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USH2A variant identified in a Han-Chinese patient with clinically suspected retinitis pigmentosa.

Hallux valgus is a common form of foot deformity, and genetic factors contribute substantially to the pathogenesis of hallux valgus deformity. We conducted a genetic study on the structural variants underlying familial hallux valgus using whole exome sequencing approach. Twenty individuals from five hallux valgus families and two sporadic cases were included in this study. A total of 372 copy number variations were found and passed quality control filtering. Among them, 43 were only present in cases but not in controls or healthy individuals in the database of genomic variants. The genes covered by these copy number variations were enriched in gene sets related to immune signaling pathway, and cytochrome P450 metabolism. The hereditary CNVs demonstrate a dominant inheritance pattern. Two candidate pathogenic CNVs were further validated by quantitative-PCR. This study suggests that hallux valgus is a degenerative joint disease involving the dysregulation of immune and metabolism signaling pathways.

In recent years, GeneMind Biosciences has presented a series of new sequencers, including GenoLab M and FASTASeq 300. Here we used the same capture DNA libraries constructed based on the Agilent V6 WES panel to evaluate the performance of the GenoLab M and FASTASeq 300 Sequencing Platforms.

Extrachromosomal circular DNA is a newly evolved hallmark in cancer and is associated with cancer genome instability, oncogene amplification, acquired resistance, and disease progression. A Cancer Circular Genome Atlas (CCGA) consortium is formed to map the missing link of circulome in cancers. Here, we report our pilot CCGA results which we comprehensively characterize the chromosomal DNA, extrachromosomal circular DNA, and transcriptomic alteration landscape in urothelial bladder carcinoma (UBC) of 80 patients by whole-genome/exon sequencing, Circle-seq, single-molecule long-read sequencing technology, and RNA sequencing. Leveraging these large amounts of pair-wise (UBC vs. normal adjacent tissue) and trans-OMICS (genome, circulome, transcriptome) data, we exploit the genome-wide landscape of circular DNA-associated somatic mutations, unbalanced structural variations, oncogene amplification, genomic distributions, structure, and correlations with altered gene expression and clinical outcomes in UBCs. Our results reveal that UBCs contain high load of extrachromosomal circular DNAs which are in cis correlated with cluster of hypermutations (kataegis), copy number variations, oncogene amplifications, structure variations, DNA repair alteration, as well as poor clinical survival. Furthermore, our analyses probe high frequency (81%) of chromothripsis-like events in UBCs, supported by the detection of an extremely chimeric circular DNA containing DNA fragments from nine chromosomes. The CCGA-UBC presents an integrative trans-OMICS analysis strategy to map landscape of extrachromosomal circular DNAs in cancers and may provide opportunities for the development of novel therapeutic strategies.

A heterozygous splicing variant and a heterozygous missense variant in the collagen type IV alpha 4 chain gene (COL4A4) were identified in two unrelated Han-Chinese families with hematuria.

Left-right asymmetry disorders are genetically heterogeneous and have variable manifestations (from asymptomatic to serious clinical problems).

Identification of DNAH17 variants in Han-Chinese patients with left-right asymmetry disorders

Liquid biopsy is a promising non-invasive alternative for cancer screening and MRD detection, although there are some concerns regarding its clinical application. To evaluate its efficiency in detecting lung cancer (LC), we applied a modified WGS-based HIFI method for LC screening and postoperative MRD detection by combining the hyper-co-methylated read approach and the circulating single-molecule amplification and resequencing technology (cSMART2.0). For early screening of LC, the LC score model was constructed using the support vector machine method, which showed satisfactory sensitivity at a high specificity of 98% and achieved an area under the curve of 0.912 in the validation set comprising 306 participants prospectively enrolled from multiple centers.

Specific aims: To identify novel genetic characterizations involved in PD-L1/2, other immune checkpoints and other driver genes in DLBCL patients and to identify patients that would benefit from immunotherapies and targeted therapies. Relevance: Immunotherapies and targeted therapies are currently the hottest topics for cancer treatment. A large number of clinical trials involved in checkpoint inhibitors and small molecule targeted drugs, including PD-1/PD-L1 antibodies and BTK inhibitors, are ongoing for various cancer types, including B cell lymphoma. Herein, we will try to identify some novel genetic variants for immune checkpoint molecules and some important oncogenes in DLBCL patients. Our findings are complementary for the genetic characterizations for these immune checkpoint molecules and oncogenes, and will also provide a theoretical foundation for the design of molecular targeted drugs and precision diagnosis and therapy.

