Multiple primary lung cancers (MPLCs) are an increasingly well-known clinical phenomenon, but there is a lack of high-level evidence for their optimal clinical diagnosis and therapeutic approaches. Thus, we analysed genetic variation to determine the intertumoural heterogeneity and branch evolution of synchronous multiple primary lung adenocarcinomas.We performed multiplex mutational sequencing on 93 synchronous multiple primary lung adenocarcinoma lesions from 42 patients who underwent surgical resection.The high discordance rate of mutation was 92.9% (n=39) between tumours in individual patients. EGFR, TP53 and KRAS mutations were detected in 57 (61.3%), 19 (20.4%) and 11 (11.8%) of the 93 tumours, respectively. 16 cases of multiple primary lung adenocarcinomas simultaneously harboured EGFR mutations and TP53 mutations. Matching mutations between paired tumours were observed in 1 (2.4%) patient for P20. The genotypes were all EGFR L858R mutations, but the pathological type of P20T1 was lepidic predominant, and P20T2 was adenocarcinoma in situ. In the phylogenetic tree, genetic variations were divided into trunk, shared and branch subtypes. Branch mutations accounted for 91.09% of variations in sMPLA, while the ratio of trunk (4.95%) and shared (3.96%) variations was significantly lower.Remarkable intertumoural heterogeneity and frequent branch mutations were found in synchronous multiple primary lung adenocarcinomas.
e20579 Background: Molecular residual disease (MRD) status is associated with the recurrence of non-small cell lung cancer (NSCLC) after complete resection. In clinical practice, MRD-positive patients are still uncertain of the specific recurrence time, and may even not relapse. Besides, it remains unclear whether the mutational signatures of circulating tumor DNA (ctDNA) based on MRD detection (ctDNA-MRD) may help predict recurrence. Therefore, we performed this analysis to explore whether the ctDNA-MRD mutational signatures could help predict recurrence, especially in MRD-positive population. Methods: Two investigators independently searched public databases for articles related with MRD in lung cancer published up to July 31, 2022. After screening, raw data from two published studies on resectable NSCLC were analyzed. Gene clusters were established based on the clearance of ctDNA after surgery. Kaplan-Meier and multivariate analyses were performed to find genes (Monitor genes) and clinical variables associated with recurrence-free survival (RFS). Lasso method was used to find recurrence-related genes based on perioperative ctDNA (preoperative and longitudinal ctDNA). Monitor genes and recurrence-related genes were defined as 9-gene signature. The mutational status of Monitor genes and 9-gene signature in perioperative ctDNA, as well as clinical variables, were used to establish prognostic models. The power of the models in distinguishing recurrence was shown as the area under the curve (AUC). Results: Data from 168 patients with at least one somatic mutation detected in tumors were included in the analysis. DNMT3A, EGFR, TP53, KEAP1, NAV3 (Monitor genes), and clinical variables (stage, adjuvant therapy) were factors associated with RFS. The AUC of the model based on Monitor gene mutations in perioperative ctDNA was 0.774, and the AUC reached 0.807 when clinical variables were included. The AUC of the models based on clinical variables, 9-gene signature (Monitor genes, KRAS, NTRK3, RPL5, and SOX2) in perioperative ctDNA for predicting the recurrence in the overall population and MRD-positive population were 0.840 and 0.832, respectively. Conclusions: This analysis reveals that perioperative ctDNA mutational signatures are helpful to predict postoperative recurrence, so it is necessary to pay attention to the specific gene mutations in ctDNA-MRD. [Table: see text]
Abstract Background Our study aimed to explore the prevalence and risk factors of refractive error (RE) in Han and Tibetan population aged 50-79 years in Xining and surrounding areas in Qinghai Province on Qinghai-Tibet Plateau. Methods As part of the China National Health Survey, our cross-sectional study compared the age-adjusted prevalence of RE in Han and Tibetan elder adults aged 50-79 years in Xining and surrounding areas. A multivariate logistic regression model was used to identify risk factors for myopia and hyperopia. Results Among 769 Han participants and 476 Tibetan participants, the age-adjusted prevalence of myopia, hyperopia, high myopia and astigmatism were 28.56%, 22.82%, 2.80%, and 69.38%. Han population have higher age-adjusted prevalence of myopia (32.93% vs 21.64%, p<0.001), high myopia (3.93% vs 1.02%, p=0.001) and astigmatism (72.14% vs 64.94%, p=0.021) compared to Tibetan population. Being Tibetan is the protective factor of myopia compared to being Han (OR 0.58, 95%CI 0.42-0.79, p<0.001). Elder age (p=0.032), longer time length in rural area (p=0.048), undergraduate/graduate education level (p=0.031), lighter active level (p=0.007) and lower BMI index (p=0.015) are risk factors for myopia. Elder age (all p<0.001) and pterygium status of the same eye (p=0.013) also increases the hyperopia risk. Conclusions Our study found an overall prevalence of myopia of 28.56% in Xining and surrounding areas in adults elder than 50 years. Han population has higher myopia risk than Tibetan population. More medical and social resources should be allocated to improve the vision and life quality of elder adults.
