Mutations In Chinese Patients Research Articles

Mutational profile evaluates metastatic capacity of Chinese colorectal cancer patients, revealed by whole-exome sequencing

Colorectal cancer (CRC) is the third most common cancer and the prevalence rate of CRC is increasing in the China. In this study, whole-exome sequencing (WES) was performed on primary tissues of 47 CRC Chinese patients including 22 metastatic and 25 non-metastatic patients. By comparison with data from western colorectal cancer patients in the Cancer Genome Atlas (TCGA), we identified a number of genes that are more likely to be mutated in Chinese colorectal cancer patients, such as MUC12, MUC12, MUC2, MUC4, HYDIN and KMT2C. Interestingly, MUC family genes including MUC12, MUC2 and MUC4, have mutation rates of >20%, while the mutation frequency was extremely low in western colorectal cancer patients, which were <3% in TCGA and 0% in Memorial Sloan Kettering Cancer Center (MSKCC). We detected metastasis-specific mutated genes including TCF7L2, MST1L, HRNR and SMAD4, while MUC4, NEB, FLG and RFPL4A alteration is more prevalent in the non-metastasis group. Further analysis reveals mutation genes in metastasis group are more focus in the Wnt and Hippo signaling pathway. APC, SMAD4 and TCF7L2 accounted for the major genetic abnormalities in this pathway. In conclusion, this study identified the unique characteristics of gene mutations in Chinese patients with colorectal cancer, and is a valuable reference for personalized treatment in Chinese CRC patients.

The Phenotypic and Genotypic Spectrum of CSF1R-Related Disorder in China.

Colony-stimulating factor 1 receptor (CSF1R)-related disorder (CRD) is a rare autosomal dominant disease. The clinical and genetic characteristics of Chinese patients have not been elucidated. The objective of the study is to clarify the core features and influence factors of CRD patients in China. Clinical and genetic-related data of CRD patients in China were collected. Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Sundal MRI Severity Score were evaluated. Whole exome sequencing was used to analyze the CSF1R mutation status. Patients were compared between different sexes, mutation types, or mutation locations. A total of 103 patients were included, with a male-to-female ratio of 1:1.51. The average age of onset was (40.75 ± 8.58). Cognitive impairment (85.1%, 86/101) and parkinsonism (76.2%, 77/101) were the main clinical symptoms. The most common imaging feature was bilateral asymmetric white matter changes (100.0%). A total of 66 CSF1R gene mutants (22 novel mutations) were found, and 15 of 92 probands carried c.2381 T > C/p.I794T (16.30%). The MMSE and MoCA scores (17.0 [9.0], 11.90 ± 7.16) of female patients were significantly lower than those of male patients (23.0 [10.0], 16.36 ± 7.89), and the white matter severity score (20.19 ± 8.47) of female patients was significantly higher than that of male patients (16.00 ± 7.62). There is no statistical difference in age of onset between male and female patients. The core manifestations of Chinese CRD patients are progressive cognitive decline, parkinsonism, and bilateral asymmetric white matter changes. Compared to men, women have more severe cognitive impairment and imaging changes. c.2381 T > C/p.I794T is a hotspot mutation in Chinese patients. © 2024 International Parkinson and Movement Disorder Society.

23P Clinical impact and prognostic value of EGFR mutation co-occurring with ALK, ROS1, RET fusions, or MET exon 14 skipping mutations in Chinese patients with non-small cell lung cancer

23P Clinical impact and prognostic value of EGFR mutation co-occurring with ALK, ROS1, RET fusions, or MET exon 14 skipping mutations in Chinese patients with non-small cell lung cancer

Germline RECQL gene mutations in Chinese patients with breast cancer.

Breast cancer is the most common malignant tumor in women, seriously threatening health and survival. TP-dependent DNA helicase Q1 (RECQL) is a breast cancer susceptibility gene with possible familial links. However, RECQL gene mutations among Chinese women with breast cancer have not been evaluated. Therefore, this study assessed RECQL mutations and their relationships with clinicopathological and epidemiological characteristics in Chinese women with breast cancer. Clinical information was also obtained via the hospital information system and a follow-up questionnaire. Peripheral venous blood (2 mL) was extracted from all patients and stored at -80°C for future use; the early venous blood samples were from our hospital's sample bank. RECQL gene sequencing were performed by the Shanghai Aishe Gene Company (China). We found that a RECQL mutation is a susceptibility factor for breast cancer. Moreover, patients with RECQL mutations were more likely to have a family history of breast cancer than those without. Also, patients with RECQL variants of uncertain significance (VUS) were less likely to develop invasive ductal carcinoma than those without. In addition, unexplained RECQL mutations occurred more often in patients with human epidermal growth factor receptor 2+ breast cancer than in those with other subtypes. These results provide a basis for creating screening criteria specific to Chinese women. However, the frequency of RECQL mutations was low, and the number of pathogenic mutations was too small and could not be analyzed. Thus, more extensive, long-term studies that include other functional experiments are needed to verify these results.

