bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pancancer analysis of KRAS alterations in Chinese population.
Authors: Hou Yan , Lou Luyan , Zhang Yanrui , Zhang Yun , Liang Xiayuan , Lou Feng , Cao Shanbo , Wang Huina 
Published: June 2022

e15127 Background: Kirsten rat sarcoma viral oncogene homologue (KRAS) is the most frequently mutated oncogene in human cancers. Sotorasib (AMG 510) has shown promising anticancer activity in patients with heavily pre-treated KRAS p.G12C mutant solid tumors. Here, we provide an overview of genomic diversity of KRAS alterations in a large cohort of Chinese patients. Methods: Molecular profiles of 16,654 tumor specimens were obtained using gene-panel target-capture next-generation sequencing, and classified based on the presence and subtypes of KRAS mutation. Tumor mutation burdens (TMB) were calculated using an Acornmed panel with 808 cancer-related genes. Results: In total,15.04% (2505/16654) of pan-cancer patients harbored RAS mutations, and 13.58% (2262/16654) patients carried KRAS mutations in the current study. Five main subtypes of KRAS mutation were detected including G12D (642, 28.38%), G12V (392, 17.33%), G12C (354, 15.65%), G13 (220, 9.73%), G12A (101, 4.47%). In our cohort, the highest KRAS G12C mutation frequency tumor type was lung cancer (12.33%) followed by colorectal cancer (1.99%), which is comparable with the previously published data. Among all patients with KRAS G12C mutation, 77.40% (274/354) of the patients were male and 22.60% (80/354) were female. Tumor mutation burdens (TMB) were calculated for 151 samples of all the 352 KRAS G12C mutation samples. The median TMB was 10.15 mut/Mb with 50.99%≥10 mut/Mb and 14.57%≥20 mut/Mb. However, according to the results of CodeBreaK 100 exploratory analysis at the 2021 ASCO annual meeting, among all patients with KRAS G12C mutation, 17.86% of the patients had ≥ 10 mut /Mb, which was defined as TMB-high. Therefore, it can be found that the TMB of domestic and foreign patients is different. Conclusions: Genomic alterations in KRAS are widespread among Chinese pan-cancer patients. Results of CodeBreaK 100 exploratory analysis presented at the 2021 ASCO Annual Meeting showed no significant difference (40% vs 42%) in objective response rates between TMB high (≥ 10 mut/Mb) and TMB low (< 10 mut/Mb). Based on our data, the threshold of TMB high in the Chinese population should be higher. The molecular marker exploration of AMG 510 efficacy in the Chinese population needs to be further carried out and confirmed.
Characterization of mutational signatures of homologous recombination deficiency (HRD) in Chinese breast cancer.
Authors: Liu Xiao , Li Mingwei , Lou Feng , Cao Shanbo , Wang Huina 
Published: June 2022

e15129 Background: Homologous recombination deficiency (HRD) is a common molecular characteristic of genomic instability and has been proved to be an important biomarker for personalized therapy decisions and stratified management in breast cancer. In this study, we explored the mutational features of HRD tumors identified by HRD score in Chinese breast cancer. Methods: Tumor tissue DNA from 68 breast cancer patients was isolated and sequenced by next-generation sequencing (NGS) technologies with AcornMed 808-genes panel. HRD score was calculated as an unweighted sum of loss of heterozygosity (LOH) score, telomeric allelic imbalance (TAI) score and large-scale state transition (LST) score by AcornHRD algorithm, and mutations in 39 homologous recombination (HR) related genes including BRCA1/2 were identified for each case. Results: Based on the mutation alternation profiles from our cohort, somatic BRCA1/2 mutations were present in 15 patients (22.1%) while 29 patients (42.6%) harbored one or more mutations in HR-related genes excluding BRCA1/2. Germline mutations of BRCA1/2 and other HR-related genes occurred in 11.8% and 4.4% of cases detected, respectively.In our cohort, the median HRD score was 40 (range from 3 to 92). Sixty-eight