A pan-cancer study on characteristic of CDK4/6 amplification between Chinese and Western patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15074-e15074
Author(s):  
Yamin Zhang ◽  
Zilin Cui ◽  
Rui Shi ◽  
Xiaolong Liu ◽  
Yang Li ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Liver Cancer ◽  
Soft Tissue Sarcoma ◽  
Lung Adenocarcinoma ◽  
Ovarian Carcinoma ◽  
Cancer Patients ◽  
Stomach Carcinoma ◽  
Chinese Cohort ◽  
Cancer Types ◽  
Pan Cancer

e15074 Background: CDK4/6 kinases associate with cyclin D proteins during transition from G1 to S phase of the cell cycle. Amplification of CDK4/6 may elicit the activity of cyclin D, which hyperphosphorylates RB, ultimately leading to uncontrolled cell proliferation. Currently, three CDK4/6 inhibitors are used in breast cancer, ovarian cancer and sarcoma. Herein, we investigate the prevalence of CDK4/6 amplification in Chinese and Western cancer patients, hope to find more cancer subtypes with CDK4/6 amplification. Methods: Next-generation sequencing data and clinical data were collected from 10828 TCGA pan-cancer patients (Western cohort). A 539-gene panel targeted sequencing assay was performed on FFPE tumor samples from 4181 Chinese pan-cancer patients (Chinese cohort). CDK4 and CDK6 amplification were calculated on the two cohorts following the same criteria. Results: In total, 182 (4.4%) of the 4181 Chinese patients and 529 (4.9%) of the 10828 Western patients had CDK4 amplification, 133 (3.2%) of the 4181 Chinese patients and 475 (4.4%) of the 10828 Western patients had CDK6 amplification. In Western cohort, the top 5 CDK4 amplification-associated cancer types were sarcoma, glioblastoma multiforme, lung adenocarcinoma, ovarian carcinoma, and adrenocortical carcinoma, and the top 5 CDK6 amplification-associated cancer types were esophageal carcinoma, ovarian carcinoma, lung squamous cell carcinoma, stomach adenocarcinoma, sarcoma. In Chinese cohort, the top 5 CDK4 amplification-associated cancer types were lung adenocarcinoma, melanoma, sarcoma, stomach carcinoma, liver cancer, and the top 5 CDK6 amplification-associated cancer types were lung adenocarcinoma, stomach carcinoma, liver cancer, melanoma, glioma. In addition, CDK4 amplification in Chinese cohort, 22 (11%) of the 203 Chinese bone and soft tissue sarcoma patients had CDK4 amplification, and 4 (2%) of the 203 had CDK6 amplification. Bone and soft tissue sarcoma types with CDK4 / 6 amplification including soft tissue sarcoma, bone cancer, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, liposarcoma, synovial sarcoma. Conclusions: Our study provided a characteristic of CDK4/6 amplification in Chinese and Western pan-cancer patients. Analysis revealed frequent CDK4 / 6 amplification in lung cancer, sarcoma, stomach carcinoma, ovarian carcinoma and liver cancer. It is suggested patient with these cancer types may potentially benefit from CDK4/6 inhibitor.

Genomic characterizations of KIT and PDGFRA in Chinese pan-cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13654-e13654
Author(s):  
Xianze Xiong ◽  
Feng Zhou ◽  
Ming Luo ◽  
Jingdong Li ◽  
Haiping Zheng ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Gastrointestinal Stromal Tumor ◽  
Cancer Patients ◽  
Clinical Laboratory ◽  
Copy Number Variations ◽  
Stromal Tumor ◽  
Cancer Genes ◽  
Driver Genes ◽  
Pan Cancer

e13654 Background: KIT and PDGFRA gene mutations have been identified as biomarkers for targeted therapy in gastrointestinal stromal tumor. Mutations and amplification of KIT and PDGFRA are also considered as potential targets in solid tumors in clinical trials. We assessed the characteristics of KIT and PDGFRA alterations in a variety of cancers and tried to provide genomic landscape of these genes. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumors and their matched blood samples were collected from 10,010 patients for 450 cancer genes targeted next-generation sequencing (NGS) panel.The testing was carried out in a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Genomic alterations including single nucleotide variations, short and long insertions/deletions, copy number variations, and gene rearrangements were assessed. Results: Alterations of KIT and PDGFRA were detected 2.1% and 1.6% respectively in Chinese pan-cancer patients. KIT alterations was detected most frequently in gastrointestinal stromal tumor (68.8%), soft tissue sarcoma (10.8%), melanoma (10.3 %), thymic tumors (7.7%) and small cell lung cancer (5.1%), and PDGFRA alterations was detected in gastrointestinal stromal tumor (18.7%), melanoma (5.2 %), primary hepatic carcinoma (4.3%), bone sarcoma (4.2%) and soft tissue sarcoma (3.4%). Particularly, KIT and PDGFRA amplifications accounted for 0.68% and 0.58% respectively in pan-cancer patients and were highly co-existed. Conversely, KIT and PDGFRA mutations were mutually exclusive which indicated an independent role of driver genes. Furthermore, tumor with microsatellite instability high (MSI-H) status had a significantly higher rate of KIT or PDGFRA mutations compared to microsatellite stable (MSS) tumors (p < 0.001). Conclusions: KIT and PDGFRA alterations occurred in 2.1% and 1.6% respectively in Chinese pan-cancer patients and mutually exclusive with known driver genes. KIT and PDGFRA alterations may act as driving oncogenic factors across cancers and warrant drug development strategy.

