Publications by authors named "Yuchen Jiao"

76 Publications

Personalized analysis of minimal residual cancer cells in peritoneal lavage fluid predicts peritoneal dissemination of gastric cancer.

J Hematol Oncol 2021 Oct 12;14(1):164. Epub 2021 Oct 12.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Panjiayuan nanli 17, Chaoyang District, Beijing, 100021, China.

Peritoneal dissemination (PD) is a major type of gastric cancer (GC) recurrence and leads to rapid death. Current approaches cannot precisely determine which patients are at high risk of PD to provide early intervention. In this study, we developed a technology to detect minimal residual cancer cells in peritoneal lavage fluid (PLF) samples with a personalized assay profiling tumor-specific mutations. In a prospective cohort of 104 GC patients, the technology detected all the cases that developed PD with 100% sensitivity and 85% specificity. The minimal residual cancer cells in PLF were associated with a significantly increased risk of PD (HR = 145.13; 95% CI 20.20-18,435.79; p < 0.001), which was the strongest independent predictor over pathologic diagnosis and cytological diagnosis. In pathologically high-risk (pT4) patients, the PLF mutation profiling model exhibited a greater specificity of 91% and a positive predictive value of 88% while retaining a sensitivity of 100%. This approach may help in the postsurgical management of GC patients by detecting PD far before metastatic lesions grow to a significant size detectable by conventional methods such as MRI and CT scanning.
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http://dx.doi.org/10.1186/s13045-021-01175-2DOI Listing
October 2021

Effects of Dance Interventions on Cognition, Psycho-Behavioral Symptoms, Motor Functions, and Quality of Life in Older Adult Patients With Mild Cognitive Impairment: A Meta-Analysis and Systematic Review.

Front Aging Neurosci 2021 20;13:706609. Epub 2021 Sep 20.

School of Nursing, Nanjing Medical University, Nanjing, China.

Dance interventions are considered beneficial for older patients with mild cognitive impairment in many aspects. We conducted a comprehensive systematic review and meta-analysis to assess the effects of dance on different aspects (cognitive function, emotions, physical function, and quality of life) of this population. A systematic search of PubMed, Web of Science, the Cochrane Central Register of Controlled Trials, Embase, American Psychological Association PsycInfo, ProQuest, Scopus, Cumulative Index to Nursing and Allied Health Literature, the Chinese BioMedical Literature Database, the VIP Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, and Wanfang Data database was performed. Two reviewers independently assessed the study quality. Fourteen studies were retrieved from the databases for analysis. The pooled results showed that dance interventions significantly improved global cognition (standardized mean difference [SMD] = 0.73, 95% confidence interval [CI]: 0.47 to 0.99, < 0.00001), rote memory (mean difference [MD] = -2.12, 95% CI: -4.02 to -0.21, = 0.03), immediate recall (SMD = 0.54, 95% CI: 0.30 to 0.78, < 0.0001), delayed recall (SMD = 0.56, 95% CI: 0.26 to 0.86, = 0.0002) and attention (SMD = 0.38, 95% CI: 0.13 to 0.64, = 0.003). No significant improvement was found in executive function, language, depression, anxiety, dementia-related behavioral symptoms, motor function, and quality of life. Dance interventions benefit most aspects of cognitive functions. The evidence for the effects of dance on psycho-behavioral symptoms, motor function and quality of life remains unclear. More trials with rigorous study designs are necessary to provide this evidence.
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http://dx.doi.org/10.3389/fnagi.2021.706609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488360PMC
September 2021

Catalytic Amination of Polylactic Acid to Alanine.

J Am Chem Soc 2021 Oct 30;143(40):16358-16363. Epub 2021 Sep 30.

Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People's Republic of China.

In comparison to the traditional petroleum-based plastics, polylactic acid, the most popular biodegradable plastic, can be decomposed into carbon dioxide and water in the environment. However, the natural degradation of polylactic acid requires a substantial period of time and, more importantly, it is a carbon-emitting process. Therefore, it is highly desirable to develop a novel transformation process that can upcycle the plastic trash into value-added products, especially with high chemical selectivity. Here we demonstrate a one-pot catalytic method to convert polylactic acid into alanine by a simple ammonia solution treatment using a Ru/TiO catalyst. The process has a 77% yield of alanine at 140 °C, and an overall selectivity of 94% can be reached by recycling experiments. Importantly, no added hydrogen is used in this process. It has been verified that lactamide and ammonium lactate are the initial intermediates and that the dehydrogenation of ammonium lactate initiates the amination, while Ru nanoparticles are essential for the dehydrogenation/rehydrogenation and amination steps. The process demonstrated here could expand the application of polylactic acid waste and inspire new upcycling strategies for different plastic wastes.
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http://dx.doi.org/10.1021/jacs.1c08159DOI Listing
October 2021

Novel genetic characteristics in low-grade fetal adenocarcinoma of the lung.

Thorac Cancer 2021 Aug 31. Epub 2021 Aug 31.

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: Low-grade fetal adenocarcinoma of the lung (L-FLAC) is a rare subtype of lung adenocarcinoma with undetermined histological features and genetic abnormalities. In this study, we attempted to investigate the pathological characteristics and genomic profiles of L-FLAC.

Methods: Among 9839 cases of primary lung adenocarcinoma resected at Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2011 and June 2016, three cases diagnosed with L-FLAC were selected. An immunohistochemical profile and whole exome sequencing (WES) using tumor and normal tissues was conducted. The last follow-up date of patients was January 2021.

Results: Three cases diagnosed with L-FLAC were finally screened, suggesting a percentage of 0.03%. All three patients were male and diagnosed as stage I following radical lobectomy. The missense variant was found to be the major gene mutation type using WES. CTNNB1 and DICER1 were the two most frequent gene mutations. All cases demonstrated positive TTF-1 expression. In addition, two patients showed positive expression of β-catenin (nuclear/cytoplasmic expression), CgA and Sny. Negative expression of PD-L1 in tumor cells was observed in all three cases. One case with a relatively high tumor mutation burden (TMB) (2.18 mut/Mb) had an inferior overall survival of 11.5 months. However, the other two cases with a lower TMB (0.12 and 0.74 mut/Mb) still acquired disease-free status up to the last follow-up date.