Eight EDA mutations in Chinese patients with tooth agenesis and genotype-phenotype analysis.

Tooth agenesis is a common craniofacial malformation, which is often associated with gene mutations. The purpose of this research was to investigate and uncover ectodysplasin A (EDA) gene variants in eight Chinese families affected with tooth agenesis. Genomic DNA was extracted from tooth agenesis families and sequenced using whole-exome sequencing. The expression of ectodysplasin A1 (EDA1) protein was studied by western blot, binding activity with receptor was tested by pull-down and the NF-κB transcriptional activity was analyzed by Dual luciferase assay. Eight EDA missense variants were discovered, of which two (c.T812C, c.A1073G) were novel. The bioinformatics analysis indicated that these variants might be pathogenic. The tertiary structure analysis revealed that these eight variants could cause structural damage to EDA proteins. Invitro functional studies demonstrated that the variants greatly affect protein stability or impair the EDA-EDAR interaction; thereby significantly affecting the downstream NF-κb transcriptional activity. In addition, we summarized the genotype-phenotype correlation caused by EDA variants and found that EDA mutations leading to NSTA are mostly missense mutations located in the TNF domain. Our results broaden the variant spectrum of the EDA gene associated with tooth agenesis and provide valuable information for future genetic counseling.

Dynamic monitoring of UBA1 somatic mutations in patients with relapsing polychondritis

BackgroundCommonly clinically diagnosed with relapsing polychondritis (RP), vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS) is a recently identified autoinflammatory disease caused by UBA1 somatic mutations. The low frequency and dynamic changes challenge the accurate detection of somatic mutations. The present study monitored these mutations in Chinese patients with RP. We included 44 patients with RP. Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood. Droplet digital polymerase chain reaction (ddPCR) was performed to screen low-prevalence somatic variants.ResultsMultiple ddPCR detections were performed using available blood samples collected at different follow-up time points. Three male patients were UBA1 somatic mutation carriers. Sanger sequencing detected the somatic UBA1 variant c.122T > C (p.Met41Thr) in two male patients. Initial ddPCR confirmed the variant in the two patients, with allele fractions of 73.75% and 88.46%, respectively, while yielding negative results in other patients. Subsequent ddPCR detected the somatic variant (c.122T > C) with low prevalence (1.02%) in another male patient from blood samples collected at a different time point, and confirmed dynamically fractional abundance in one patient with VEXAS, with allele fractions of 73.75%, 61.28%, 65.01%, and 73.75%. Nine patients assessed by ddPCR at different time points remained negative.ConclusionWe report UBA1 variants in patients with RP in the Chinese population for the first time. Multiple ddPCR detections from samples collected at different time points can enhance sensitivity and should be considered for patients with initial negative ddPCR results.

Identification of Arrhythmia-Associated Gene Mutations in Chinese Patients with Primary Electrical Disorders or Sudden Cardiac Death

Background: Sudden cardiac death (SCD), unexpected death based on sudden cardiac ejection cessation, accounts for 15–20% of unnatural deaths in developed countries. Primary electrical disorders (PEDs), a group of cardiac rhythm abnormalities without detectable structural heart disease, are a major cause of SCD in people younger than 35 years of age. Cardiac muscle contraction and relaxation are triggered by the action potential (AP), which is generated by ionic changes across the cell membrane. Thus, PEDs are influenced by mutations in AP-associated genes, such as KCNE1 and RYR2. Methods: We recruited six patients with SCD and 42 patients with arrhythmia with onset under the age of 25, and used targeted sequencing to determine the genetic etiologies. Results: We identified five mutations (RYR2: c.12269C&gt;T, p.P4090L; KCNE1: c.169T&gt;C, p.F57L; KCNQ1: c.853A&gt;C, p.K285Q; KCNH2: c.793T&gt;C, p.C265R, and TRPM4: c.2985_3012del, p.E996Gfs*118) in five families with PED/SCD. Conclusions: We detected five mutations and expanded the mutation spectrum of PED-associated genes, thus contributing to the clinical diagnosis of PED.

HR-positive/HER2-negative breast cancer arising in patients with or without BRCA2 mutation: different biological phenotype and similar prognosis.