Exploration of the MSI landscape in Chinese pan-cancer patient by Next-Generation Sequencing.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14576-e14576
Author(s):  
Xinlu Liu ◽  
Jiasheng Xu ◽  
Jian Sun ◽  
Deng Wei ◽  
Xinsheng Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Correlation Analysis ◽  
Cancer Patients ◽  
Cancer Type ◽  
Multiple Tumor ◽  
Treatment Plans ◽  
Cancer Types ◽  
Chinese Cancer Patients ◽  
Colorectal Cancer Patients ◽  
Pan Cancer

e14576 Background: Clinically, MSI had been used as an important molecular marker for the prognosis of colorectal cancer and other solid tumors and the formulation of adjuvant treatment plans, and it had been used to assist in the screening of Lynch syndrome. However, there were currently few reports on the incidence of MSI-H in Chinese pan-cancer patients. This study described the occurrence of MSI in a large multi-center pan-cancer cohort in China, and explored the correlation between MSI and patients' TMB, age, PD-L1 expression and other indicators. Methods: The study included 8361 patients with 8 cancer types from multiple tumor centers. Use immunohistochemistry to detect the expression of MMR protein (MLH1, MSH2, MSH6 and PMS2) in patients with various cancer types to determine the MSI status and detect the expression of PD-L1 in patients. Through NGS technology, 831 genes of 8361 Chinese cancer patients were sequenced and the tumor mutation load of the patients was calculated. The MSI mutations of patients in 8 cancer types were analyzed and the correlation between MSI mutations of patients and the patient's age, TMB and PD-L1 expression was analyzed. Results: The test results showed that MSI patients accounted for 1.66% of pan-cancers. Among them, MSI-H patients accounted for the highest proportion in intestinal cancer, reaching 7.2%. The correlation analysis between MSI and TMB was performed on patients of various cancer types. The results showed that: in each cancer type, MSI-H patients had TMB greater than 10, and 26.83% of MSI-H patients had TMB greater than 100 in colorectal cancer patients. The result of correlation analysis showed that there was no significant correlation between the patient's age and the risk of MSI mutation ( P> 0.05). In addition to PAAD and LUAD, the expression of PD-L1 in MSI-H patients was higher than that in MSS patients in other cancer types( P< 0.05). The correlation analysis between PD-L1 expression and TMB in patients found that in colorectal cancer, the higher the expression of PD-L1, the higher the patient's TMB ( P< 0.05). Conclusions: In this study, we explored the incidence of MSI-H in pan-cancer patients in China and found that the TMB was greater than 10 in patients with MSI-H. Compared with MSS patients, MSI-H patients have higher PD-L1 expression, and the higher the PD-L1 expression in colorectal cancer, the higher the TMB value of patients.

An ultrasensitive method for noninvasive pan-cancer early detection based on targeted methylation sequencing of cell-free DNA.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10544-10544
Author(s):  
Tiancheng Han ◽  
Yuanyuan Hong ◽  
Pei Zhihua ◽  
Song Xiaofeng ◽  
Jianing Yu ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Cancer Detection ◽  
Real World ◽  
Early Stage ◽  
Validation Dataset ◽  
Cpg Sites ◽  
Free Dna ◽  
Cancer Types ◽  
Discovery Dataset ◽  
Pan Cancer

