1963P A pan-cancer study of GNAQ/GNA11 mutations in Chinese cancer patients

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13663 ◽

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.

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A comprehensive pan-cancer analysis of CD274 gene amplification, tumor mutation burden, microsatellite instability, and PD-L1 expression in Chinese cancer patients

Annals of Translational Medicine ◽

10.21037/atm-21-853 ◽

2021 ◽

Vol 9 (8) ◽

pp. 677-677

Author(s):

Guanghui Gao ◽

Xiao-Dong Zhang ◽

Hu Qu ◽

Bing Yao ◽

Yuxi Zhou ◽

...

Keyword(s):

Microsatellite Instability ◽

Cancer Patients ◽

Gene Amplification ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Chinese Cancer Patients ◽

Pan Cancer

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Exploration of the TMB and hypermutation landscape in Chinese pan-cancer patient by next-generation sequencing.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e14575 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e14575-e14575

Author(s):

Shuo Wang ◽

Jiasheng Xu ◽

Jian Sun ◽

Deng Wei ◽

Xinsheng Zhang ◽

...

Keyword(s):

Cancer Patient ◽

Cancer Patients ◽

Age And Gender ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Cancer Types ◽

And Gender ◽

Chinese Cancer Patients ◽

Pan Cancer ◽

Generation Sequencing

e14575 Background: Among a variety of malignant tumors, the level of the patient's TMB was currently an important criterion for clinical judgment whether to adopt immunotherapy. Hypermutation could produce many nearby mutation sites at the same time, which seriously damages genetic material and may cause cancer. Therefore, performing TMB detection on cancer patients and understanding the occurrence of hypermutation in pan-cancer patients will help clinical researchers to further understand the disease characteristics of cancer patients and helped the choice of treatment methods. Previously, TMB and Hypermutation had been tested and studied in pan-cancer patients in the United States and Europe, but rare research was reported in China. In this study, we explored the TMB and hypermutation landscape in Chinese pan-cancer patient by next-generation sequencing. Methods: A total of 8,361 cancer patients from multiple cancer hospitals and research centers in China were included in the study. We sequenced 8,361 Chinese cancer patients from 8 cancer types using the oncopanscan product of Genetron Health Co., Ltd. and calculated the tumor mutation burden of the patients. We separately analyzed the tumor mutation burden of patients in 8 cancer types and analyzed the relationship between the occurrence of hypermutation and the patient's age and gender. Results: The results showed that in pan-cancer, hypermutation patients accounted for 16.97%, and ultrahypermutation patients accounted for 0.78%. Among them, patients with lung cancer have the highest proportion of hypermutation, reaching 27.72%, and patients with colorectal cancer have the highest proportion of ultrahypermutation, reaching 2.86%. Correlation analysis between TMB and age and gender was carried out on 8336 patients. The results showed that in the patients with intrahepatic bile duct cancer, the proportion of men and women was the same. Among the other cancer types, hypermutation patients were more male, and the proportion of men with liver cancer was the largest, with 90 percent. We further explored the correlation between the TMB of pan-cancer patients and the patient’s age, and found that in gastric cancer, liver cancer, and melanoma, the older patients have higher TMB; however, the younger the patients in brain cancer, the higher the TMB ( P<0.05). Conclusions: In this study, we explored the TMB and hypermutation landscape in Chinese pan-Cancer patient for the first time. We found that among Chinese cancer patients, lung cancer patients have the highest proportion of hypermutation. In a variety of cancers, hypermutation patients account for a higher proportion of men, and the older the patient, the higher the TMB.

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A DNA-mutational panel for liquid biopsy-based pan-cancer early detection.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13687 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13687-e13687

Author(s):

Zhao Yi ◽

Weizhi Chen ◽

Ji He

Keyword(s):

Early Detection ◽

Cancer Patients ◽

Liquid Biopsy ◽

Somatic Mutations ◽

Asian Population ◽

Plasma Samples ◽

Sequencing Data ◽

Cancer Early Detection ◽

Chinese Cancer Patients ◽

Pan Cancer

e13687 Background: Early detection through liquid biopsy can significantly increase the successful chances of treatment. The sensitivity and specificity of early detection are limited by lower signal-to-noise ratio. Thus, well design of liquid biopsy panel is important. Methods: We adopted comprehensive data sources for designing the liquid biopsy panel, including databases of TCGA, ICGC, COSMIC, MSK Cancer Hotspots, while the panel of HCCscreen and CancerSeek. We also considered the database of somatic mutations in Chinese cancer patients generated by us (Genecast (Beijing) Biotechnology Co., Ltd.). We first calculated pan-cancer carrier ratio of somatic mutations in each database and constructed the distribution of mutation counts on step-wise increased carrier ratio. Then, we selected the set of somatic mutations with “elbow point” carrier ratio from each database as part of the panel. Finally, we integrated collected hotspots with the panel of HCCscreen and CancerSeek. Results: We selected 408, 521, 214, 146 and 330 hotspots from databases of TCGA, ICGC, COSMIC, MSK Cancer Hotspots and somatic mutations in Chinese cancer patients, respectively. After integration with the panel of HCCscreen and CancerSeek, this designed panel contains 3,334 bases distributed on 23 chromosomes and 915 gene models. Comparison of hotspots collected from different databases showed that few of them shared the same genomic location except for ones from the database of MSK Cancer Hotspots, indicating the well complementarity between them. Especially, there are 186 unique hotspots collected from the database of somatic mutations in Chinese cancer patients, which can improve the sensitivity of early detection for Chinese and Asian population. Next, we evaluated detected sensitivity of the designed panel based on sequencing data of plasma samples from more than 12,000 Chinese cancer patients collected in Genecast. The result showed that the maximum sensitivity is 66.67% for small cell lung cancer and the overall sensitivity is 45.71% for 26 cancer types, in which hotspots uniquely collected from the database of somatic mutations in Chinese cancer patients accounted for 5.11%. Conclusions: We designed a liquid biopsy panel for pan-cancer early detection and evaluated its sensitivity based on sequencing data of plasma samples from more than 12,000 Chinese cancer patients. Satisfactory performance of our designed panel shows its potential application in cancer screening for healthy and highly risky individuals.