BRCA2 plays a key role in homologous recombination. However, information regarding its mutations in Chinese patients with breast cancer remains limited. This study aimed to assess the clinicopathological characteristics of BRCA2 mutation breast cancer and explore the mutation's effect on hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer survival in China. This hospital-based cohort study prospectively included 629 women with breast cancer diagnosed from 2008 to 2023 at Zhejiang Cancer Hospital in China. We compared the clinicopathological characteristics and metastatic patterns and analysed the invasive disease-free survival (iDFS), distant relapse-free survival (DRFS) and first-line progression-free survival (PFS1) of patients with HR-positive/HER2-negative breast cancer according to BRCA2 mutations. Among the 629 patients, 78 had BRCA2 mutations (12.4%) and 551 did not (87.6%). The mean age at diagnosis was lower in the BRCA2 mutation breast cancer group than in the non-mutation breast cancer group (38.91 versus 41.94 years, p = 0.016). BRCA2 mutation breast cancers were more likely to be lymph node-positive than non-mutation breast cancers (73.0% versus 56.6%, p = 0.037). The pathological grade was higher in 47.1% of BRCA2 mutation breast cancers than in 29.6% of non-mutation breast cancers (p = 0.014). The proportions of patients with BRCA2 mutations who developed contralateral breast cancer (19.2% versus 8.8%, p = 0.004), breast cancer in the family (53.8% versus 38.3%, p = 0.009) and ovarian cancer in the family (7.6% versus 2.4%, p = 0.022) were higher than those of patients without the mutation. The median follow-up time was 92.78 months. Multivariate analysis showed that BRCA2 mutation was not associated with poorer iDFS [hazard ratio = 0.9, 95% confidence interval (CI) = 0.64-1.27, p = 0.56] and poorer distant relapse-free survival (DRFS) (hazard ratio = 1.09, 95% CI = 0.61-1.93, p = 0.76). There was no significant difference between the two groups with regard to metastatic patterns in the advanced disease setting. In the first-line metastatic breast cancer setting, PFS1 expression was broadly similar between the two groups irrespective of chemotherapy or endocrine therapy. HR-positive/HER2-negative breast cancer with BRCA2 mutations differs from those without mutations in clinical behaviour and reflects more aggressive tumour behaviour. Our results indicate that BRCA2 mutations have no significant effect on the survival of Chinese women with HR-positive/HER2-negative breast cancer.

Familial FTD in China:progress and prospects

AbstractBackgroundFrontotemporal dementia (FTD) is a set of clinical syndromes characterized by progressive abnormalities in behavior, executive function, language, with a strong genetic background. However, the familiar FTD studies were rare in China. Here we aim to review the previous cross‐sectional reports of Chinese FTD patients with gene mutations, as well as the update status of the longitudinal familiar FTD study by the Chinese Familial Frontotemporal Lobar Degeneration Consortium (CFFC).MethodTo review current status of Chinese FTD patients with gene mutations, we performed a comprehensive electronic searches of Medline, PubMed, and Embase databases were performed by using the combination of a number of medical subject headings, Emtree subject headings, and free‐text terms (“frontotemporal lobar degeneration” or “frontotemporal dementia” for clinical categories; “Chinese” or “China” for ethnics). To start a multi‐center longitudinal cohort of familiar FTD, we established the CFFC in October 2022 by involving 7 top teaching hospitals across China. Patients with MAPT, GRN and C9orf72 mutations were enrolled and followed up according the designed framework.ResultBased on the previous reports, genetic mutations accounted for 5.13%‐27.9% as reported in a few cross‐sectional cohort of Chinese FTD patients. Mostly reported pathogenic variants were MAPT, followed by GRN, TBK1, CHCHD10, C9orf72 repeat expansions, VCP, and SQSTM1. Up till now, there were 26 pedigrees with MAPT mutations, 11 pedigrees with GRN mutations and 9 pedigrees with C9orf72 repeat expansions mutations have been enrolled in the longitudinal multi‐center cohort study by CFFC.ConclusionThe high prevalence of MAPT mutations in Chinese patients with FTD, may implies a genetic heterogeneity between Chinese and other ethnics. Longitudinal studies with larger sample size to modeling the trajectory of biomarkers in genetic mutation carriers for earlier diagnosis and intervention are needed in the future.