10544 Background: Screening the biomarkers from the cell-free DNA (cfDNA) of peripheral blood is a non-invasive and promising method for cancer diagnosis. Among diverse types of biomarkers, epigenetic biomarkers have been reported to be one of the most promising ones. Epigenetic modifications are widespread on the human genome and generally have strong signals due to the similar methylation patterns shared by adjacent CpG sites. Although some epigenetic diagnostic methods have been developed based on cfDNAs, few of them could be applied to pan-cancer and their sensitivities are barely satisfactory for early cancer detection. Methods: Targeted methylation sequencing was performed using our in-house-designed panel targeting regions with abundant cancer-specific methylation CpGs. The cfDNA samples from 80 healthy individuals and 549 cancer patients of 14 cancer types were separately sequenced. The dataset was randomly split into one discovery dataset and one validation dataset. Moreover, cfDNA samples from four cancer patients were diluted with the healthy cfDNAs to generate 12 in vitro simulated samples with low circulating tumor DNA (ctDNA) fraction. Additionally, DNAs extracted from 130 unmatched tumor formalin fixation and paraffin embedding (FFPE) samples of 10 cancer types were sequenced to screen the diagnostic biomarkers. Adjacent CpG sites were first merged into methylation-correlated blocks (MCB) according to their correlations of methylation levels in tumor DNAs. The MCBs with higher methylation levels in tumor DNAs than that of healthy cfDNAs (from the discovery dataset) were defined as our hypermethylation biomarkers. For each cfDNA sample, a hypermethylation score (HM-score) was computed to measure the overall methylation level difference of selected biomarkers. The performance of our method was evaluated with the real-world dataset, while the limit of detection was estimated using the simulated low-ctDNA samples. Results: Our model based on 37 hypermethylation MCB biomarkers achieved an area under the curve (AUC) of 0.89 and 0.86 in the real-world pan-cancer discovery and validation cfDNA datasets, respectively. Furthermore, the overall specificity and sensitivity are 100% and 76.19% in the discovery dataset, and 96.67% and 72.86% in the validation dataset. In the validation dataset, 28/40 (70%) of early-stage colorectal cancer patients and 10/20 (50%) of non-small-cell lung cancer patients were successfully diagnosed. Additionally, all the simulated samples with theoretical ctDNA factions over 0.5% were predicted as diseased, demonstrating the ability of our method to detect tumor signals at early stages. Conclusions: Our cfDNA-based epigenetic method outperforms currently available methods in various cancer types, and is promising to be applied to early-stage cancer detection and samples with low ctDNA fractions.

Immunotherapy for Soft Tissue Sarcoma: Tomorrow Is Only a Day Away

2016 ◽  
pp. 281-290 ◽  
Author(s):  
Alex Lee ◽  
Paul Huang ◽  
Ronald P. DeMatteo ◽  
Seth M. Pollack
Keyword(s):  
T Cells ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Immune Responses ◽  
Cytotoxic Lymphocytes ◽  
Immune Microenvironment ◽  
Advanced Soft Tissue Sarcoma ◽  
Novel Treatments ◽  
Cancer Types ◽  
Made In

Despite the advances taking place for patients with many types of cancer, to date there has been little success in meeting the great need for novel treatments of advanced soft tissue sarcoma with effective immunologic therapies. Here, we review recent clinical and preclinical data that indicate immune responses against sarcomas occur spontaneously and can also be successfully provoked. Efforts to manipulate the sarcoma immune microenvironment have the potential to eradicate disease and may also sensitize tumors to other tumor-targeted immunotherapeutic approaches. Other approaches, including vaccines and genetic engineering of T cells, offer a promising opportunity to actively direct cytotoxic lymphocytes toward antigen-bearing sarcomas. Drawing parallels with recent advances made in other cancer types, we identify ways in which sarcomas can be included in the ongoing immunotherapy revolution.

The prevalence of CDK12 alterations in Chinese cancer patients and the association with tumor mutation burden(TMB) and survival.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13663-e13663
Author(s):  
Ke Li ◽  
Xi Guo ◽  
Yunhua Mao ◽  
Mengmei Yang ◽  
Mengli Huang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Molecular Subtype ◽  
Prostate Adenocarcinoma ◽  
Chinese Patients ◽  
Cyclin Dependent Kinase ◽  
Poor Prognostic Factor ◽  
Cancer Types ◽  
Chinese Cancer Patients ◽  
Pan Cancer