Abstract Background Our study aimed to explore the prevalence and risk factors of refractive error (RE) in Han and Tibetan population aged 50–79 years in Xining and surrounding areas in Qinghai Province on Qinghai-Tibet Plateau. Methods As part of the China National Health Survey, our cross-sectional study compared the age-adjusted prevalence of RE in Han and Tibetan older adults aged 50–79 years in Xining and surrounding areas. A multivariate logistic regression model was used to identify risk factors for myopia and hyperopia. Results Among 769 Han participants and 476 Tibetan participants, the age-adjusted prevalence of myopia (spherical equivalent (SE) < − 0.5D), hyperopia (SE > + 0.5D), high myopia (SE < -6.0D) and astigmatism (cylindrical equivalent > = 0.5D) is 28.56, 22.82, 2.80, and 69.38%. Han participants have higher age-adjusted prevalence of myopia (32.93% vs 21.64%, p < 0.001), high myopia (3.93% vs 1.02%, p = 0.001) and astigmatism (72.14% vs 64.94%, p = 0.021) compared to Tibetan participants. Being Tibetan is the protective factor of myopia compared to being Han (OR 0.58, 95%CI 0.42–0.79, p < 0.001). Older age ( p = 0.032), longer time length in rural area ( p = 0.048), undergraduate/graduate education level ( p = 0.031), lighter active level ( p = 0.007) and lower BMI ( p = 0.015) are risk factors for myopia. Older age (all p < 0.001) and pterygium status of the same eye ( p = 0.013) also increase the hyperopia risk. Conclusions Our study found an overall prevalence of myopia of 28.56% in Xining and surrounding areas in adults older than 50 years. Han population has higher myopia risk than Tibetan population. More medical and social resources should be allocated to improve the vision and life quality of older adults.
Abstract Background: Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer (BC) is associated with lower survival and higher risk of disease recurrence. A new subtype of HER2-low BC which has been proposed from several studies demonstrates that HER2-low patients have distinct somatically genetic alterations and clinical outcomes. We have previously reported that HER2-low BC had distinct clinical and somatic mutational feature compared with HER2-zero and HER2-high tumors. We have therefore extended studies by comparing germline mutation expression among these HER2 subgroups. Methods: 530 Chinese women with BC were enrolled in a prospective protocol between May 2021 to March 2023 at Guangdong Provincial People's Hospital. Genomics data was generated from a gene panel that surveys 102 tumor mutations. Germline variants were classified into pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB) and benign (B) groups according to the ACMG/AMP Standards and Guidelines. The cohort was divided into three groups based on HER2 status as HER2-zero (n = 107), HER2-low (n = 259), and HER2-high (n = 127) according to immunohistochemistry and/or fluorescence in situ hybridization results. Results: The most common mutated genes were ATM, FANCD2, ATR, BRACA2, RECQL4 and APC. A total of 71 pathogenic or likely pathogenic (P/LP) mutations were identified in 25 cancer susceptibility genes from 64 patients (12.16%). The most frequent mutated P/LP genes are BRCA2, BRCA1, PALB2, PMS2, MUTYH and PTEN in the HER2-low group; BRCA2, BRCA1 and PALB2 in the HER2-zero cohort; Interestingly, among the nine HER2-high patients, we detected unique P/LP genes in each sample including MRE11, FANCM, ATM, FLCN, NTRK1, TP53, BRCA1, CHEKE2 and FANCA. In addition to P/LP mutations, 751 variants of uncertain significance (VUS) in 95 cancer susceptibility genes were also detected in 361 patients (68.11%). The most frequent mutated VUS mutations occurred genes are FANCD2, ATM, RECQL4, RAD54B and ATR in HER2-low group; ATM, FANCA, POLE, MSH2 and FANCD2 in HER2-zero cohort; and ATM, BRCA2, RECQL4, POLE, FANCI and FANCM for HER2-high patients. Most of mutated genes were homologous recombination repair (HRR) or DNA damage repair (DDR) pathway related genes. Several genes were differentially altered across HER2 subgroups, including the mutation frequency of the BMPR1A (p=0.0344), MSH2 (p=0.0103), and RAD51C (p=0.0336) genes that were significantly higher in HER2-zero group. It’s worth noting that RAD51C was only mutated in HER2-zero subgroup. BMPR1A and MSH2 were also mutated in HER2-low patients. Differentially mutated genes in specific HER2 subgroups may contribute to better research and choice of future therapeutic approaches. In 115 patients who received neoadjuvant therapy and 84 of them were evaluable for pathological response data, HER2-low patients had lower pathological complete response (pCR) rates than HER2-zero and HER2-high subgroups (p=0.0008). In particular, DDR pathway gene ERCC1 have significantly higher mutation