The Incidence, Clinical Application and Prognostic Significance of MYD88 and CXCR4 Mutation in Chinese Patients with Lymphoplasmacytic Lymphoma/ Waldenström Macroglobulinemia

Introduction Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare B-cell lymphoma with prevalent somatic mutations, including MYD88 and CXCR4. However, their mutation rates in Chinese LPL/WM and the comparison of different detection methods remain unclear. Moreover, the clinical implications of MYD88 and CXCR4 mutations in the immunochemotherapy and targeted therapy eras need exploration. Methods This study included 458 LPL/WM patients (418 WM, 40 non-IgM LPL) from December 2014 to June 2023. Four methods, such as Sanger sequencing, next-generation sequencing (NGS), allele-specific quantitative polymerase chain reaction (AS-PCR), and droplet digital polymerase chain reaction (ddPCR), were used to detect MYD88L265P and CXCR4 mutations. Demographic data, clinical characteristics, tumor burden, cytogenetic abnormalities, treatment regimens, and survival data were collected. Results A total of 458 patients were assessed for MYD88 L265P mutation, of whom 266 were tested by Sanger sequencing, 300 by NGS, 370 for AS-PCR, 251 for ddPCR. The MYD88 L265P mutation was found in 398/458 (86.9%) of the patients. AS-PCR and ddPCR showed the highest sensitivity (97.2% and 96.5%, respectively), outperforming Sanger sequencing and NGS, which had higher false-negative rates in low tumor load patients. A high false-negative rate for MYD88 by Sanger sequencing and NGS was observed in patients with tumor burden less than 10% (40.0% and 21.9% respectively). There was no significant difference in the MYD88 mutation rate detected by ddPCR and ASPCR among patients with different tumor burden groups (P=0.402, P=0.252). MYD88 mutation was detected in a high incidence of 86.7% and 85.5% in less than 1% infiltrated WM tumor cells specimens by ddPCR and ASPCR. Thus, ddPCR and ASPCR assay were effective and accurate enough for un-sorted low infiltrated WM specimens. CXCR4 mutation testing was performed in 428 patients of LPL/WM, comprising 311 with Sanger sequencing, 300 with NGS, and 371 with AS-PCR. Overall, 31.8% (136/428) patients were identified as having the CXCR4 mutation. NGS exhibited the highest sensitivity (79.2%) among the three detection means. Among the 458 patients of LPL/WM, 60 (13.1%) were classified as MYD88 wild-type patients. MYD88 wild-type patients had a significantly lower hemoglobin levels (median 83g/L vs. 92g/L, P=0.044), lower proportion of males (56.7% vs. 72.5%, P=0.012) and a significantly higher proportion elevated β2-macroglobulin (81.5% vs. 68.5%, P=0.027), and lactic dehydrogenase (32.2% vs. 11.1%, P&amp;lt;0.001). However, there were no significant differences in either PFS or OS between MYD88 L265P wild-type and MYD88 L265P mutation group (PFS: median 35.7 months vs. 52.9 months, P=0.40; OS: 5-year rate 72.0% vs. 81.8%, P=0.62). MYD88 wild-type patients had worse PFS and post-BTKi failure-free survival under immunochemotherapy (median 34.3 months vs. 58.4 months, P=0.03), and BTKi regimens (median: 26.2 months vs. 45.2 months, P=0.02), respectively. Patients with CXCR4 mutation tended to be older (median 64 vs. 60, P=0.001), had lower hemoglobin levels (median 83g/L vs. 94g/L, P=0.008), and higher baseline BM involvement (by FCM, median 12.6% vs. 6.2%, P&amp;lt;0.001) compared with CXCR4 wild-type patients. The proportion of patients with thrombocytopenia (43.7% vs. 20.6%, P&amp;lt;0.001), serum IgM level more than 40g/L (47.4% vs. 34.6%, P=0.019) was significantly higher, the proportion of patients with low risk profile of IPSSWM (17.2% vs. 30.5%, P=0.007) was significantly lower in mutation group. Notably, CXCR4 mutation group had significantly worse survival compared with the wild-type group (PFS: median 40.5 months vs. 62.5 months, P=0.024; OS: median 103.8 months vs. not reached, P=0.022). Meanwhile, patients with CXCR4 mutation experienced inferior post-BTKi failure-free survival (median 30.4 months vs. 57.6 months, P=.04) and post-BTKi overall survival (3-year rate 71.9% vs. 84.9%, P=0.03) in BTKi therapy groups. Conclusions This study sheds light on MYD88 and CXCR4 mutations in Chinese WM/LPL based on a large cohort. AS-PCR and ddPCR were highly sensitive for MYD88 mutation detection, especially in low infiltrated WM. NGS was the most sensitive method for detecting CXCR4 mutation. MYD88 mutation had prognostic significance in BTKi-based therapy, while CXCR4 mutation indicated higher tumor burden and inferior survival in BTKi-based therapy.