cases were divided into HRD-high or HRD-low group based on a cut-off value of ≥ 42 or < 42, with HRD-high group accounting for approximately 47% of our cohort, indicating the combination with HRD score yielded an increment of 26.5% in coverage of HRD within BRCA1/2 wildtype cases. The HRD-high group covered 82.4% of the BRCA-mutated cases and also showed higher mutation level of BRCA1/2-excluded HR genes than HRD-low group (p = 0.001). Prevalence of mutations in a total of 12 genes, including BRCA1(31.3% vs 5.6%, p = 0.009) and NBN (25% vs 5.6%, p = 0.038), were significant difference between HRD-high and HRD-low group. Besides, Cosmic Signature 1 (spontaneous deamination of 5-methylcytosine) and 5 (unknown) were existed in both groups, whereas Signature 6 (defective DNA mismatch repair) was only discovered in HRD-high group. Compared with HRD-low ones, copy number variations ratio was higher in HRD-high group (p = 0.031). Meanwhile, the patients with ERBB2 amplification (HER2+) showed a lower level of HRD score than HER2- ones. Conclusions: This study comprehensively delineated the genetic characteristics of HRD tumors, which suggests that HRD status marked by HRD score is strongly associated with BRCA1/2 and HR-related genes mutation as well as other genomic instability signatures, thus indicating its predictive value as a promising biomarker for DNA repair deficiency related drugs or therapies in Chinese breast cancer.
Clinical and genomic characteristics of lung cancer concomitant chronic obstructive pulmonary disease (COPD).
Authors: Ma Hongxia , Zhang Qian , Duan Qianqian , Zhang Qin , Tan Yuan , Sun Tingting , Qi Chuang 
Published: June 2022

e15131 Background: Lung cancer and chronic obstructive pulmonary disease (COPD) often coexist. Lots of clinical and genomic descriptions related lung cancer have been investigated. However, the clinical and genomics characteristics of lung cancer coexisting COPD are still unclear. Herein, we explored the clinical characteristics and somatic mutational landscape of lung cancer coexisting COPD (COPD-LC) and compared with non-COPD Lung cancer (non-COPD-LC). Methods: We retrospectively collected total COPD-LC and non-COPD-LC patients who performed next generation sequencing (NGS) simultaneously from The Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University during December 2018 to August 2021. And collected COPD-LC data from TCGA to further analysis. COPD was defined as incompletely reversible airflow obstruction associated with post-bronchodilator forced expiratory volume in one second (FEV1) and its ratio to forced vital capacity (FEV1/FVC) < 0.7. Results: Of the 139 patients enrolled in the study, 51 were categorized as COPD and 88 as non-COPD. In our clinical cohort, compared with non-COPD-LC, amount of male gender, older age and smoking patients were significantly higher than non-COPD in term of clinical data (all P < 0.01). As for somatic mutation in our cohort, compared with non-COPD-LC, COPD-LC had higher mutation frequency of LRP1B (43% vs 9%, P = 0.001), EPHA5 (24% vs 1%, P = 0.002), PRKDC (14% vs 1%, P = 0.039) and PREX2 (14% vs 0%, P = 0.012), which had relationship with improved tumor immunity. Immunotherapy biomarker of PD-L1 positive expression (62.5% vs 52.0%, P = 0.397) and TMB (P = 0.004) also were higher in COPD group. Whereas, COPD-LC had lower frequency of EGFR (19% vs 50%, P = 0.013). And survival analysis showed in EGFR mutant patients with targeted therapy, COPD-LC had worse PFS than non-COPD-LC (HR = 3.52, 95%CI: 1.27-9.80, P = 0.01). TCGA cohort mutation data differed from the results of our cohort. In addition, RNA data from TCGA indicated COPD-LC increased tumor immunity. Conclusions: In our research, COPD-LC had unique clinical and molecular features. High PD-L1 expression and TMB indicated these patients may benefit from immunotherapy. Notably, mutation difference between Chinese and TCGA cohort and COPD-LC immunotherapy efficacy need prospective further study.