Conclusions: L-FLAC has a specific molecular background which is different from lung adenocarcinoma. Furthermore, gene heterogeneity was found and might be the reason for a dramatically different prognosis in these L-FLAC patients.
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http://dx.doi.org/10.1111/1759-7714.14126DOI Listing
August 2021

AHR mediates the aflatoxin B1 toxicity associated with hepatocellular carcinoma.

Signal Transduct Target Ther 2021 Aug 9;6(1):299. Epub 2021 Aug 9.

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

Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma (HCC) in individuals infected with the hepatitis virus. However, the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined. Here, we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1 (AFB1) targets. Among the most significant hits was the aryl hydrocarbon receptor (AHR), a ligand-binding transcription factor regulating cell metabolism, differentiation, and immunity. AHR-deficient cells tolerated high concentrations of AFB1, in which AFB1 adduct formation was significantly decreased. AFB1 triggered AHR nuclear translocation by directly binding to its N-terminus. Furthermore, AHR mediated the expression of P450 induced by AFB1. AHR expression was also elevated in primary tumor sections obtained from AFB1-HCC patients, which paralleled the upregulation of PD-L1, a clinically relevant immune regulator. Finally, anti-PD-L1 therapy exhibited greater efficacy in HCC xenografts derived from cells with ectopic expression of AHR. These results demonstrated that AHR was required for the AFB1 toxicity associated with HCC, and implicate the immunosuppressive regimen of anti-PD-L1 as a therapeutic option for the treatment of AFB1-associated HCCs.
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http://dx.doi.org/10.1038/s41392-021-00713-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352983PMC
August 2021

A male-ABCD algorithm for hepatocellular carcinoma risk prediction in HBsAg carriers.

Chin J Cancer Res 2021 Jun;33(3):352-363

State Key Lab of Molecular 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.

Objective: Hepatocellular carcinoma (HCC) development among hepatitis B surface antigen (HBsAg) carriers shows gender disparity, influenced by underlying liver diseases that display variations in laboratory tests. We aimed to construct a risk-stratified HCC prediction model for HBsAg-positive male adults.

Methods: HBsAg-positive males of 35-69 years old (N=6,153) were included from a multi-center population-based liver cancer screening study. Randomly, three centers were set as training, the other three centers as validation. Within 2 years since initiation, we administrated at least two rounds of HCC screening using B-ultrasonography and α-fetoprotein (AFP). We used logistic regression models to determine potential risk factors, built and examined the operating characteristics of a point-based algorithm for HCC risk prediction.

Results: With 2 years of follow-up, 302 HCC cases were diagnosed. A male-ABCD algorithm was constructed including participant's age, blood levels of GGT (γ-glutamyl-transpeptidase), counts of platelets, white cells, concentration of DCP (des-γ-carboxy-prothrombin) and AFP, with scores ranging from 0 to 18.3. The area under receiver operating characteristic was 0.91 (0.90-0.93), larger than existing models. At 1.5 points of risk score, 26.10% of the participants in training cohort and 14.94% in validation cohort were recognized at low risk, with sensitivity of identifying HCC remained 100%. At 2.5 points, 46.51% of the participants in training cohort and 33.68% in validation cohort were recognized at low risk with 99.06% and 97.78% of sensitivity, respectively. At 4.5 points, only 20.86% of participants in training cohort and 23.73% in validation cohort were recognized at high risk, with positive prediction value of 22.85% and 12.35%, respectively.

Conclusions: Male-ABCD algorithm identified individual's risk for HCC occurrence within short term for their HCC precision surveillance.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2021.03.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286891PMC
June 2021

An m6A-Related Prognostic Biomarker Associated With the Hepatocellular Carcinoma Immune Microenvironment.

Front Pharmacol 2021 24;12:707930. Epub 2021 Jun 24.

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

N6-methyladenosine (m6A) is related to the progression of multiple cancers. However, the underlying influences of m6A-associated genes on the tumor immune microenvironment in hepatocellular carcinoma (HCC) remain poorly understood. Therefore, we sought to construct a survival prediction model using m6A-associated genes to clarify the molecular and immune characteristics of HCC. HCC case data were downloaded from The Cancer Genome Atlas (TCGA). Then, by applying consensus clustering, we identified two distinct HCC clusters. Next, four m6A-related genes were identified to construct a prognostic model, which we validated with Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) datasets. Additionally, the molecular and immune characteristics in different subgroups were analyzed. m6A RNA methylation regulators were differentially expressed between HCC and normal samples and linked with immune checkpoint expression. Using consensus clustering, we divided HCC samples into two subtypes with distinct clinical features. Cluster 2 was associated with unfavorable prognosis, higher immune checkpoint expression and immune cell infiltration levels. In addition, the immune and carcinogenic signaling pathways were enriched in cluster 2. Furthermore, we constructed a risk model using four m6A-associated genes. Patients with different risk scores had distinct survival times, expression levels of immunotherapy biomarkers, TP53 mutation rates, and sensitivities to chemotherapy and targeted therapy. Similarly, the model exhibited an identical impact on overall survival in the validation cohorts. The constructed m6A-based signature may be promising as a biomarker for prognostics and to distinguish immune characteristics in HCC.
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http://dx.doi.org/10.3389/fphar.2021.707930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263919PMC
June 2021

The commensal consortium of the gut microbiome is associated with favorable responses to anti-programmed death protein 1 (PD-1) therapy in thoracic neoplasms.

Cancer Biol Med 2021 May 7. Epub 2021 May 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 100021, China.

