tumor DNA as a potential prognostic and predictive biomarker during interventional therapy of unresectable primary liver cancer.

J Gastrointest Oncol 2020 Oct;11(5):1065-1077

Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China.

Background: Imaging and alpha fetoprotein (AFP) measurement are used as surveillance methods during interventional therapy in patients with unresectable liver cancer, but their accuracy has been challenged in patients receiving drug perfusion therapy. Circulating tumor DNA (ctDNA) can reflect tumor load and treatment efficacy. Studies of the prognostic value of ctDNA in unresectable liver cancer are needed.

Methods: Forty-two patients with unresectable liver cancer were prospective enrolled in this study. Pre-treatment, in-treatment plasma samples and available matched tissue samples were collected. Targeted-capture sequencing of 1,021 genes that are frequently mutated in solid tumors.

Results: Targeted-capture sequencing of 1,021 genes that are frequently mutated in solid tumors revealed that the most frequently mutated genes in ctDNA were TP53 (52.4%) and TERT (35.7%). The ctDNA abundance was more closely correlated with tumor size than the AFP level and was also related to BCLC stage (P<0.001). Gene mutations profile in ctDNA with progressed disease. PD patients were enriched in TP53 mutation group compared with TP53 wildtype group (P=0.0221). Moreover, interventional therapy was more effective in patients without TP53 mutation (OS: P=0.0589; PFS: 0.0411). The dynamic change of ctDNA showed consistent or more sensitivity than imaging for evaluating treatment response. The tumor mutation burden was highly consistent between tissue and blood samples (P<0.0001).

Conclusions: ctDNA was a reliable biomarker to assist in diagnosis and evaluation of prognosis and treatment efficacy in advanced liver cancer. Considering that biopsy is unnecessary when advanced liver cancer is diagnosed, ctDNA may be an ideal biomarker for evaluating tumor mutation burden prior to immunotherapy.
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http://dx.doi.org/10.21037/jgo-20-409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657842PMC
October 2020

Molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer.

NPJ Breast Cancer 2020 30;6:59. Epub 2020 Oct 30.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 China.

Human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification is an important predictive biomarker for identifying patients with breast cancer, who may benefit from HER2-targeted therapy. However, little is known about the molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer. We analysed the HER2 mutation features of 1184 patients with invasive breast cancer. In addition, a single-arm, prospective, phase-II study (NCT03412383) of pyrotinib was conducted in patient with metastatic HER2 amplification-negative, mutation-positive breast cancer. Peripheral blood was collected from each patient and circulating tumour DNA (ctDNA) sequencing was performed using a 1021 gene panel. HER2 mutations were detected in 8.9% (105/1184) of patients. The HER2 amplification-positive patients had a higher mutation frequency than the HER2 amplification-negative patients (19.5% vs. 4.8%,  < 0.001). A multivariate Cox regression analysis indicated that patients with HER2 mutations had a shorter progression-free survival (PFS) than HER2 wild-type patients (median PFS 4.7 months vs. 11.0 months, hazard ratio 2.65, 95% confidence interval 1.25-5.65,  = 0.011). Ten HER2 amplification-negative, mutation-positive patients who received pyrotinib monotherapy were ultimately included in the efficacy analysis. The median PFS was 4.9 months. The objective response rate (complete response + partial response) was 40.0% and the clinical benefit rate (complete response + partial response + stable disease over 24 weeks) was 60%. In conclusion, a HER2 gene mutation analysis is potentially useful to identify biomarkers of trastuzumab resistance in HER2 amplification-positive patients. Patients with HER2-mutated, non-amplified metastatic breast cancers may benefit from pyrotinib.
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http://dx.doi.org/10.1038/s41523-020-00201-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603305PMC
October 2020

Mutational characteristics determined using circulating tumor DNA analysis in triple-negative breast cancer patients with distant metastasis.

Cancer Commun (Lond) 2020 12 3;40(12):738-742. Epub 2020 Oct 3.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, P. R. China.