Distribution features of genomic amplifications in microsatellite stable Chinese colorectal cancer.
Authors: Yang Zhenhuai , Li Guanning , Yang Junjie , Yang Zetian , Geng Yi , Shi Zhenjun , Liu Xinyi , Huang Mengli 
Published: June 2022

e15509 Background: Genomic amplification is key mutational events in microsatellite stable (MSS) colorectal cancer (CRC). A distinctive amplification region of CRC is Chr20q. It was revealed by several investigations the most recurrent amplified band in CRC and often co-exist with Chr8q. However, there is very little data to describe the characteristics of chromosome co-exist amplifications in CRC. We did an exploratory analysis in this issue in a large size of Chinese CRC. Methods: A total of 1977 CRC with detected genomic amplifications were included in this analysis. Calling of single nucleotide variants (SNV), copy number variants (CNV), insertion/deletions (indels), fusions were performed using a wide panel next-generation sequencing (NGS) testing. Amplifications were stratified as high-level, moderate-level and low-level according to the number of copies (cut-off: 20, 8 copies). Results: Nine chromosome arm were detected amplified in more than 10% cases in this cohort. Chr20q (65.9%), Chr13q (57.1%) and Chr8q (34.3%) were the most frequent. Chr17q and Chr12q had more high-level amplifications than other chromosome arms with ratio of 54.9% and 33.7%, respectively. In contrast, Chr20q and ChrX substantially had low-level amplifications. 36.2% (715/1977) cases had amplifications on more than two chromosome arms (median 2, range 2-7). In patients (92%) with 2-4 co-current amplified chromosome arms, the most frequent co-amplified patterns were Chr20q-Chr13q (20%) and Chr20q-Chr8q (15%). Most patients among this subgroup had more than three amplified genes in Chr20q while only one amplified gene in Chr8q. In patients (8%) with 5-7 co-current amplified chromosome arms, the most frequent amplified regions were Chr20q, Chr8q and Chr7q, and more than 60% cases harbored Chr20q-Chr8q. Interestingly, these patients mainly had multiple amplified genes in Chr8q and only one amplified gene in Chr20q, in the contrary to the patients with 2-4 co-current amplified chromosome arms. In addition, high-level focal amplifications in Chr17q and Chr12q participated equally to the amplifications with other chromosome arms. Conclusions: Our analysis results suggested the heterogeneity of Chr20q co-amplifications patterns in CRC. Amplifications in Chr20q and Chr8q may play distinct critical roles in the tumorigenesis of CRC. High-level amplifications were, on the other hand, independent of their driven process.
The prognostic impact of intramural invasion in patients undergoing surgery for non-metastatic colon cancer.