Objective: Immune checkpoint inhibitors have revolutionized cancer therapy for multiple types of solid tumors, but as expected, a large percentage of patients do not show durable responses. Biomarkers that can predict clinical responses to immunotherapies at diagnosis are therefore urgently needed. Herein, we determined the associations between baseline gut commensal microbes and the clinical treatment efficiencies of patients with thoracic neoplasms during anti-programmed death protein 1 (PD-1) therapy.

Methods: Forty-two patients with advanced thoracic carcinoma who received anti-PD-1 treatment were enrolled in the study. Baseline and time-serial stool samples were analyzed using 16S ribosomal RNA gene sequencing. Tumor responses, patient progression-free survival, and overall survival were used to measure clinical outcomes.

Results: The diversities of the baseline gut microbiota were similar between responders ( = 23) and nonresponders ( = 19). The relative abundances of the , , , and bacterial families were significantly higher in the responder group. These 5 bacterial families acted as a commensal consortium and better stratified patients according to clinical responses ( = 0.014). Patients with a higher abundance of commensal microbes had prolonged PFS ( = 0.00016). Using multivariable analysis, the abundance of the commensal consortium was identified as an independent predictor of anti-PD-1 immunotherapy in thoracic neoplasms (hazard ratio: 0.17; 95% confidence interval: 0.05-0.55; = 0.003).

Conclusions: Baseline gut microbiota may have a critical impact on anti-PD-1 treatment in thoracic neoplasms. The abundance of gut commensal microbes at diagnosis might be useful for the early prediction of anti-PD-1 immunotherapy responses.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2020.0450DOI Listing
May 2021

A Urine-Based Liquid Biopsy Method for Detection of Upper Tract Urinary Carcinoma.

Front Oncol 2020 9;10:597486. Epub 2021 Feb 9.

Department of Urology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.

Background: Conventional clinical detection methods such as CT, urine cytology, and ureteroscopy display low sensitivity and/or are invasive in the diagnosis of upper tract urinary carcinoma (UTUC), a factor precluding their use. Previous studies on urine biopsy have not shown satisfactory sensitivity and specificity in the application of both gene mutation or gene methylation panels. Therefore, these unfavorable factors call for an urgent need for a sensitive and non-invasive method for the diagnosis of UTUC.

Methods: In this study, a total of 161 hematuria patients were enrolled with (n = 69) or without (n = 92) UTUC. High-throughput sequencing of 17 genes and methylation analysis for CpG sites were combined as a liquid biopsy test panel. Further, a logistic regression prediction model that contained several significant features was used to evaluate the risk of UTUC in these patients.

Results: In total, 86 UTUC- and 64 UTUC+ case samples were enrolled for the analysis. A logistic regression analysis of significant features including age, the mutation status of promoter, and methylation level resulted in an optimal model with a sensitivity of 94.0%, a specificity of 93.1%, the positive predictive value of 92.2% and a negative predictive value of 94.7%. Notably, the area under the curve (AUC) was 0.957 in the training dataset while internal validation produced an AUC of 0.962. It is worth noting that during follow-up, a patient diagnosed with ureteral inflammation at the time of diagnosis exhibiting both positive mutation and methylation test results was diagnosed with ureteral carcinoma 17 months after his enrollment.

Conclusion: This work utilized the epigenetic biomarker for the first time in the detection of UTUC and discovered its superior performance. To improve its sensitivity, we combined the biomarker with high-throughput sequencing of 17 genes test. It was found that the selected logistic regression model diagnosed with ureteral cancer can evaluate upper tract urinary carcinoma risk of patients with hematuria and outperform other existing panels in providing clinical recommendations for the diagnosis of UTUC. Moreover, its high negative predictive value is conducive to rule to exclude patients without UTUC.
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http://dx.doi.org/10.3389/fonc.2020.597486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901537PMC
February 2021

The mutational landscape of spinal chordomas and their sensitive detection using circulating tumor DNA.

Neurooncol Adv 2021 Jan-Dec;3(1):vdaa173. Epub 2020 Dec 8.

Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background: Chordomas are the most common primary spinal column malignancy in the United States. The aim of this study was to determine whether chordomas may be detected by evaluating mutations in circulating tumor DNA (ctDNA).

Methods: Thirty-two patients with a biopsy-confirmed diagnosis of chordoma had blood drawn pre-operatively and/or at follow-up appointments. Mutations in the primary tumor were identified by whole exome sequencing and liquid biopsy by ddPCR and/or RACE-Seq was used to detect one or more of these mutations in plasma ctDNA at concurrent or later time points.

Results: At the time of initial blood draw, 87.1% of patients were ctDNA positive (.001). Follow-up blood draws in twenty of the patients suggest that ctDNA levels may reflect the clinical status of the disease. Patients with positive ctDNA levels were more likely to have greater mutant allele frequencies in their primary tumors ( = .004) and undergo radiotherapy ( = .02), and the presence of ctDNA may correlate with response to systemic chemotherapy and/or disease recurrence.

Conclusions: Detection of ctDNA mutations may allow for the detection and monitoring of disease progression for chordomas.
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http://dx.doi.org/10.1093/noajnl/vdaa173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850091PMC
December 2020

Single cell sequencing reveals cell populations that predict primary resistance to imatinib in chronic myeloid leukemia.

Aging (Albany NY) 2020 11 23;12(24):25337-25355. Epub 2020 Nov 23.

State Key Lab of Molecular 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.