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http://dx.doi.org/10.1002/cac2.12102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7743003PMC
December 2020

Dielectrophoresis Separation of Platelets Using a Novel Zigzag Microchannel.

Micromachines (Basel) 2020 Sep 25;11(10). Epub 2020 Sep 25.

School of Electromechanical Engineering, Henan University of Technology, Zhengzhou 450001, China.

Platelet separation and purification are required in many applications including in the detection and treatment of hemorrhagic and thrombotic diseases, in addition to transfusions and in medical research. In this study, platelet separation was evaluated using a novel zigzag microchannel fluidic device while leveraging a dielectrophoresis (DEP) electric field using the COMSOL multiphysics software package and additional experimentation. The zigzag-shaped microchannel was superior to straight channel devices for cell separation because the sharp corners reduced the required horizontal distance needed for separation and also contributed to an asymmetric DEP electric field. A perfect linear relationship was observed between the separation distance and the corner angles. A quadratic relationship ( = 0.99) was observed between the driving voltage and the width and the lengths of the channel, allowing for optimization of these properties. In addition, the voltage was inversely proportional to the channel width and proportional to the channel length. An optimal velocity ratio of 1:4 was identified for the velocities of the two device inlets. The proposed device was fabricated using laser engraving and lithography with optimized structures including a 0.5 mm channel width, a 120° corner angle, a 0.3 mm channel depth, and a 17 mm channel length. A separation efficiency of 99.4% was achieved using a voltage of 20 V and a velocity ratio of 1:4. The easy fabrication, lower required voltage, label-free detection, high efficiency, and environmental friendliness of this device make it suitable for point-of-care medicine and biological applications. Moreover, it can be used for the separation of other types of compounds including lipids.
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http://dx.doi.org/10.3390/mi11100890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599473PMC
September 2020

Circulating Tumor DNA Predicts the Response and Prognosis in Patients With Early Breast Cancer Receiving Neoadjuvant Chemotherapy.

JCO Precis Oncol 2020 27;4. Epub 2020 Mar 27.

Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Purpose: Many patients with breast cancer still relapse after curative treatment. How to identify the ones with high relapse risk remains a critical problem. Circulating tumor DNA (ctDNA) has recently become a promising marker to monitor tumor burden. Whether ctDNA can be used to predict the response and prognosis in patients with breast cancer receiving neoadjuvant chemotherapy (NAC) is unknown. Our study aimed to evaluate the clinical value of the presence and dynamic change of ctDNA to predict the tumor response and prognosis in patients with breast cancer treated with NAC.

Materials And Methods: Fifty-two patients with early breast cancer who underwent NAC were prospectively enrolled. Serial plasma samples before, during, and after NAC and paired tumor biopsies were harvested and subjected to deep targeted sequencing using a large next-generation sequencing panel that covers 1,021 cancer-related genes.

Results: Positive baseline ctDNA was detected in 21 of 44 patients before NAC. Most patients with positive ctDNA had one or more mutations confirmed in paired primary tumor. The ctDNA level after 2 cycles of NAC was predictive of local tumor response after all cycles of NAC (area under the curve, 0.81; 95% CI, 0.61 to 1.00). ctDNA tracking during NAC outperformed imaging in predicting the overall response to NAC. More importantly, positive baseline ctDNA is significantly associated with worse disease-free survival ( = .011) and overall survival ( = .004) in patients with early breast cancer, especially in estrogen receptor-negative patients.

Conclusion: Our study demonstrated that ctDNA can be used to predict tumor response to NAC and prognosis in early breast cancer, providing information to tailor an individual's therapeutic regimen.
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http://dx.doi.org/10.1200/PO.19.00292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450928PMC
March 2020

Amplification Contributes to Immunosuppression and Is Associated With a Poor Prognosis to Immune Checkpoint Inhibitors in Solid Tumors.

Front Immunol 2020 10;11:1620. Epub 2020 Aug 10.