Clinicopathological relevance of BRAF and SMO mutations in Chinese patients with ameloblastoma

Ameloblastomas are benign tumors associated with recurrence and morbidity. Mutations in the V-Raf murine sarcoma viral oncogene homolog B1 (BRAF) and smoothened (SMO) genes have been identified in ameloblastomas. The mutation rate of BRAF in different regions and mutation sites of SMO remains controversial. This study assesses the relationship between these mutations and clinicopathological features of ameloblastoma in Chinese patients. Ameloblastomas were surgically removed from 30 patients and BRAF gene polymorphisms were detected using DNA sequencing analysis. We also examined the relationship between BRAF or SMO mutations and clinicopathological parameters. BRAF V600E mutation was detected in 18 of 30 ameloblastomas. No significant correlation was found between BRAF V600E mutation and age, sex, location, histologic type, capsular invasion, or tumor recurrence. Five cases carried an SMO T364N mutation in exon 5, whereas six carried an SMO S590 T mutation in exon 10. The SMO mutation rate in patients aged ≤ 20 years was significantly higher than that in patients aged > 20 years. SMO T364N and S590 T mutations were closely related to age and capsular invasion. These findings indicate that BRAF V600E, SMO T364N, and SMO S590 T mutations play important roles in the pathogenesis of ameloblastoma. Key highlights The BRAF V600E mutation was highly prevalent in Chinese patients with ameloblastoma. SMO T364N and S590 T mutations are closely related to age and capsular invasion. The BRAF V600E, SMO T364N, and SMO S590 T mutations play important roles in the pathogenesis of ameloblastoma.

Two novel GCK mutations in Chinese patients with maturity-onset diabetes of the young.

Heterozygous inactivating mutations in the glucokinase (GCK) gene result in the asymptomatic fasting hyperglycemia named as GCK-MODY or MODY2. The genetic testing can effectively avoid the misdiagnosis and inappropriate treatment for GCK-MODY. A total of 25 unrelated families with MODY were screened for mutations in coding region of GCK by using direct sequencing. Three different bioinformatics tools such as PolyPhen2, Mutation Taster and PROVEAN were performed to predict the function of mutant proteins. The glucose profile was recorded by continuous glucose monitoring system (CGMS) to evaluate the glycemic variability for the GCK-MODY patient. Our study identified five GCK mutations in 24% of the families (6/25): two novel mutations (I126fs and G385A) and three already described mutations (G44S, H50fs and S383L). In silico analyses predicted that these mutations altered structural conformational changes. The values of mean amplitude of glycemic excursions (MAGE), an important index of blood glucose fluctuation in CGMS system, were 0.81 in the first 24 h and 1.61 in the second 24 h record in the patient with GCK-MODY (F3), suggesting little glucose fluctuation. The genetic testing is suggested to be important to differentiate GCK-MODY from other types of diabetes. CGMS might be used to screen GCK-MODY cases prior to genetic testing.

519P The landscape of PDGFRA mutation in Chinese patients with glioma

519P The landscape of PDGFRA mutation in Chinese patients with glioma

Clinical and genetic findings in 13 Chinese children with keratinopathic ichthyosis.

Keratinopathic ichthyosis (KPI) represents a group of predominantly autosomal dominant genodermatoses resulting from mutations in the KRT1, KRT2, or KRT10 genes. In KPI, the relationship between genotype and phenotype is complex. To analyze the clinical manifestations and gene mutations in Chinese patients with KPI. Clinical data were collected from 13 children diagnosed with KPI, and peripheral blood DNA samples were extracted from both the patients and their parents Next-generation sequencing was performed using a congenital ichthyosis multi-gene panel, and the selected variants in the patients and their parents were further validated using the Sanger sequencing method. Genetic analysis identified missense mutations in either KRT1 or KRT10 in ten patients exhibiting varying degrees of severity and distinct features of epidermolytic ichthyosis. A missense hotspot mutation in KRT2 was identified in one patient with superficial epidermolytic ichthyosis. Additionally, two truncation mutations in KRT10 were detected, leading to the development of generalized ichthyosiform erythroderma. Ear malformation and ectropion at birth, scalp involvement, and palmoplantar hyperkeratosis were observed as early signs of ichthyosis with confetti. We analyzed the genotype-phenotype correlations in KPI, revealing that the types and locations of different mutations are associated with distinct phenotypic characteristics. Oral acitretin could be considered a treatment option for severe patients at an appropriate dosage and timing.