The treatment of chronic myeloid leukemia (CML), a disease caused by t(9;22)(q34;q11) reciprocal translocation, has advanced largely through the use of targeted tyrosine kinase inhibitors (TKIs). To identify molecular differences that might distinguish TKI responders from non-responders, we performed single cell RNA sequencing on cells (n = 41,723 cells) obtained from the peripheral blood of four CML patients at different stages of treatment to generate single cell expression profiles. Analysis of our single cell expression profiles in conjunction with those previously obtained from the bone marrow of additional CML patients and healthy donors (total = 69,263 cells) demonstrated that imatinib treatment significantly altered leukocyte population compositions in both responders and non-responders, and affected the expression profiles of multiple cell populations, including non-neoplastic cell types. Notably, in imatinib poor-responders, patient-specific pre-treatment unique stem/progenitor cells became enriched in peripheral blood compared to the responders. These results indicate that resistance to TKIs might be intrinsic in some CML patients rather than acquired, and that non-neoplastic immune cell types may also play vital roles in dispersing the responsiveness of patients to TKIs. Furthermore, these results demonstrated the potential utility of peripheral blood as a diagnostic tool in the TKI sensitivity of CML patients.
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http://dx.doi.org/10.18632/aging.104136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803567PMC
November 2020

Multiregion whole-exome sequencing of intraductal papillary mucinous neoplasms reveals frequent somatic mutations predominantly in low-grade regions.

Gut 2021 May 7;70(5):928-939. Epub 2020 Oct 7.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Objective: Intraductal papillary mucinous neoplasms (IPMNs) are non-invasive precursor lesions that can progress to invasive pancreatic cancer and are classified as low-grade or high-grade based on the morphology of the neoplastic epithelium. We aimed to compare genetic alterations in low-grade and high-grade regions of the same IPMN in order to identify molecular alterations underlying neoplastic progression.

Design: We performed multiregion whole exome sequencing on tissue samples from 17 IPMNs with both low-grade and high-grade dysplasia (76 IPMN regions, including 49 from low-grade dysplasia and 27 from high-grade dysplasia). We reconstructed the phylogeny for each case, and we assessed mutations in a novel driver gene in an independent cohort of 63 IPMN cyst fluid samples.

Results: Our multiregion whole exome sequencing identified , a previously unreported genetic driver of IPMN tumorigenesis, with hotspot mutations in one of two codons identified in >50% of the analyzed IPMNs. Mutations in were significantly more prevalent in low-grade regions in our sequenced cases. Phylogenetic analyses of whole exome sequencing data demonstrated diverse patterns of IPMN initiation and progression. Hotspot mutations in were also identified in an independent cohort of IPMN cyst fluid samples, again with a significantly higher prevalence in low-grade IPMNs.

Conclusion: Hotspot mutations in occur at high prevalence in IPMNs. Unique among pancreatic driver genes, mutations are enriched in low-grade IPMNs. These data highlight distinct molecular features of low-grade and high-grade dysplasia and suggest diverse pathways to high-grade dysplasia via the IPMN pathway.
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http://dx.doi.org/10.1136/gutjnl-2020-321217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262510PMC
May 2021

Genome-wide mutation analysis in precancerous lesions of endometrial carcinoma.

J Pathol 2021 01 13;253(1):119-128. Epub 2020 Nov 13.

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

Clinicopathological evidence supports endometrial atypical hyperplasia (AH) or endometrial intraepithelial neoplasia as the precursor of uterine endometrioid carcinoma (EC), the most common gynecologic malignancy. However, the pathogenic progression from AH to EC remains unclear. Here, we employed whole-exome sequencing to identify somatic mutations and copy number changes in micro-dissected lesions from 30 pairs of newly diagnosed AH and EC. We found that all but one pair of AHs shared the same DNA mismatch repair status as their corresponding ECs. The percentage of common mutations between AH lesions and corresponding ECs varied significantly, ranging from 0.1% to 82%. Microsatellite stable AHs had fewer cancer driver mutations than ECs (5 versus 7, p = 0.017), but among microsatellite unstable AHs and ECs there was no difference in mutational numbers (36 versus 38, p = 0.65). As compared to AH specimens, 19 (79%) of 24 microsatellite stable EC tumors gained new cancer driver mutations, most of which involved PTEN, ARID1A, PIK3CA, CTNNB1, or CHD4. Our results suggest that some AH lesions are the immediate precursor of ECs, and progression depends on acquisition of additional cancer driver mutations. However, a complex clonal relationship between AH and EC can also be appreciated, as in some cases both lesions diverge very early or arise independently, thus co-developing with distinct genetic trajectories. Our genome-wide profile of mutations in AH and EC shines new light on the molecular landscape of tumor progression. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5566DOI Listing
January 2021

Integrated molecular characterization reveals potential therapeutic strategies for pulmonary sarcomatoid carcinoma.

Nat Commun 2020 09 28;11(1):4878. Epub 2020 Sep 28.

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

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer with poor prognosis. Here, we perform multi-omics analysis of 56 PSC samples, 14 of which are microdissected to analyze intratumoral heterogeneity. We report the mutational landscape of PSC. The epithelial and sarcomatoid components share numerous genomic alterations, indicating a common progenitor. We find that epithelial-mesenchymal transition (EMT) plays important roles in the carcinogenesis of PSC. The pan-cancer analysis reveals high tumor mutation burden and leukocyte fraction of PSC. Integrated molecular classification shows three subgroups with distinct biology, prognosis and potential therapeutic strategies. Actionable mutations are enriched in C1 and C2, patients in C3 have a significantly longer overall survival, and C1 and C2 exhibit T-cell inflamed microenvironments. The three subgroups show molecular similarities to specific subtypes of conventional lung cancer. In conclusion, our study reveals the molecular characteristics and provides entry points for the treatment of PSC.
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http://dx.doi.org/10.1038/s41467-020-18702-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522294PMC
September 2020

Telomere Maintenance Associated Mutations in the Genetic Landscape of Gynecological Mucosal Melanoma.

Front Oncol 2020 2;10:1707. Epub 2020 Sep 2.

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

Purpose: Gynecological melanomas (GMs) are rare tumors with a poor prognosis. Here, we performed exome sequencing to generate the mutational landscape of GMs.

Methods: Next-generation sequencing was carried out on mucosal melanoma samples ( = 35) obtained from gynecological sites. The alternative telomere lengthening (ALT) phenotype was verified by fluorescence hybridization and the C-circle assay. Immunohistochemistry was performed to detect ATRX protein. Copy number variations in were detected by droplet digital polymerase chain reaction.