Authors: Ozer Leyla , Şenocak Taşçi Elif , Mutlu Arda Ulaş , Piyade Betul , Ramoğlu Nur , Ajredini Mırac , Gurleyik Damla , Çeçen Recep , Dinçer Sena Nur , Musevitoglu Turan , Erdamar Çetin Ayşe Sibel , Yildiz Ibrahim , Aytac Erman 
Published: June 2022

e15516 Background: The invasion of extramural veins is an independent predictor of poor outcome in colorectal cancer whereas the significance of intramural component of venous as well as lymphatic and perineural invasion is less clear. We aimed to search the prognostic impact of these invasion patterns and their association with various clinicopathological variables. Methods: All patients undergone surgery for colon cancer between December 2014 and December 2020 were analyzed retrospectively and patients with stage II and III disease were enrolled. The patients were divided into four categories as no invasion, intramural invasion only, extramural invasion only or both (intramural and extramural) for vascular invasion (VI), lymphatic invasion (LI) and perineural invasion (PNI). 5-year disease-free (DFS) and overall-survival (OS) were the primary outcomes. Results: 626 patients were included (47.1% stage II patients). There was no significant difference between the presence of ‘intramural only’ venous (DFS, 87.2 vs 88.4% p = 0.84; OS, 88.3 vs 90.7% p = 0.90), lymphatic (DFS, 89.5 vs 85.1%, p = 0.13; OS, 89.5 vs 89.4%, p = 0.9) and perineural invasion (DFS, 89.1 vs 80.9%, p = 0.26; OS, 90.6 vs 84.8%, p = 0.12) compared to ‘no invasion’ in terms of DFS and OS. Invasion of both intramural and extramural compartments for each of these parameters demonstrated poor survival. Presence of exclusively extramural venous and perineural invasion without intramural invasion had adverse effect on DFS (87.2 vs 78.7%, p = 0.036, 89.1 vs 80.9%, p = 0.044, respectively) but not OS (88.3 vs 89.3%, p = 0.78, 90.6 vs 83.8%, p = 0.215, respectively). Tumor sidedness did not have impact on the depth and rate of lymphatic invasion however right-sided and dMMR tumors exhibited less venous and perineural invasion (24.7 vs 33.9% p = 0.007; 34.5 vs 41.5% p = 0.034 and 13.5 vs 33.5% p < 0.001; 25 vs 41.4% p = 0.004, respectively). The ratio of stage III patients with venous, lymphatic and perineural invasion was consistently higher when compared with stage II patients (for LI 69.8 vs 39.7% vs p < 0.001; for VI 36.9 vs 22.7% p < 0.001; for PNI 51.4 vs 24.4% p < 0.001). Low grade tumors exhibited less LI and PNI when compared with high grade tumors (for LI 53.2 vs. 71.3% p = 0.004, for PNI 37.1 vs. 48.3% p = 0.031) however there was no significant difference for venous invasion rates among two groups. Conclusions: Presence of merely intramural component of invasion may not be considered a synonym for lymphovascular invasion which is supposed to be a high-risk factor for systemic recurrence.
Homologous recombination pathway alternations in relation to prognosis of MSS/pMMR colorectal cancer patients treated with immune checkpoint inhibitors (ICIs).
Authors: Liu Xing , Fu Zhichao 
Published: June 2022

e15517 Background: Colorectal cancer is a common malignant tumor in the gastrointestinal tract and represents the third deadliest cancer worldwide. Recently, the advent of immune checkpoint inhibitors (ICIs) has provided significant survival benefit for colorectal cancer(CRC) patients with MSI-H/dMMR. However, the majority of MSS/pMMR CRC patients show poorly durable responses of immunotherapy, and more proper predictive biomarker is required to guiding immunotherapy treatment for these CRC cancer patients. The purpose of the present study was to explore the role of Homologous recombination (HR) pathway alternations in predicting the prognosis of MSS/pMMR CRC patients treated with ICIs. Methods: All data of patients undergoing immunotherapy were obtained from the cBioPortal database (https://www. cbioportal.org), which include genomic sequencing datasets and clinical data for eight diverse cancers from MSKCC, and RNAseq data and clincial data for CRC from International Cancer Genome Consortium (TCGA). Results: In the MSKCC cohort, HR mutation was analyzed by univariate Cox regression in nine different cancers, the analysis performed revealed HR mutation were associated with a better prognosis of colcrectal cancer (p = 0.003; HR, 0.24; 95%Cl, 0.09-0.62) and melanoma (p = 0.042; HR,0.66; 95% Cl, 0.09-0.62), with no significant correlations in other cancers. By doing survival analysis of the CRC patients without MSI-H/dMMR status by Kaplan–Meier (KM) method. The results showed that the OS of the patients with HR-MT was signifcantly longer than that of patients with HR-WT (P = 0.0029), and no significance association has been identified between Tumor Mutational Burden (TMB) and overall prognosis of patients without MSI-H/dMMR. Notably, in TCGA CRC dataset, we found TMB and Neoantigens were significantly higher in HR-MT patients than that of HR-WT patients(p < 0.0001), and a higher-level expression of CD8 T cell were also observed in the HR-MT patients patients in TCGA dataset (p = 0.036). Conclusions: Our study results showed that HR-mutation is a favorable prognostic factor in these CRC patients with MSS/pMMR, which can be used as a potential biomarker for predicting the immunotherapy efficacy of these patients.