Comparison of concomitant mutational of type I/II/III BRAF mutation in colorectal cancer between Chinese and Western populations.

e15634 Background: BRAF V600E CRC had a relatively poor prognosis.The efficacy of BRAFi is unpredictable just that intrinsic genetic complexity and partially unknown reason.Therefore, To understand co-mutation mechanism can help improve treatment and follow-up strategy. Methods: 339 Chinese CRC patients and 125 Western CRC data from the cBioPortal were included in study. Co-occurrence mutation analysis, GO and KEGG pathway enrichment analysis was enabled in this study. Results: 35/339 (10.32%) patients were BRAF mutation, with 17 patients were BRAFV600E in Beijing hospital. Patients with BRAF mutation had significantly associated with TMB-H (p = 0.0004) and MSI (p = 0.0003) than those with BRAF wild-type. In 125 BRAF mutation western cohort, The frequency clinicpathologic features, MSI, TMB, and BRAF mut-type were consistent with Chinese data. However, the primary tumor location showed significant statistical differences (P &lt; 0.0001). In Chinese cohort, class 1 (BRAFV600E, A deeper classification system of BRAF mutations) were more likely to occur in Elder, Female, western cohort was consistent with above. Other clinicpathologic features were not associated with mut-type in Chinese cohort. However, Western cohort showed class 1 exhibited primary sample type predominance(vs class NA, P &lt; 0.05; vs class 3, P &lt; 0.05). Right-sided was more likely to occur in class 1(P &lt; 0.05), this was inconsistent with the data analyzed above. Meantime, The data showed TMB-H (57.69% vs 11.76%, P &lt; 0.001) and MSI-H (28.21% vs 14.29%, P &lt; 0.005) of the class 1 were significantly higher, compared with class 3. In concurrent oncogenic mutations. Compared with non-class 1, class 1 were more likely co-passenger mutation. Data from Western populations show similar results. We also found that the class 1 was mutually exclusive with co-KRASmt in CRC, and co-APCmt appeared more frequently in non-class 1. In pathway enrichment, KEGG pathway showed that fewer proto-cancer signaling pathways were enriched in the class 1, which further confirmed that this type had stronger tumorigenicity. GO enrichment also proved that class1 had stronger tumorigenicity. Finally, Prognostic analysis showed median overall survival(OS) of 47.57 months in class 1 versus 19.43 months in non-class 1(p = 0.0002). Further study showed that the mOS of class 1/2/3/NA was 19.43 months, 28.50 months, 47.57 months and NA months(P = 0.0001), respectively. Conclusions: This study shown class 1/non-class 1 BRAF mutation in CRC have significantly differences in co-mutation features, genomic markers and prognioses. Especially, class I BRAF mutation in Chinese patients have higher TMB and MSI,maybe we could choose BRAFi and immunotherapy for them. Understanding BRAF mutation types and co-mutation mechanism will contribute to accurately grasp treatment, follow-up strategies and promote the development of precision therapy for CRC in the future.

Molecular characteristics of KRAS mutations in Chinese patients with cancer.

e15070 Background: Sotorasib, the first KRAS G12C inhibitor, has been approved for the treatment of non-small cell lung cancer (NSCLC) patients with KRAS G12C mutation-positive. Understanding the molecular characteristics of KRAS in Chinese patients with cancer is imperative, which is conducive to screening the beneficiary groups. Here, we focus on the molecular characterization of KRAS in NSCLC, colorectal cancer (CRC), pancreatic cancer (PC), and gastric cancer (GC). Methods: This study enrolled 17,775 pan-cancer patients detected by next-generation sequencing (NGS) from June 2021 to February 2022, in which NSCLC, CRC, PC and GC were 48.67% (8651/17775), 10.87% (1933/17775), 1.92% (342/17775) and 5.37% (955/17775), respectively. Results: The KRAS mutation rate in pan-cancer is 16.28% (2893/17775). In NSCLC, CRC, PC and GC cohorts, the mutation rates of KRAS were 13.28% (1149/8651), 50.34% (973/1933), 66.67% (228/342) and 7.64% (73/955), respectively. In NSCLC cohort, 1274 KRAS mutations were detected, and the subtypes were concentrated in G12C (346;27.16%), G12D (205;16.10%), G12V (194;15.23%), G12A (86;6.75) and Q61H (57;4.47%). In CRC cohort, 1094 KRAS mutations were detected. The subtypes were mainly distributed in G12D (350;31.40%), G13D (184;16.82%), G12V (180;16.45%), A146P (66;6.03%) and G12C (49;4.48%). In PC cohort, 251 KRAS mutations were detected, and the subtypes were concentrated in G12D (109;43.43%), G12V (70;27.89%), G12R (32;12.75%), G12C (9;3.59%) and Q61H (9;3.59%). In GC cohort, 82 KRAS mutations were detected. The subtypes of these mutations were concentrated in G12D (23;28.05%), G13D (12;14.63%), Q61H (7;8.54%), G12V (5;6.10%) and Q61R (5;6.10%). Conclusions: In NSCLC, CRC, PC and GC cohorts, K RAS mutations were concentrated in exon 2, accounting for 78.41% (999/1274), 81.63% (893/1094), 91.63% (230/251) and 64.63% (53/82), respectively. In NSCLC cohort, KRAS G12C was the molecular subtype with the highest mutation rate. However, in other cohorts, KRAS G12D was the predominant molecular subtype. G12D mutation will become the next research hotspot, and the breakthrough will help to further expand the beneficiary population of KRAS mutations.