Results: In the 58 formalin-fixed paraffin-embedded samples, we identified 33 (56.9%) ALT-positive cases, with 23 showing loss of ATRX protein. promoter mutation was not detected in GMs ( = 40), but copy number variations in the region were observed in 20% (7/35) of the samples. amplification was mutually exclusive with ALT ( < 0.05). Kaplan-Meier revealed that ALT relative to amplification was associated with longer overall survival in GM patients without metastasis.

Conclusion: These findings indicate that telomere maintenance mechanisms play a critical role in the tumorigenesis of GMs and may aid in the prediction of clinical prognosis and the development of targeted therapy for the treatment of GM.
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http://dx.doi.org/10.3389/fonc.2020.01707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492295PMC
September 2020

A CRISPR knockout negative screen reveals synergy between CDKs inhibitor and metformin in the treatment of human cancer in vitro and in vivo.

Signal Transduct Target Ther 2020 08 19;5(1):152. Epub 2020 Aug 19.

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

Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent. However, the lack of a clear understanding of the indications of metformin limits its efficacy. Here, we performed a genome-wide CRISPR knockout negative screen to identify potential targets that might synergize with metformin. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells after 18 days of metformin treatment (T18) compared to those of the untreated cells at day 0 (T0) yielded candidate genes. Knockdown of a group of cyclin-dependent kinases (CDKs), including CDK1, CDK4, and CDK6, confirmed the results of the screen. Combination treatment of the CDKs inhibitor abemaciclib with metformin profoundly inhibited tumor viability in vitro and in vivo. Although cell cycle parameters were not further altered under the combination treatment, investigation of the metabolome revealed significant changes in cell metabolism, especially with regard to fatty acid oxidation, the tricarboxylic acid cycle and aspartate metabolism. Such changes appeared to be mediated through inhibition of the mTOR pathway. Collectively, our study suggests that the combination of CDKs inhibitor with metformin could be recognized as a potential therapy in future clinical applications.
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http://dx.doi.org/10.1038/s41392-020-0203-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434905PMC
August 2020

Methylation silencing of TGF-β receptor type II is involved in malignant transformation of esophageal squamous cell carcinoma.

Clin Epigenetics 2020 02 11;12(1):25. Epub 2020 Feb 11.

State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Research Building, No.17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.

Background: Although massive studies have been conducted to investigate the mechanisms of esophageal squamous cell carcinoma (ESCC) carcinogenesis, the understanding of molecular alterations during the malignant transformation of epithelial dysplasia is still lacking, especially regarding epigenetic changes.

Results: To better characterize the methylation changes during the malignant transformation of epithelial dysplasia, a whole-genome bisulfite sequencing analysis was performed on a series of tumor, dysplastic, and non-neoplastic epithelial tissue samples from esophageal squamous cell carcinoma (ESCC) patients. Promoter hypermethylation in TGF-β receptor type II (TGFBR2), an important mediator of TGF-β signaling, was identified. Further, we evaluated the methylation and expression of TGFBR2 in tumor samples through The Cancer Genome Atlas multiplatform data as well as immunohistochemistry. Moreover, treatment of ESCC cell lines with5-Aza-2'-deoxycytidine, a DNA methyltransferase inhibitor, reactivated the expression of TGFBR2. The lentiviral mediating the overexpression of TGFBR2 inhibited the proliferation of ESCC cell line by inducing cell cycle G2/M arrest. Furthermore, the overexpression of TGFBR2 inhibited the tumor growth obviously in vivo.

Conclusions: The characterization of methylation silencing of TGFBR2 in ESCC will enable us to further explore whether this epigenetic change could be considered as a predictor of malignant transformation in esophageal epithelial dysplasia and whether use of a TGFBR2 agonist may lead to a new therapeutic strategy in patients with ESCC.
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http://dx.doi.org/10.1186/s13148-020-0819-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014638PMC
February 2020

Genome-Wide CRISPR-Cas9 Screen Reveals Selective Vulnerability of -Mutant Cancers to WEE1 Inhibition.

Cancer Res 2020 02 24;80(3):510-523. Epub 2019 Sep 24.

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

The tumor suppressor gene is frequently mutated in a variety of tumors including gliomas and liver cancers, which are highly unresponsive to current therapies. Here, we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for -mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase , uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines , as well as xenografts . The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage-induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring mutations, indicating that the synthetic lethal relationship between and could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in . SIGNIFICANCE: -mutant cancer cells depend on WEE1, which provides a basis for therapeutically targeting WEE1 in -deficient cancers..
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3374DOI Listing
February 2020

A liquid biopsy assay for identifying early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals.

Mol Cell Oncol 2019 28;6(5):e1614419. Epub 2019 May 28.

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

Biannual screening of hepatocellular carcinoma (HCC) by ultrasonography and serum α-fetoprotein has been proposed to the HBsAg-seropositive individuals. The widespread application to all of them was restricted due to limited acceptability of resource and anxiety-producing procedures. We recently developed a novel liquid biopsy assay to identify HCC cases in asymptomatic HBsAg-positive individuals.
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http://dx.doi.org/10.1080/23723556.2019.1614419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736321PMC
May 2019

Intraductal Papillary Mucinous Neoplasms Arise From Multiple Independent Clones, Each With Distinct Mutations.

Gastroenterology 2019 10 5;157(4):1123-1137.e22. Epub 2019 Jun 5.

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland. Electronic address:

Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) are lesions that can progress to invasive pancreatic cancer and constitute an important system for studies of pancreatic tumorigenesis. We performed comprehensive genomic analyses of entire IPMNs to determine the diversity of somatic mutations in genes that promote tumorigenesis.