Cancer Bio-immunotherapy Center, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, China.

amplification relevant to malignant biological behavior exists in solid tumors. The prevalence and utility of amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown. Our study is a preliminary investigation mainly focused on the predictive function of amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome. We examined the prevalence of amplification and its potential as a biomarker for the efficacy of ICI therapy for solid tumors using a local database ( = 6,536), The Cancer Genome Atlas (TCGA) database ( = 10,606), and the Memorial Sloan Kettering Cancer Center (MSKCC) database ( = 10,109). Comprehensive profiling was performed to determine the prevalence of amplification and the correlation with the prognosis and the response to ICIs. A amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy. Transcriptomic analysis showed various degrees of immune cell exclusion, including cytotoxic cells, T cells, CD8 T cells, dendritic cells (DCs), and B cells in the TME in a TCGA amplification population. The gene set enrichment analysis suggested that amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial-mesenchymal transition, transforming growth factor (TGF)-β signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors. These findings indicate that amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.
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http://dx.doi.org/10.3389/fimmu.2020.01620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7438829PMC
April 2021

Oncogenic mutations within the β3-αC loop of EGFR/ERBB2/BRAF/MAP2K1 predict response to therapies.

Mol Genet Genomic Med 2020 10 5;8(10):e1395. Epub 2020 Aug 5.

Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, China.

Background: β3-αC loop is a highly conserved structural domain across oncogene families, which is a switch for kinase activity. There have been numerous researches on mutations within β3-αC loop in EGFR, but relatively less in ERBB2, BRAF, and MAP2K1. In addition, previous studies mainly focus on β3-αC deletion in EGFR, which is the most common type affecting kinase activity and driving lung cancer. Other mutation types are not well studied.

Methods: Here we analyzed the profile of β3-αC loop mutations in a total of 10,000 tumor biopsy and/or ctDNA patient samples using hybridization capture-based next-generation sequencing.

Results: We identified 1616 mutations within β3-αC loop in this cohort. Most mutations were located in EGFR, with less percentage in ERBB2, BRAF, and MAP2K1. EGFR β3-αC deletions occurred at a high percentage of 96.7% and were all drug-relevant. We also detected rare EGFR β3-αC insertions and point mutations, most of which were related to EGFR TKIs resistance. ERBB2 β3-αC deletions were only found in breast cancers and sensitive to EGFR/ERBB2 inhibitor. Moreover, BRAF and MAP2K1 mutations within β3-αC loop also demonstrated drugs relevance.

Conclusion: Our study showed that oncogenic mutations within the β3-αC loop of ERBB2, MAP2K1, and BRAF are analogous to that of EGFR, which have profound effect on drug response. Understanding the mutation profile within the β3-αC loop is critical for targeted therapies.
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http://dx.doi.org/10.1002/mgg3.1395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549570PMC
October 2020

Tumor immune microenvironment and mutational analysis of tracheal adenoid cystic carcinoma.

Ann Transl Med 2020 Jun;8(12):750

State Key Laboratory of Respiratory Disease, National Clinical Research Center of Respiratory Disease, Guangzhou Institute of the Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Background: Tracheal adenoid cystic carcinoma (TACC) is the second most common type of cancer in bronchial tumors with poor prognosis. Studies on the genomic profiles and tumor immune microenvironment (TIME) of TACC are still relatively rare.

Methods: Here, we performed whole-exome sequencing (WES), T cell repertoire (TCR) sequencing, and immunohistochemistry (IHC) on the resected tumors and matched peripheral blood leukocytes (PBLs) samples from 25 TACCs collected from April-2010 to Mar-2019.