Screening the key pathogenic mutations in Chinese patients with colorectal cancers using liquid and tissue biopsy.

e15637 Background: Colorectal cancer (CRC) is the third most common cancer worldwide. Over the past decades, significant progress has been made in the clinical treatment of CRC. Targeted therapy is an optional approach that has successfully prolonged overall survival for CRC patients. It is necessary to determine the personalized targets for guiding the usage of specific drugs, which requires biopsy to obtain pathological samples for analysis. Both tissue biopsy and liquid biopsy are commonly used in clinical diagnosis, while each has its own advantages and limitations. The mutation detection rate of tissue biopsy is usually higher, and more genes can be detected, but most tissue biopsies require surgery to obtain samples and may be biased due to the intra-tumor heterogeneity. Liquid biopsy is less harmful to patients, but the detection sensitivity is much lower than tissue biopsy. Methods: In this study, 353 paraffin tissue section samples were used as tissue biopsy samples and 112 blood samples were used as liquid biopsy samples. All samples are from Chinese patients and are collected from December 2021 to August 2022. Whole-genome sequencing was performed, and several processes have been conducted to eliminate noise, duplicates and reads with low depth, therefore the gene mutations detected in the samples were considerably reliable. We selected APC, TP53, KRAS, PIK3CA and BRAF as the key pathogenic genes for CRC, analyzed the mutation detection results in tissue and blood samples. The detection difference between two types of biopsies was assessed using Pearson's Chi-squared test. Results: Among all samples, 21 (5.95%) tissue biopsy samples and 37 (33.04%) liquid biopsy samples did not contain any key pathogenic genes. For all biopsy samples, the detection rates for APC in tissue biopsy samples (n = 236, 66.86%) and liquid biopsy samples (n = 49, 43.75%) demonstrate significant difference (p = 2.02e-05). The differential detection rates were also observed in TP53 (n = 223 vs. n = 51, 63.17% vs. 45.54%, p = 0.0014) and KRAS (n = 183 vs. n = 39, 51.84% vs. 34.82%, p = 0.0024). There is no significant difference in detection rates of PIK3CA (n = 77 vs. n = 15, 21.81% vs. 13.39%, p = 0.0699) and BRAF. Only 25 (7.08%) tissue biopsy samples and 8 (7.14%) liquid biopsy samples were found to detect BRAF (p = 1). Conclusions: Generally, there is no doubt that the overall detection sensitivity of tissue biopsy is higher than that of liquid biopsy for CRC, and our analysis provided the statistical support. But for some relatively rare disease-causing genes, there is not much difference between the two biopsy methods. For patients, tissue biopsies can be more painful than liquid biopsies, so how to improve the detection of liquid biopsy in CRC is still a subject that requires efforts.

Significance of the FGFR3 mutation in Chinese patients with bladder cancer.

Bladder cancer (BC) is the 10th most common malignancy worldwide. The high recurrence rates of BC lead to significant treatment challenges. With the development of molecular biology techniques, research has shown that gene abnormalities are closely related to the occurrence and development of BC. This study analyzed the detection results of gene mutations in the tissue samples of BC patients and explored the relationship between fibroblast growth factor receptor 3 (FGFR3) and the prognosis and recurrence of BC. This study examined 82 Chinese patients with BC. Of these patients, 34 underwent radical cystectomy (RC), and 48 underwent transurethral resection with intravesical instillation. In addition, multi-gene panel targeted next-generation sequencing (NGS) of the samples was performed. The mutational spectra revealed that C > T was the most common base substitution. Single nucleotide polymorphism (SNP) and deletion (DEL) were the common variant types in our cohort. The top 10 mutant genes were ROS1 (37%), PIK3CA (35%), FGFR3 (34%), BRAF (34%), ERBB2 (32%), ALK (27%), RET (27%), NTRK1 (24%), MET (23%), and EGFR (18%). FGFR3 mutations were detected more frequently in non-muscle-invasive bladder cancer (stages 0a, I) patients than in muscle-invasive bladder cancer (stage II, III, and IV) patients. The top 3 altered types of FGFR3 were p.Ser249Cys, p.Tyr375Cys, and p.Arg248Cys. This study examined the mutated types and frequency of FGFR3 and the prognosis of Chinese BC patients with FGFR mutations. We hope that our findings will enable clinical individualization strategies for BC patients to be optimized.