Methods: We microdissected neoplastic tissues from 6-24 regions each of 20 resected IPMNs, resulting in 227 neoplastic samples that were analyzed by capture-based targeted sequencing. Somatic mutations in genes associated with pancreatic tumorigenesis were assessed across entire IPMN lesions, and the resulting data were supported by evolutionary modeling, whole-exome sequencing, and in situ detection of mutations.

Results: We found a high prevalence of heterogeneity among mutations in IPMNs. Heterogeneity in mutations in KRAS and GNAS was significantly more prevalent in IPMNs with low-grade dysplasia than in IPMNs with high-grade dysplasia (P < .02). Whole-exome sequencing confirmed that IPMNs contained multiple independent clones, each with distinct mutations, as originally indicated by targeted sequencing and evolutionary modeling. We also found evidence for convergent evolution of mutations in RNF43 and TP53, which are acquired during later stages of tumorigenesis.

Conclusions: In an analysis of the heterogeneity of mutations throughout IPMNs, we found that early-stage IPMNs contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. These findings challenge the model in which pancreatic neoplasms arise from a single clone. Increasing our understanding of the mechanisms of IPMN polyclonality could lead to strategies to identify patients at increased risk for pancreatic cancer.
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http://dx.doi.org/10.1053/j.gastro.2019.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756950PMC
October 2019

Characterization of rare NEIL1 variants found in East Asian populations.

DNA Repair (Amst) 2019 07 3;79:32-39. Epub 2019 May 3.

Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, 97239, United States; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97239, United States; Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR, 97239, United States. Electronic address:

The combination of chronic dietary exposure to the fungal toxin, aflatoxin B (AFB), and hepatitis B viral (HBV) infection is associated with an increased risk for early onset hepatocellular carcinomas (HCCs). An in-depth knowledge of the mechanisms driving carcinogenesis is critical for the identification of genetic risk factors affecting the susceptibility of individuals who are HBV infected and AFB exposed. AFB-induced mutagenesis is characterized by G to T transversions. Hence, the DNA repair pathways that function on AFB-induced DNA adducts or base damage from HBV-induced inflammation are anticipated to have a strong role in limiting carcinogenesis. These pathways define the mutagenic burden in the target tissues and ultimately limit cellular progression to cancer. Murine data have demonstrated that NEIL1 in the DNA base excision repair pathway was significantly more important than nucleotide excision repair relative to elevated risk for induction of HCCs. These data suggest that deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To investigate this hypothesis, publicly-available data on variant alleles of NEIL1 were analyzed and compared with genome sequencing data from HCC tissues derived from individuals residing in Qidong County (China). Three variant alleles were identified and the corresponding A51V, P68H, and G245R enzymes were characterized for glycosylase activity on genomic DNA containing a spectrum of oxidatively-induced base damage and an oligodeoxynucleotide containing a site-specific AFB-formamidopyrimidine guanine adduct. Although the efficiency of the P68H variant was modestly decreased, the A51V and G245R variants showed nearly wild-type activities. Consistent with biochemical findings, molecular modeling of these variants demonstrated only slight local structural alterations. However, A51V was highly temperature sensitive suggesting that its biological activity would be greatly reduced. Overall, these studies have direct human health relevance pertaining to genetic risk factors and biochemical pathways previously not recognized as germane to induction of HCCs.
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http://dx.doi.org/10.1016/j.dnarep.2019.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677271PMC
July 2019

Genome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies.

Theranostics 2019 30;9(4):1115-1124. Epub 2019 Jan 30.

State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Collaborative Innovation Center for Cancer Medicine, Beijing, China.

: Epstein-Barr virus (EBV) is associated with multiple malignancies with expression of viral oncogenic proteins and chronic inflammation as major mechanisms contributing to tumor development. A less well-studied mechanism is the integration of EBV into the human genome possibly at sites which may disrupt gene expression or genome stability. : We sequenced tumor DNA to profile the EBV sequences by hybridization-based enrichment. Bioinformatic analysis was used to detect the breakpoints of EBV integrations in the genome of cancer cells. : We identified 197 breakpoints in nasopharyngeal carcinomas and other EBV-associated malignancies. EBV integrations were enriched at vulnerable regions of the human genome and were close to tumor suppressor and inflammation-related genes. We found that EBV integrations into the introns could decrease the expression of the inflammation-related genes, , , and , in NPC tumors. In the EBV genome, the breakpoints were frequently at or terminal repeats. These breakpoints were surrounded by microhomology sequences, consistent with a mechanism for integration involving viral genome replication and microhomology-mediated recombination. : Our finding provides insight into the potential of EBV integration as an additional mechanism mediating tumorigenesis in EBV associated malignancies.
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http://dx.doi.org/10.7150/thno.29622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401403PMC
January 2020

Detection of early-stage hepatocellular carcinoma in asymptomatic HBsAg-seropositive individuals by liquid biopsy.

Proc Natl Acad Sci U S A 2019 03 11;116(13):6308-6312. Epub 2019 Mar 11.

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

Liquid biopsies, based on cell free DNA (cfDNA) and proteins, have shown the potential to detect early stage cancers of diverse tissue types. However, most of these studies were retrospective, using individuals previously diagnosed with cancer as cases and healthy individuals as controls. Here, we developed a liquid biopsy assay, named the hepatocellular carcinoma screen (HCCscreen), to identify HCC from the surface antigen of hepatitis B virus (HBsAg) positive asymptomatic individuals in the community population. The training cohort consisted of individuals who had liver nodules and/or elevated serum α-fetoprotein (AFP) levels, and the assay robustly separated those with HCC from those who were non-HCC with a sensitivity of 85% and a specificity of 93%. We further applied this assay to 331 individuals with normal liver ultrasonography and serum AFP levels. A total of 24 positive cases were identified, and a clinical follow-up for 6-8 mo confirmed four had developed HCC. No HCC cases were diagnosed from the 307 test-negative individuals in the follow-up during the same timescale. Thus, the assay showed 100% sensitivity, 94% specificity, and 17% positive predictive value in the validation cohort. Notably, each of the four HCC cases was at the early stage (<3 cm) when diagnosed. Our study provides evidence that the use of combined detection of cfDNA alterations and protein markers is a feasible approach to identify early stage HCC from asymptomatic community populations with unknown HCC status.
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http://dx.doi.org/10.1073/pnas.1819799116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442629PMC
March 2019

Mutational signatures and the genomic landscape of betel quid chewing-associated tongue carcinoma.