The role of ACAA2 in colorectal caner patient with active glucose metabolism.
Authors: Yuan Yitao , Liu Tianshu , Liu Mengling , Gan Lu 
Published: June 2022

e15522 Background: colorectal cancer(CRC) is third in incidence and mortality in worldwide with a 5-year survival rate is 65%. CRC patients(pts) with active glucose metabolism have a worse outcome. Molecular biological mechanisms in this subgroup have not been well uncovered. Here we identified ACAA2 has a significant prognostic role in CRC pts and more down-regulated in those with higher standardized uptake value(SUV). Then we focused on its functions and mechanisms behind it. Methods: Clinical and transcriptional data of pts with CRC obtained from GSE39582 dataset (n = 510) and a Zhongsh an Hospital Fudan University Cohort(ZHFUC) with CRC diagnosed at 6/2015-12/2018 were collected (n = 441). The ACAA2 protein expression of ZHFUC was evaluated by immunohistochemistry staining. Metabolic activity was evaluated by SUV. Overall survival (OS) was analyzed via Kaplan-Meier Curves with Log-rank test and multivariable Cox regression. Silencing (KD) and over-expression (OE) of ACAA2 were performed in CRC cells, respectively(KD: HCT116;RKO and OE: DLD1;RKO). The effect of ACAA2 was tested through CCK8, colony formation assays, cell cycle assays, seahorse for glucose metabolism and subcutaneous xenograft models. The potential mechanism under ACAA2 contribution was explored by RNA sequencing and western blot. Results: ACAA2 of ZHFUC was down-regulated in CRC compared to normal tissues. Pts divided into ACAA2 high (n = 226) and low (n = 215) with an evenly distribution in their clinicopathological features.Of 143 pts with available PETCT imaging took as a SUV-related group), 78 were identified as ACAA2 high and 65 were low. In comparison to ACAA2 high ones, pts in ACAA2 low showed an higher SUV (p < 0.05) and a significantly worse OS (total pts: p = 0.012; SUV-related group:p = 0.024; median OS is not reached). The multivariate analysis showed that ACAA2 low was independently associated with inferior OS [total pts: HR 1.99(95%CI: 1.2 ¨C 3.2), p < 0.001; SUV-related group: HR 2.51(95%CI: 1.1 ¨C 5.7), p =< 0.05]. Over-expression ACAA2 inhibited tumor growth both in vitro and in vivo, and lower glucose metabolism and arrested G0/G1 cell cycle were observed in HCT116-OE cells, while reversed effects in RKO-KD cells. gene expression profiling analysis and consistent results in western blot highlighted the role of AKT signaling pathway in those contributions of ACAA2. A AKT inhibitor could suppress cell proliferation causing by silencing ACAA2 both in vitro and in vivo. Conclusions: while ACAA2 expression was an independent prognostic factor for CRC pts. And those of them with an active glucose metabolism had a lower ACAA2 expression. The silencing and over-expression of ACAA2 expression in CRC cell lines promoted and inhibited cell proliferation and tumor growth in vitro and in vivo, oppositely. ACAA2 expression levels might classified a subtype of CRC pts, who might benefit from AKT inhibitors treatment.
Necroptosis-related lncRNA biomarkers for colon cancer prognosis and the associations with the immune landscape.