采集了家系里面20位AVNRT病人，进行了全外显子测序后，筛选出可靠性较高的致病基因。

本研究为一项开放式，单臂，单中心，前瞻性II期临床研究，旨在评价局部晚期(cT3~4aN+M0)的近端胃腺癌患者中，进行以PD-1抗体SHR-1210联合放化疗的新辅助治疗继以根治术的疗效与安全性。

the next-generation sequencing of a panel of 1021 genes in 34 Clear cell carcinoma of the ovary (OCCC)

对101例中国单中心晚期非小细胞肺癌样本进行研究，基于NGS测序探索一线治疗相关的预后标志物

Lung adenocarcinoma (LUAD) usually contain heterogeneous histological subtypes, among which the micropapillary (MIP) subtype was associated with poor prognosis while the lepidic (LEP) subtype possessed the most favorable outcome. However, the genomic features of MIP subtype responsible for its malignant behaviors is largely unknown. In this study, 8 FFPE samples from LUAD patients were micro-dissected to isolate MIP and LEP components, then sequenced by whole-exome sequencing. A more comprehensive analysis involving our samples and public validation cohorts on the two subtypes was performed to better decipher the key biological and evolutionary mechanisms. As expected, the LEP and MIP subtypes exhibited largest disease free survival (DFS) difference in our patients. EGFR was found with highest mutation frequency. Shared mutations were observed between paired LEP and MIP components from single patients and were verified in Lung-Broad, Lung-OncoSG as well as TCGA-LUAD cohort. Distinct biological processes or pathways were involved in the evolutionary of the two components. Besides, analyses on copy number variation (CNV) and intratumor heterogeneity (ITH) further discovered the possible immunosurveillance escape, the discrepancy between mutation and CNV level ITH and the pervasive DNA Damage Response as well as WNT pathway gene alternations in MIP component. Phylogenetic analysis on 5 pairs of LEP and MIP components further confirmed the presence of ancestral EGFR mutations. Through comprehensive analyses in our samples and public cohorts, PTP4A3, NAPRT and RECQL4 were identified to be co-amplified. Multi-omics data showed immunosuppression prevalence in MIP component. Our results suggest that MIP and LEP components from one patient were derived from same initiation cells and the pathway-specific mutations acquired after EGFR clonal mutation could shape the subtype-specificity. Immunosuppression prevalence in MIP subtype may contribute to its unfavorable prognosis.

6 tissue samples including 3 primary tumors, 2 relapse tumors and 1 normal control were collected from a PMME patient, and were subjected to whole exome sequencing to track the dynamic genetic changes.

Specific aims: To identify genetic subtypes of follicular lymphoma (FL) based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. Relevance: FL is a clinically and genetically heterogeneous disease and still considered to be incurable. Genomic sequencing studies in FL have focused on recurrent mutations in individual genes, revealing oncogenic mechanisms. We hypothesized that a nosology of FL based on shared genetic pathogenesis could aid in our understanding of treatment response and identify therapeutic vulnerabilities. Herein, we uncovered genetic subtypes of FL with distinct genotypic, epigenetic, and clinical characteristics through whole-genome integrative analysis. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into FL pathogenesis. The coordinate genetic signatures also predict outcome and suggest precision-medicine strategies in FL.

We investigated 14 patients with advanced non-small cell lung cancer who had transformed into small cell lung cancer.14 tumor samples from 7 patients (including NSCLC and SCLC samples from each patient) were sequenced to analyze gene changes before and after transformation.

Study on the prediction of the curative effect of immunotherapy in patients with lung cancer

133 azoospermia patients were enrolled to undergo WES in this study, fertile men as control.

Hepatitis B virus (HBV) infection has been associated with an increased risk for B-cell lymphomas. We previously showed that diffuse large B-cell lymphoma (DLBCL) patients with concomitant HBV infection (surface antigen positive, HBsAg+) are characterized by distinct clinical and genetic features. Here, we showed that 24% of follicular lymphoma (FL) patients from China, an endemic area of HBV infection, are HBsAg+. Compared to the HBsAg-negative FL patients, HBsAg+ patients are younger, have a higher histological grade at diagnosis and higher incidence of progression of disease within 24 months (POD24). Moreover, by sequencing the genomes of 109 FL tumors, we observed an enhanced mutagenesis and a unique set of highly mutated genes including TNFAIP3, FAS, HIST1H1C, KLF2, TP53, PIM1, TMSB4X and DUSP2 in HBsAg+ FLs. These HBsAg+ tumors often lack the hallmark of HBsAg-negative FLs, i.e. IGH/BCL2 translocations and CREBBP mutations. Transcriptomic analyses further showed that HBsAg+ FLs displayed gene expression signatures resembling the activated B-cell (ABC) subtype of DLBCL, involving IRF4-targeted genes and NF-���B/MYD88 signaling pathways. Finally, we identified an increased number of tumor-infiltrating CD8+ memory T-cells, CD4+ Th1-cells, M1 macrophages and higher T-cell exhaustion signature in HBsAg+ FL samples. Taken together, we present new genetic/epigenetic evidence that links chronic HBV infection to B-cell lymphomagenesis, and HBV-associated FL is likely to have a distinct cell-of-origin and represent as a separate subtype of FL. Targetable genetic/epigenetic alterations identified in tumors and their associated tumor microenvironment may also provide potential novel therapeutic approaches for this subgroup of patients.

Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. In addition, the genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a potential nosology for precision-medicine strategies in DLBCL.

Tumor and matched metastatic tissues were collected from 16 patients diagnosed with colorectal cancer and subjected to whole-exome sequencing (WES) and RNA sequencing (RNA-seq) for studying colorectal cancer clonal evolution and immune escape during colorectal liver metastasis(CLM).

We performed whole-exome sequencing, RNA sequencing and immunohistochemistry profiling on 46 pairs of PSCCE and matched normal samples.

Background: Tumor mutational burden (TMB) is a promising biomarker for stratifying patient subpopulation who would benefit from immune checkpoint blockade (ICB) therapies. However, TMB measurements between different methods are poorly comparable. Furthermore, the effect of low tumor content on TMB estimation has never been systematically investigated. A standardized data analysis pipeline for TMB calculation and reporting for samples with variable tumor content is needed. Design: We built a linear model to correlate TMB estimated using whole exome sequencing (wesTMB) with targeted panel sequencing (psTMB). We further produced 12 series of reference DNA samples derived from tumor-normal paired cell lines with variable TMB in the parental tumor cell lines. Each tumor cell line was mixed with its matched normal at 0% (control), 1%, 2%, 5%, and 10% mass-to-mass ratio to mimic the variable tumor content in clinical setup. The reference standards were distributed to five vendors. This comparative test was intended to challenge both the quantitative coherence of TMB measurement by different vendors and the validity of our in-silico model. Results: Simulated psTMB and wesTMB of standard samples fitted the linear model trained by TCGA data. Dilution simulation demonstrated the decisive role of low-VAF variations to TMB detection in low tumor content samples. For 5% and 10% diluted reference standards, variants calling were reproducible and could be confirmed compared to parental cell lines. Futhermore, psTMB and wesTMB correlated closely for TMB-high patient stratification based on the linear model. Conclusions: We developed a linear model to establish the quantitative correlation between wesTMB and psTMB. A set of DNA reference standards was produced in aid to standardize TMB measurements in samples with low tumor content across different targeted sequencing panels. This study is a significant contribution aiming to harmonize TMB estimation and extend its future application in clinical samples with low tumor content.

Genetic alterations in many components of the homologous recombination, DNA damage response and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes including familial pancreatic cancer. In this study, we examined the genetic alterations in a companion diagnostic 15-gene HR-DDR panel and a comprehensive analysis of HR-DDR deficient in eight pancreatic ductal adenocarcinoma (PDAC) patients by the whole exome and whole genome sequencing . Our study provided a support including RAD51B in the germline test of HR-DDR pathway genes.

研究来自天津肿瘤医院IMPC乳腺癌的冰冻组织样本WES和WGS等多组学数据

In this study, 32 patients with non-traumatic femoral head necrosis and 30 healthy subjects were selected as the subjects. Total exome sequencing was performed on the necrotic tissue and blood of the patients and the blood of normal subjects to analyze and identify embryonic and somatic gene mutations in non-traumatic femoral head necrosis.In order to provide molecular targets for clinical diagnosis and treatment, the role of embryonic genetic factors and somatic mutations in the development of femoral head necrosis was investigated.

We collected tumor samples from 16 patients with lower grade gliomas (LGG) and 35 patients with glioblastoma (GBM), and performed whole exome sequencing (WES) analysis on them to compare the genomic characterization between LGG and GBM.

Osteosarcoma (OTS) is aggressive bone malignancy without wellrecognized prognosis biomarker, predominantly occurring in children and adolescents as well as adults aged 40 years and over.Although neoadjuvant and adjuvant chemotherapy or surgical resection improves the 5- year survival rates from 20% to 70% since 1970s, the 5-year survival rate for patients with metastatic or relapsed OTS is only about 10%~30%. Informative prognostic biomarker is in need for better patient’s stratification in terms of medication strategy. TMB is defined as total number of non-synonymous somatic mutations in coding areas of per tumor genomic megabase. Numerous studies have demonstrated that tumor mutational burden (TMB) is an independent biomarker to predict clinical outcomes. However, its prognostic value in OTS remains unknown. In this study, we aim to evaluate the implication of TMB in OTS patients. .