Cancer Med 2019 02 22;8(2):701-711. Epub 2019 Jan 22.

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

Our study presents the genetic landscape betel quid chewing-associated tongue carcinomas (BQ-TCs). We compared the genetic landscape and mutational signatures of 15 BQ-TCs, five nonbetel quid chewing-associated tongue carcinomas (nBQ-TCs), and 82 tongue carcinomas in general population from the TCGA (TCGA-TCs) project. The highlights of this research mainly include: (a) The genetic landscape of BQ-TC was characterized with frequent mutations in RASA1 gene and in CpG islands throughout the genome. (b) The BQ-TC had a distinct mutational signature from that of nBQ-TC and tongue carcinomas in the general population, and this signature was associated with the mutations in RASA1 and in CpG islands. (c) Our study indicates that betel quid (BQ) chewing classifies a distinct group of tongue carcinoma. The BQ chewing might not contribute to the tumorigenesis of tongue carcinomas as a mutagen.
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http://dx.doi.org/10.1002/cam4.1888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382727PMC
February 2019

Genomic landscape and evolutionary trajectories of ovarian cancer precursor lesions.

J Pathol 2019 05 15;248(1):41-50. Epub 2019 Feb 15.

Departments of Pathology and Gynecology/Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, USA.

The clonal relationship between ovarian high-grade serous carcinoma (HGSC) and its presumed precursor lesion, serous tubal intraepithelial carcinoma (STIC), has been reported. However, when analyzing patients with concurrent ovarian carcinoma and tubal lesion, the extensive carcinoma tissues present at diagnosis may have effaced the natural habitat of precursor clone(s), obscuring tumor clonal evolutionary history, or may have disseminated to anatomically adjacent fimbriae ends, masquerading as precursor lesions. To circumvent these limitations, we analyzed the genomic landscape of incidental tubal precursor lesions including p53 signature, dormant STIC or serous tubal intraepithelial lesion (STIL) and proliferative STIC in women without ovarian carcinoma or any cancer diagnosis using whole-exome sequencing and amplicon sequencing. In three of the four cancer-free women with multiple discrete tubal lesions we observed non-identical TP53 mutations between precursor lesions from the same individual. In one of the four women with co-existing ovarian HGSC and tubal precursor lesion we found non-identical TP53 mutations and a lack of common mutations shared between her precursor lesion and carcinoma. Analyzing the evolutionary history of multiple tubal lesions in the same four patients with concurrent ovarian carcinoma indicated distinct evolution trajectories. Collectively, the results support diverse clonal origins of tubal precursor lesions at the very early stages of tumorigenesis. Mathematical modeling based on lesion-specific proliferation rates indicated that p53 signature and dormant STIC may take a prolonged time (two decades or more) to develop into STIC, whereas STIC may progress to carcinoma in a much shorter time (6 years). The above findings may have implications for future research aimed at prevention and early detection of ovarian cancer. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618168PMC
May 2019

Promising efficacy of SHR-1210, a novel anti-programmed cell death 1 antibody, in patients with advanced gastric and gastroesophageal junction cancer in China.

Cancer 2019 03 3;125(5):742-749. Epub 2018 Dec 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, China.

Background: The clinical response to anti-programmed cell death 1 (PD-1) antibodies in patients with advanced gastric and gastroesophageal junction (GEJ) cancer in China has not been reported.

Methods: This study evaluated the efficacy and safety of SHR-1210, an anti-PD-1 antibody, in patients with advanced gastric/GEJ cancer in a phase 1 trial. The associations between candidate biomarkers (programmed death ligand 1 [PD-L1] expression, mismatch repair status, tumor mutation load, and lactate dehydrogenase [LDH] levels) and the efficacy of SHR-1210 were also explored.

Results: Thirty patients with recurrent or metastatic gastric/GEJ adenocarcinoma who were refractory or intolerant to previous chemotherapy were enrolled between June 2, 2016, and June 8, 2017. Seven patients (23.3%) demonstrated objective responses, including 1 complete response. The objective response rates for patients with PD-L1-positive and PD-L1-negative tumors were 23.1% (3 of 13) and 26.7% (4 of 15), respectively (P = 1.000). Two treatment-related grade 3 or higher adverse events were reported: one was grade 3 pruritus, and the other (3.3%) was grade 5 interstitial lung disease. All 20 patients tested for the mismatch repair status had mismatch repair-proficient tumors, and the response rate was 30.0% (95% confidence interval, 11.9%-54.3%). Patients with a higher mutation load (4 of 10) tended to have better responses than those with fewer mutations (2 of 10), but the difference was not significant (P = .628). Patients with a >10% relative increase from the baseline LDH level were more likely to experience disease progression (90% [9 of 10]) than patients with a ≤10% change (40% [8 of 20]; P = .017).

Conclusions: Anti-PD-1 antibody SHR-1210 shows encouraging efficacy in patients with advanced gastric/GEJ cancer in China, including mismatch repair-proficient subgroups.
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http://dx.doi.org/10.1002/cncr.31855DOI Listing
March 2019

Hereditary brain tumor with a homozygous germline mutation in PMS2: pedigree analysis and prenatal screening in a family with constitutional mismatch repair deficiency (CMMRD) syndrome.

Fam Cancer 2019 04;18(2):261-265

Department of Pathology, Duke University Medical Center, 199B-MSRB Building, Research Drive, DUMC-3156, Durham, NC, 27710, USA.