Specific Mutations in APC, with Prognostic Implications in Metastatic Colorectal Cancer.

Loss-of-function mutations in the adenomatous polyposis coli (APC) gene are common in metastatic colorectal cancer (mCRC). However, the characteristic of APC specific mutations in mCRC is poorly understood. Here, we explored the clinical and molecular characteristics of N-terminal and C-terminal side APC mutations in Chinese patients with mCRC. Hybrid capture-based next-generation sequencing was performed on tumor tissues from 275 mCRC pati-ents to detect mutations in 639 tumor-associated genes. The prognostic value and gene-pathway difference between APC specific mutations in mCRC patients were analyzed. APC mutations were highly clustered, accounting for 73% of all mCRC patients, and most of them were truncating mutations. The tumor mutation burden of the N-terminal side APC mutations group (n=76) was significantly lower than that of the C-terminal side group (n=123) (p < 0.001), further confirmed by the public database. Survival analysis showed that mCRC patients with N-terminus side APC mutations had longer overall survival than C-terminus side. Tumor gene pathway analysis showed that gene mutations in the RTK/RAS, Wnt and transforming growth factor β signaling pathways of the C-terminal group were significantly higher than those of the N-terminal group (p < 0.05). Additionally, KRAS, AMER1, TGFBR2, and ARID1A driver mutations were more common in patients with C-terminal side APC mutations. APC specific mutations have potential function as mCRC prognostic biomarkers. There are obvious differences in the gene mutation patterns between the C-terminus and N-terminus APC mutations group, which may have certain guiding significance for the subsequent precise treatment of mCRC.

Tumor grade-associated genomic mutations in Chinese patients with non-small cell lung cancer.

Lung cancer is the most prevalent cancer worldwide and accounts for approximately 20% of cancer-related death in China every year. High-grade lung cancer poses a significant threat to patients, and developing a novel treatment for these patients requires an understanding of its underlying mechanism. Chinese patients with lung cancer were enrolled. The tumor samples were collected by surgery or puncture and applied for next-generation sequencing. A panel of pan-cancer genes was targeted, and the sequencing depth was set to over 1,000 to improve the sensitivity of detecting mutations. Short-length mutations (substitution, insertion, and deletion), copy number variation, and gene fusion were called. Gene mutations were compared between low-grade, middle-grade, and high-grade tumors using Fisher's exact test. The enriched pathways in each grade of tumors were also inferred. The study included 173 Chinese patients with non-small cell lung cancer, of whom 98 (56.6%) patients were female and 75 (43.4%) were male, with a mean age of 56.8 years. All patients were microsatellite stable; 66.4% were at the early stages (Stages 0, I, and II) with a tumor mutational burden of approximately 2.5 (confidence interval = [0, 48.3]). Compared to low-grade tumors, high-grade tumors had a significantly higher percentage of mutations in TP53 (75.9% vs 34.4%, p = 1.86e-3) and PIK3CA (24.1% vs. 0%, p = 3.58e-3). Pathway analysis found that high-grade tumors were enriched with mutations in bacterial invasion of epithelial cells (31% vs. 0%, p = 5.8e-4), Epstein-Barr virus infection (79.3% vs. 37.5%, p = 1.72e-3), and the Wnt signaling pathway (75.9% vs. 34.4%, p = 1.91e-3). High-grade tumors had a significantly higher tumor mutational burden than low-grade tumors (p-value = 0.0017). However, actionable mutations with high-level evidence were lower in high-grade tumors. Patients with high-grade tumors from lung cancer may be more affected by bacteria and Epstein-Barr virus than low-grade tumors. High-grade tumors were specially mutated in TP53 and PIK3CA and may benefit more from immunotherapy. Further research on the underlying mechanism of high-grade lung cancer is necessary to develop new therapeutic options. Lung cancer, tumor grade, genomic mutations, Epstein-Barr virus, pathway analysis.