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Genomic landscape of FGF/FGFR pathway alternations across 12,372 pan-cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e13503 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e13503-e13503

Author(s):

Yongmei Yin ◽

Wei Zuo ◽

He Yan ◽

Zhengyi Zhao ◽

Yuzi Zhang ◽

...

Keyword(s):

Growth Factor ◽

Microsatellite Instability ◽

Fibroblast Growth Factor ◽

Cancer Patients ◽

Growth Factor Receptor ◽

Great Promise ◽

Fibroblast Growth ◽

Tract Cancer ◽

Chinese Cancer Patients ◽

Pan Cancer

e13503 Background: The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling pathway is involved in diverse biological processes and plays a crucial role in carcinogenesis. FGFR targeted therapies have shown great promise in the treatment of a multitude of malignancies. This study aimed to assess the alternations of FGF/FGFR pathway and explore the potential relationships between the genetic alternations in a pan-cancer setting. Methods: Next-generation sequencing was conducted with formalin-fixed, paraffin-embedded tumor specimens from 12,372 Chinese cancer patients with over 21 tumor types, including lung cancer (n = 3557), liver cancer (n = 1433), colorectal cancer (n = 1310), biliary tract cancer (n = 960), gastric cancer (n = 758), etc. Somatic mutations including single nucleotide variations (SNVs), amplifications, and fusions were analyzed, and microsatellite instability status was also assayed. Results: Of all patients, the frequency of genomic alterations in FGF/FGFR pathway (FGF3/4/6/10/14/19/23 and FGFR1-4) ranged from 54.1% (86/159) in esophagus cancer, 40.7% (112/275) in bladder/urinary tract cancer, 28.4% (73/257) in head and neck cancer to 5.3% (5/95) in prostate cancer and 4.0% (22/548) in kidney cancer. Amongst all, the highest mutational prevalence fell in FGFR SNV (5.13%) and FGF amplification (5.08%), followed by FGF SNV (3.90%), FGFR amplification (2.89%), FGFR fusion (0.88%), and FGF fusion (0.06%). Partial co-occurrence was observed between alternations of FGFR1 and 11q13 (FGF3/4/19) and between FGF6 and FGF23. On the other side, alternations of FGFR1, FGFR2, FGFR3, and FGFR4 were found to be mutually exclusive ( p< 0.001). In addition, microsatellite instability was found to be positively correlated with FGF/FGFR pathway mutation ( p< 0.001), while was negatively correlated with pathway amplifications ( p= 0.002). Conclusions: Our study investigated the molecular landscape of FGF/FGFR pathway alternations and the interplay between co-occurrence and mutual exclusivity between pathway genes in a large pan-cancer cohort. FGF/FGFR pathway mutations occurs in a variety of solid tumors, indicating that these patients may benefit from FGFR inhibitors.

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Comparing of pan-cancer tumor immune microenvironment.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15100 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15100-e15100

Author(s):

Jiaan Ye ◽

Longgang Cui ◽

Xiaochen Zhao ◽

Guanghui Lan

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

Natural Killer Cell ◽

Natural Killer ◽

Cancer Patients ◽

Killer Cell ◽

Immune Microenvironment ◽

Hepatobiliary Cancer ◽

Tumor Immune Microenvironment ◽

Pan Cancer

e15100 Background: Cancer treatment has entered the era of immune checkpoint inhibitors (ICI), but different tumors have different responses to ICI drugs. For example, non-small cell lung cancer and melanoma have higher response rates to ICIs than colorectal cancer and liver cancer patients. Previous studies have shown that tumor immune microenvironment have a great impact on the efficacy of ICI. Methods: This study retrospectively included pan-cancer patient specimens, using multiple fluorescent labeling immunohistochemistry to explore the differences in the immune microenvironment of different tumors. Shapiro-Wilk was used for normality test, and ANOVA or Kruskal Wallis test was used according to the results. Two-sided P < 0.05 was considered a significant difference. Results: The study included 308 patients, including 119 (38.6%) NSCLC patients, 72 (23.4%) Colorectal cancer patients, 51 (16.6%) Hepatobiliary cancer patients and 66 (21.4%) Others types of cancer patients. Among them, there was 192 (62.3%) Male, and 116 (37.7%) Female, and the median age was 57 (50-66). The proportion of CD8+ T cells and natural killer cell in tumor was statistically different. The proportion of CD8+ T cells in NSCLC, Colorectal cancer, Hepatobiliary cancer and others was 2.16%, 1%, 1.77% and 2.63%, p < 0.01; the proportion of natural killer cell was 16.44 %, 4.91%, 5.58% and 3.29%, p < 0.01. Conclusions: Different tumor types have different immune microenvironments. These results may provide valuable clues for future ICI trail design.

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