Precise genetic counseling and prenatal diagnosis are often hindered by incomplete penetrance of risk variance and complex patterns of inheritance. Here, we performed a clinical and genetic study of a five-generation Pakistani family with a history of multiple cases of childhood brain tumors. Six affected individuals died of brain tumors at very early ages and three were confirmed as having a homozygous mutation in exon 6 of the PMS2 gene (c.543delT). Fifteen members of the family were identified as heterozygous carriers of this mutation with a lack of cancer incidence. Both clinical manifestations and genetic test results of brain tumor patients in the family support the diagnosis of constitutional mismatch repair deficiency (CMMRD) syndrome, a condition in which individuals carry homozygous germline mutations in mismatch repair machinery genes with an early onset of malignancies such as glioma. This information was used to guide prenatal diagnosis with genetic testing on chorionic villus samples for the family. This is the first report of prenatal genetic diagnosis of hereditary brain tumor.
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http://dx.doi.org/10.1007/s10689-018-0112-4DOI Listing
April 2019

Molecular profiling of tumors of the brainstem by sequencing of CSF-derived circulating tumor DNA.

Acta Neuropathol 2019 02 20;137(2):297-306. Epub 2018 Nov 20.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Nan Si Huan Xi Lu 119, Fengtai District, Beijing, 100070, China.

Brainstem gliomas are molecularly heterogeneous diseases, many of which are difficult to safely surgically resect and have limited treatment options due to their eloquent location. These constraints pose challenges to biopsy, which limits the use of routine molecular profiling and identification of personalized therapies. Here, we explored the potential of sequencing of circulating tumor DNA (ctDNA) isolated from the cerebrospinal fluid (CSF) of brainstem glioma patients as a less invasive approach for tumor molecular profiling. CSF was obtained from patients either intraoperatively (91.2%, 52/57), from ventricular-peritoneal shunt (3.5%, 2/57), or by lumbar puncture (5.3%, 3/57), all prior to surgical manipulation of the tumor. Deep sequencing of glioma-associated genes was performed on CSF-derived ctDNA and, where available, matched blood and tumor DNA from 57 patients, including nine medullary and 23 diffuse intrinsic pontine gliomas (DIPG). At least one tumor-specific mutation was detected in over 82.5% of CSF ctDNA samples (47/57). In cases with primary tumors harboring at least one mutation, alterations were identified in the CSF ctDNA of 97.3% of cases (36/37). In over 83% (31/37) of cases, all primary tumor alterations were detected in the CSF, and in 91.9% (34/37) of cases, at least half of the alterations were identified. Among ten patients found to have primary tumors negative for mutations, 30% (3/10) had detectable somatic alterations in the CSF. Finally, mutation detection using plasma ctDNA was less sensitive than sequencing the CSF ctDNA (38% vs. 100%, respectively). Our study indicates that deep sequencing of CSF ctDNA is a reliable technique for detecting tumor-specific alterations in brainstem tumors. This approach may offer an alternative approach to stereotactic biopsy for molecular profiling of brainstem tumors.
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http://dx.doi.org/10.1007/s00401-018-1936-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523750PMC
February 2019

Sensitive and rapid detection of TERT promoter and IDH mutations in diffuse gliomas.

Neuro Oncol 2019 03;21(4):440-450

The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina, USA.

Background: Mutations in telomerase reverse transcriptase promoter (TERTp) and isocitrate dehydrogenase 1 and 2 (IDH) offer objective markers to assist in classifying diffuse gliomas into genetic subgroups. However, traditional mutation detection techniques lack sensitivity or have long turnaround times or high costs. We developed GliomaDx, an allele-specific, locked nucleic acid-based quantitative PCR assay to overcome these limitations and sensitively detect TERTp and IDH mutations.

Methods: We evaluated the performance of GliomaDx on cell line DNA and frozen tissue diffuse glioma samples with variable tumor percentage to mimic use in clinical settings and validated low percentage variants using sensitive techniques including droplet digital PCR (ddPCR) and next-generation sequencing. We also developed GliomaDx Nest, which incorporates a high-fidelity multiplex pre-amplification step prior to allele-specific PCR for low-input formalin-fixed paraffin embedded (FFPE) samples.

Results: GliomaDx detects the TERTp and IDH1 alterations at an analytical sensitivity of 0.1% mutant allele fraction, corresponding to 0.2% tumor cellularity. GliomaDx identified TERTp/IDH1 alterations in a cohort of frozen tissue samples with variable tumor percentage of all major diffuse glioma histologic types. GliomaDx Nest is able to detect these hotspot mutations with similar sensitivity from pre-amplified samples and was successfully tested on a cohort of clinical FFPE samples. Testing of a cohort of previously identified TERTpWT-IDHWT gliomas (by Sanger sequencing) revealed that 26.3% harbored low-percentage mutations. Analysis by ddPCR and whole exome sequencing of these tumors confirmed the low mutant fraction of these alterations and overall mutation-based tumor purity.

Conclusions: Our results show that GliomaDx can rapidly detect TERTp/IDH mutations with high sensitivity, identifying cases that might be missed due to the lack of sensitivity of other techniques. This approach may facilitate more objective classification of diffuse glioma samples in clinical settings such as intraoperative diagnosis or in testing cases with low tumor purity.
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http://dx.doi.org/10.1093/neuonc/noy167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422442PMC
March 2019

Precancerous neoplastic cells can move through the pancreatic ductal system.

Nature 2018 09 3;561(7722):201-205. Epub 2018 Sep 3.

The David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. However, the evolutionary and genetic relationships among co-existing lesions are unclear. Here we analysed the somatic variants of pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to invasive pancreatic cancer. We estimate that this multi-step progression generally spans many years. These new data reframe the step-wise progression model of pancreatic cancer by illustrating that independent, high-grade pancreatic precursor lesions observed in a single pancreas often represent a single neoplasm that has colonized the ductal system, accumulating spatial and genetic divergence over time.
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http://dx.doi.org/10.1038/s41586-018-0481-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342205PMC
September 2018
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