Results: WES results revealed that and were recurrently mutated genes, with no classical lung cancer drivers in TACCs (n=8). The median tumor mutation burden (TMB) was 3.67, lower than other solid tumors. Unexpectedly, one patient showed high microsatellite instability (MSI). Recurrent copy number variations (CNVs) affected genes commonly involved in p53, cell cycle, and PI3K-Akt signaling pathways. For TCR estimators of 13 PBLs, the median clonality and Shannon index was 0.15 and 7.02, respectively. Shannon index showed marginally negative association with age (Pearson r =-0.53, P=0.062). Clonotype number and Shannon index of 7 TACC tissues were significantly lower than those of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) (Mann-Whitney test, both P<0.001, both P<0.001). Furthermore, programmed cell death 1 ligand 1 (PD-L1), a vital player in TIME, was negative (tumor proportion score, TPS <1%) in all samples (n=14). Patients with less clonotypes had longer progression-free survival (PFS) than those with more PFS (15.0 . 9.5 months, P<0.001, HR 12.5, 95% CI: 0.2-675.7). In particular, the clinical and molecular characteristics of one TACC patient receiving immunotherapy have been explained in detail.

Conclusions: In summary, despite the existence of one patient with MSI-H and chromosome instability, TACC was characterized by a lack of common drivers of lung cancer, negative PD-L1 expression, and low CD3+ and CD8+ T cell infiltration.
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http://dx.doi.org/10.21037/atm-20-3433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333116PMC
June 2020

A hybrid electrically-and-piezoelectrically driven micromixer built on paper for microfluids mixing.

Biomed Microdevices 2020 07 8;22(3):47. Epub 2020 Jul 8.

School of Electromechanical Engineering, Henan University of Technology, Zhengzhou, 450001, China.

This study aims to explore the channel patterns and the characteristic parameters of the zigzag microchannel based on microfluidic paper-based analytical devices (μPADs), in which the mixing efficiency and speed can be greatly enhanced. Better mixing of the solutions was obtained by adding a simple directing electric field to the optimized structure of the zigzag microchannel on paper-based chips instead of the traditional complex devices. A higher mixing efficiency was reached when the direct-current (DC) power supply reached 20 V. Meanwhile, a piezoelectric transducer (PZT) driver was used in the mixing experiment with the paper-based zigzag microchannel. The results show that the mixing efficiency reached a maximum value when the input voltage and frequency were 30 V and 150 Hz, respectively. These paper-based devices meet the requirements of the biochemical analysis field because they are low cost, easy to operate, and have high efficiencies, giving them good prospects for future applications. Graphical Abstract.
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http://dx.doi.org/10.1007/s10544-020-00502-7DOI Listing
July 2020

An integrated platform for fibrinogen quantification on a microfluidic paper-based analytical device.

Lab Chip 2020 08 26;20(15):2724-2734. Epub 2020 Jun 26.

College of Electromechanical Engineering, Henan University of Technology, Zhengzhou 450001, China.

Fibrinogen (FIB) plays a key role in blood coagulation and thrombosis and its concentration in blood can directly reflect health conditions, thus efficient detection of FIB would benefit the treatments of certain diseases such as liver and heart diseases. However, there is a lack of sensitive, simple, rapid and cheap FIB detection device currently, in lieu of expensive and sophisticated approaches in laboratories. Here, we propose a novel plasma separation and FIB detection platform based on a microfluidic paper-based analytical device (μPAD). It is the first time that dielectrophoretic (DEP) force is combined with capillary force on paper for plasma separation, and the separation efficiency of plasma reaches about 95%, ensuring reliable downstream FIB detection, for which we also propose a new method called the resistance-fibrinogen detection (RFD) method. It not only avoids the use of large-scale instruments for detection, but also possesses high precision and simplicity. The method is found to be reliable in FIB detection for various concentrations ranging from 127.0 to 508.0 mg dL. Moreover, the results obtained from the proposed μPAD show an excellent agreement (R = 0.9985) with those obtained from an automatic coagulation analyzer with natural human blood samples. Overall, the proposed platform provides a low-cost and reliable approach for FIB detection, especially for clinical use in resource-limited areas.
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http://dx.doi.org/10.1039/d0lc00439aDOI Listing
August 2020

Impact of T-cell receptor and B-cell receptor repertoire on the recurrence of early stage lung adenocarcinoma.

Exp Cell Res 2020 09 12;394(2):112134. Epub 2020 Jun 12.