胃、肠、胰腺、食道、胆囊神经内分泌癌全外显子测序信息

PALB2可能是单倍体功能不全的一个例子，因为单个杂合突变会导致恶性表型。但是，有人认为，PALB2功能拷贝中的继发性体细胞点突变会导致杂合性（LOH）和恶性肿瘤的丧失。我们从196名晚期乳腺癌（ABC）患者和另外480名患有各种家族性癌症的患者中筛选了种系PALB2突变的肿瘤和血液标本。我们分析了28个PALB2胚系突变患者的LOH和突变特征

通过视网膜色素变性家系研究，阐述中国人群的遗传特点以及基因型频谱，对临床诊断、预防具有极其重要的意义

Rare inherited variations in multiplex families with Gilles de la Tourette Syndrome (GTS) are suggested to play an important role in the genetic etiology of GTS. In order to explore the rare inherited variations with the risk of GTS, whole-exome sequencing (WES) was performed in a family with three affected patients with GTS. Among the five novel rare variations identified by WES, CLCN2 G161S was presented in three patients, but not in four unaffected individuals, and thus co-segregated with GTS. A validation study was also performed in a cohort of Chinses Han population to further examine the identified rare variants. CLCN2 G161S was genotyped in 207 sporadic patients with tic disorder including 111 patients with GTS and 489 healthy controls. Compared with controls (AF=0), CLCN2 G161S had higher variant allele frequency in patients with tic (AF=0.00483) and in patients with GTS (0.00900), respectively. However, this variant was absent from the current 1000 Genome databases and the variant allele frequency is very low in the current public databases including ExAC (AF=0.00001) and GnomAD (AF=0.00003). Our results suggest that CLCN2 G161S might play a major role in the genetic etiology of GTS, at least in a Chinese Han population.

通过眼底黄色斑点症家系研究系统阐述中国人群ABCA4基因遗传致病机制

家族性渗出性玻璃体视网膜病变（familial exudative vitreoretinopathy , FEVR）是一种少见的以玻璃体视网膜异常为主的疾病，主要表现有周边部视网膜血管异常和新生血管，可并发玻璃体混浊、黄斑移位和牵拉性视网膜脱离等。本病患病率较低，多为常染色体显性遗传 。自1969 年Schepens和Criswick 首先提出并命名以来，国内外对于FEVR 的研究日益深入。但因FEVR 临床表现多种多样，易被漏诊或误诊，延误治疗时机。荧光素眼底血管造影（fundus fl uorescein angiography，FFA）是上世纪60 年代兴起的眼科检查技术，能动态观察活体眼底循环结构，自使用以来在眼底疾病的诊断、治疗及观察等多方面做出了重要贡献 。随着FFA 在临床上的进一步推广，其在FEVR 的诊断、确定病变范围以及提示病情发展等方面发挥着愈加重要的作用。本研究回顾性分析了一例临床诊断为家族性渗出性玻璃体视网膜病变的家系患者，分析了疾病不同阶段的FFA检查结果和临床表现，论证了TSPAN12基因的起始密码子突变在同一家系不同患者之间呈现高度临床异质性表现，进一步阐述了临床诊断及预防中该疾病的指导意义

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

青岛大学附属医院对35例阴茎癌样本进行全外显子测序及生物信息分析，探索阴茎癌发生发展及预后相关的基因变异。

通过对130个癌症细胞进行单细胞全外显子测序，解析胃癌异质性与发生发展机制。

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare and distinct subtype of primary lung cancer characterized by Epstein-Barr virus (EBV) infection. In this study, we present a whole-exome sequencing, targeted deep sequencing and single-nucleotide polymorphism arrays analysis to uncover comprehensive genomic landscape of pulmonary LELC. Our study represents the first mutational landscape of pulmonary LELC and provide a road map to facilitate genome-guided personalized treatment.

14 breast cancer exomes and matched transcriptomes generated from BGISEQ-500 sequencing platform.

通过对55例小细胞食管癌病人的全外显子组测序，构建小细胞食管癌变异图谱，解析小细胞食管癌发生发展机制。

心脏传导阻滞是具有遗传性的疾病，并且发病机制尚不明确。找到致病基因是了解发病机制并进行治疗干预的基本。

Whole exome sequencing of esophageal cancer

a Colon cancer Exome sequencing study

We sequenced 5 Fanconi anaemia affecting families.

The purpose of the project is to support the discovery and understanding of genetic variants that influence human disease. DNA for sequencing was extracted from whole blood