e13663 Background: Cyclin-dependent kinase 12 (CDK12) is a cyclin-dependent kinase that regulates transcription and RNA splicing, thereby modulating multiple cellular processes. It has been suggested that CDK12 loss-of-function mutations lead to a higher neoantigen burden and favorable responses to PD-1 inhibitors in advanced prostate cancer. Given this potentially actionable molecular subtype, we sought to determine the prevalence of CDK12 alterations in Chinese cancer patients and the association with TMB and overall survival(OS). Methods: The prevalence of CDK12 alterations were queried in 3D Medicines database with 15,745 Chinese cancer patients involved. Whole-exome sequencing data of 464 patients with prostate adenocarcinoma(PRAD) from the Cancer Genome Altas (TCGA) were downloaded to explore the association between CDK12 gene alteration and OS. And the association with TMB were analyzed in a cohort of 731 patients with various cancer types published by Memorial Sloan Kettering (MSKCC) (Samstein et al., Nature Genetics, 2019). Results: Any CDK12 and known or likely deleterious CDK12 mutations were identified in 598(3.8%) and 98(0.62%) patients, respectively. Across all cancer types, prostate adenocarcinoma(PRAD) was found to have the highest frequency of deleterious mutations(8.75%, 23/263), followed by breast cancer (4.97%, 25/503). Mutations were also detected in multiple cancer types including bladder cancer, ovarian cancer, lung cancer, colorectal cancer and so on with a frequency of less than 1%. CDK12 mutations were associated with shorter OS (HR = 15.25; 95% CI, 2.88-80.73; p < 0.001) in TCGA PRAD and cholangiocarcinoma datasets, which was not seen in other cancer types. Patients harboring CDK12 mutation had a significant higher TMB(p < 0.001) in the pan-cancer study of publicly-available cohort from MSKCC. Conclusions: CDK12 alterations existed across tumor types in Chinese patients with relatively high frequencies detected in PRAD and breast cancer and represent extremely rare events in multiple cancers. CDK12 mutation was a poor prognostic factor in PRAD and cholangiocarcinoma. In a pan cancer analysis patients with CDK12 mutation tended to have a significant higher TMB and may benefit from PD-1/L1 blockade immunotherapy.

Hepatocellular carcinoma with ARID1A mutation is associated with higher TMB and poor survival.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16667-e16667 ◽  
Author(s):  
Yaorong Peng ◽  
Bowen Gao ◽  
Zhenyu Zhou ◽  
Tingting Chen ◽  
Wenzhuan Xie ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cancer Patients ◽  
Gene Mutation ◽  
Sequencing Data ◽  
Coding Region ◽  
Poor Prognostic Factor ◽  
Synonymous Mutations ◽  
Significant Difference ◽  
Chinese Cohort ◽  
Pan Cancer

e16667 Background: Hepatocellular carcinoma (HCC) is a heterogeneous disease that lacks molecular predictors of response to available treatments. AT-rich interactive domain 1A (ARID1A), a SWI/SNF chromatin remodeling gene, is commonly mutated in human cancers and hypothesized to be a tumor suppressor gene. In recent years, immune checkpoint blockade immunotherapies (ICIs) are promising therapies for multiple cancers including HCC, and tumor mutation burden (TMB) was an important biomarker to predict the efficacy of ICIs. Besides, previous research reported that ARID1A deficiency was associated with mismatch repair (MMR) in cancer, and may cooperated with ICIs. Methods: Whole exome sequencing data of 10336 pan-cancer patients including 353 HCC patients was obtained from the Cancer Genome Altas (TCGA). Next generation sequencing (NGS) data of 15849 pan-cancer patients including 1926 HCC patients from Chinese clinical dataset were analyzed to explore the correlation between ARID1A gene mutation and TMB. TMB was defined as total number of somatic non-synonymous mutations in coding region. Prognostic data of 136 HCC patients were obtained from the MSK-IMPACT Clinical Sequencing Cohort (MSKCC). Results: In total, 8.62% (891/10336) of pan-cancer patients in TCGA harboring ARID1A mutation and 8.47% (3188/37628) in Chinese cohort, while mutant percentage of HCC was 9.35% (33/353) in TCGA, 9.03% (174/1926) in Chinese cohort, the alternation frequency of ARID1A in two cohorts was no significant difference (P = 0.3334). The medium TMB level of ARID1A mutant group was higher than wild-type group with significant difference both in Chinese pan-cancer and HCC (medium TMB level, P < 0.0001). Results of 18 kinds of ARID1A mutated tumors patients in TCGA cohort indicated that ARID1A mutation was an independent risk factor in liver cancer affecting overall survival (OS, HR 2.43, 95% IC 1.07-5.54, P = 0.0286). Besides, Kaplan-Meier analysis was performed on HCC patients in MSKCC cohort, ARID1A statue resulted in significantly shorter OS (median, 12.2 vs 21.43 months; HR 2.5; P = 0.0092). Conclusions: The results indicated that ARID1A gene mutation was a poor prognostic factor in hepatocellular carcinoma, and these mutational states were associated with higher TMB level, which might be a potential positive biomarker of immunotherapy.

Sign in / Sign up

Export Citation Format

Share Document