Cancer Center, Daping Hospital, Army Medical University (Third Military Medical University), No. 10 Changjiang Zhi Rd., Yuzhong Dist., Chongqing, 400042, China. Electronic address:

Surgical resection is the only curative treatment for patients with early stage non-small cell lung cancer. However, approximately 33% of non-small cell lung cancer patients recur with the stage I disease, which may be attributed to a deficiency in antitumor immunity. In the present study, for early stage lung adenocarcinoma patients with early recurrence and early non-recurrence, we investigated the quantity of tumor-infiltrating T and B cells by immunohistochemistry, as well as the genes in the complementarity determining region 3 of the T-cell receptor β chain and the B-cell receptor immunoglobulin heavy chain. A decreased number of tumor-infiltrating lymphocytes cells (CD3, CD4, CD8 and CD20) was present in early recurrence patients. A significant increase in oligoclones and a reduction in T-cell receptor diversity were observed in the early recurrence group. Furthermore, there was a preference for V, J gene, and VJ gene combinations in patients with early recurrence versus non-recurrence, suggesting that this may be a new biomarker for the recurrence of early stage lung adenocarcinoma. These data indicate that T and B cell receptor repertoires influence the depth of human adaptive immune responses, and in addition to the quantity of tumor infiltrating T and B cells, may contribute to the prevention of early stage lung adenocarcinoma recurrence after surgical resection. Our study illustrates the potential value of the immune repertoire for predicting clinical efficacy and patient outcomes.
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http://dx.doi.org/10.1016/j.yexcr.2020.112134DOI Listing
September 2020

Prevalence of PRKDC mutations and association with response to immune checkpoint inhibitors in solid tumors.

Mol Oncol 2020 09 30;14(9):2096-2110. Epub 2020 Jun 30.

Cancer Bio-immunotherapy Center, Fujian Medical University Cancer Hospital & Fujian Cancer Hospital, Fuzhou, China.

Predictive biomarkers of response to immune checkpoint inhibitors (ICI) help to identify cancer patients who will benefit from immunotherapy. Protein kinase, DNA-activated, catalytic subunit (PRKDC) is an important gene for DNA double-strand break (DSB) repair and central T-cell tolerance. We aimed to investigate the association between PRKDC mutations and tumor mutation burden (TMB), tumor microenvironment (TME), and response to ICI. Whole-exome sequencing data of 4023 solid tumor samples from the Cancer Genome Atlas (TCGA) and panel-based sequencing data of 3877 solid tumor samples from Geneplus-Beijing, China, were used to analyze the TMB. The mRNA expression data of 3541 solid tumor samples from TCGA were used to explore the effect of PRKDC mutations on the TME. Four ICI-treated cohorts were analyzed for verifying the correlation between PRKDC mutations and the response to ICI. In both the TCGA and Geneplus datasets, we found that the TMB in PRKDC mutation samples was significantly higher than in PRKDC wild-type samples (P < 0.05 and P < 0.0001, respectively). Further, TCGA datasets showed that PRKDC mutation samples were associated with a significantly increased expression of CD8 T cells, NK cells, immune checkpoint, chemokines, etc. compared to PRKDC wild-type samples (P < 0.05). In ICI-treated cohorts, we also found the PRKDC mutations were associated with increased survival (median PFS, not reached vs. 6.8 months, HR, 0.2893; 95% CI, 0.1255-0.6672; P = 0.0650, Hellmann cohort; median OS, 1184 days vs. 250 days, HR, 0.5126; 95% CI, 0.2715-0.9679; P = 0.1020, Allen cohort), and the increase was significant in multivariate analysis (HR, 0.361; 95% CI, 0.155-0.841; P = 0.018, Allen cohort; HR, 0.240 95% CI, 0.058-0.998; P = 0.050, Hellmann cohort). In summary, we found that PRKDC mutation often appeared to co-exist with deficiency in some other DNA damage repair mechanism and is nonetheless one of the important factors associated with increased TMB, inflamed TME, and better response to ICI.
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http://dx.doi.org/10.1002/1878-0261.12739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463346PMC
September 2020
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