Authors: Wang Tao , Xu Shaohua , Wang Qian , Xiao Shanshan ,   Hangzhou Repugene Technology Co,.Ltd
Published: June 2022

e15525 Background: Necroptosis is a regulated caspases-independent cell death involved in colon cancer development and antitumor activity. lncRNAs are widely considered as biomarkers in various diseases. In this study, we identified prognosis biomarkers using necroptosis-related lncRNAs, and predict immunotherapeutic responses for colon cancer. Methods: A total of 453 colon cancer (CRC) patients (480 normal and 41 tumor samples) were enrolled in this study. The RNA expression dataset were obtained from The Cancer Genome Atlas (TCGA-COAD). They were randomly grouped as training set and validation set(7:3 ratio). Necroptosis-related lncRNAs were identified using Pearson’s correlation analysis with 67 necroptosis-related genes previously reported. Stepwise Cox regression and LASSO algorithm were performed to construct the prognostic risk score model. The overall survival (OS) difference between the high- and low-risk groups(cutoff using median risk score) was compared using Kaplan-Meier statistics. Furthermore, we evaluated the associations between the identified lncRNAs and the immune-related phenotypes including tumor micro-environment (TME) scores calculated by ESTIMATE, immune cell infiltration estimated by CIBERSORT, chemotherapeutics sensitivity predicted by pRRophetic and immune checkpoint expression,etc. Results: A total of 1926 necroptosis-related lncRNAs were identified and four lncRNAs (LINC02753, AC073283, AC010973, AP003555) were found to be correlated with 10 differential expressed necroptosis-related genes. The identified four lncRNAs were used to construct the prognostic model. The identified biomarkers was found to significantly correlate with worse prognosis in TCGA cohort (Train set: HR = 4.65, 95%CI = 2.42-8.93, P < 0.001; Validation set: HR = 3.06, 95%CI = 1.32-7.12, P = 0.006; Whole set: HR = 4.04, 95%CI = 2.41-6.76, P < 0.001) and was found to be independent to clinicopathological parameters. In addition, the lower TME scores suggested the lower infiltration of non-tumor cells in high-risk group and eight drugs were predicted to be more effective in high-risk group (i.e., PAC-1, AS601245). Further immune-related analysis revealed that the infiltrating immune cells including B cells, CD4 T cells, resting NK cells, M1 macrophages, monocytes, were all significantly different between the two groups. Moreover, TNF superfamily members (i.e., TNFSF14/15/25) were found to be substantially increased in high-risk group, which was considered as a type of important immune checkpoint molecule and participates in the initiation and regulation of necroptosis. Conclusions: The identified 4-lncRNA signature based on necroptosis showed potential prognosis value in CRC patients. The results can also help to guide immunotherapy and clinical research with TNFSF inhibitors for colon cancer patients with further experimental and clinical validation.
Detection of the presence of polymorphisms in the DPYD gene in patients with colorectal and non-colorectal digestive tumors.
Authors: Gallego Jimenez Inmaculada , Garcia De Veas Jose Luis , Garcia Grove Clara , Tallafigo Fernando Leopoldo , Limon M. Luisa 
Published: June 2022

e15530 Background: Recently the European Medicines Agency (EMA) and the Spanish Medicines Agency (AEMPS) recommend performing a phenotypic and/or genotypic test before starting treatment with fluoropyrimidines The objective of this work has been to analyze the detection of polymorphisms in the DPYD gene in order to predict toxicity to fluoropyrimidines in our study population. Methods: Prospective study of 6 months duration in which patients diagnosed with CRC and non-CRC digestive tumors with an age range of 18-99 years have been included. The technique is performed on a sample of DNA extracted from lymphocytes in peripheral blood in an EDTA tube, performing a specific fluorescent allele amplification study (AMRS), which detects point mutations, insertions or deletions of DNA. Results: During the study period, 260 patients have been included, of whom 16 mutations have been detected, all in heterozygosity. Conclusions: Various variants of DPYD have been reported to cause the absence or reduction of dihydropyrimidine dehydrogenase (DPP) activity. Through this technique we avoid the risk of serious toxicity with the administration of these drugs.[Table: see text]