frequency in pCR patients (p=0.0115). Conclusion: HER2-low BC patients have distinct germline mutational signatures and differential clinical outcomes under neoadjuvant systemic therapy. These results have provided additional evidence that HER2-low patients comprise a fourth subtype of BC that needs to be accounted for separately in terms of clinical treatment and outcome reporting. Keywords: breast cancer, germline mutations, human epidermal growth factor receptor 2 (HER2), HER2-low, targeted therapy, next-generation sequencing Table 1. List of most frequent mutated genes in HER2-zero, HER2-low and HER2-high groups Citation Format: Ning Liao, Weiqi Zhang, Liangqiu Liu, Wendy Wu, Siqi Wang, Li Cao, Jianguo Lai, Xueying Zhang, Airong Yang, Yulei Wang, Cheukfai Li, Guochun Zhang, Chongyang Ren, Lingzhu Wen. Unique molecular signatures of germline mutations in low expression of human epidermal growth factor receptor 2 (HER2) breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-08-09.
Qinghai province is located in the northeastern part of the Tibetan Plateau, and is an underdeveloped province of inland China. Chinese government gives high priority to the improvement of the wellbeing of Qinghai people, and have provided great supports in aspects of policy, funding, and professional resource to the development of health care and medical system in Qinghai. Great progress has been made, and wellness of residents in Qinghai has been significantly improved. This article reviews the strategies and measures from central and provincial government in improving health care of Qinghai province under the leadership of the Communist Party of China.
To examine the association between food diversity and health status of Han and Tibetan elderly highlanders in Qinghai Plateau, China.The study population consisted of 240 community-dwelling elderly subjects aged 60 years or more (176 Han elderly subjects, 64 Tibetan ones). Food diversity was determined using an 11-item Food Diversity Score Kyoto (FDSK-11). Subjects were interviewed on health status including activities of daily living (ADL), screening-based depression and quality of life (QOL). Blood chemical investigation was carried out in association with food diversity.ADL was significantly lower in both Han and Tibetan elderly with lower food diversity than those with higher diversity. In Han elderly with lower food diversity, QOL was significantly lower in the items of subjective sense of health, relationship with family and subjective happiness, but not significant in Tibetan elderly. A close association was found between lower food diversity and lower financial satisfaction in both Han and Tibetan subjects. No association was found between food diversity and age or body mass index. Higher food diversity was associated with lower blood glucose level in Han elderly subjects, but the opposite association was found in Tibetan ones.Food diversity was associated with ADL and QOL in highlanders in Qinghai, China. Food assessment is very important as a useful indicator to establish the actual condition of diet and its relation to health status of community-dwelling elderly as well as the change of economic background in the Qinghai highlands.
Background: Liquid biopsy is a promising non-invasive alternative for cancer screening and MRD detection, although there are some concerns regarding its clinical application.Methods: To evaluate its efficiency in detecting lung cancer (LC), we applied a modified WGS-based HIFI method for LC screening and postoperative MRD detection by combining the hyper-co-methylated read approach and the circulating single-molecule amplification and resequencing technology (cSMART2.0).Findings: For early screening of LC, the LC score model was constructed using the support vector machine method, which showed satisfactory sensitivity at a high specificity of 98% and achieved an area under the curve of 0.912 in the validation set comprising 306 participants prospectively enrolled from multiple centers. The LC score model outperformed other models. Especially for stage I patients, the LC-score model achieved a sensitivity of more than 60% at a specificity of 90.8%. When applied the HIFI model to the real social population, an NPV of 99.92% was achieved in the Chinese population at 0.15% prevalence. Additionally, the MRD detection rate improved significantly by combining WGS and ctDNA detection, with a sensitivity of 74.00% at the same high specificity (98%).Interpretation: In conclusion, the HIFI method is promising for the diagnosis and treatment of LC.Trial Registration: This study was registered on Clinical Trails.gov (NCT04558255).Funding: This study was supported by Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Chinese Academy of Medical Sciences（2021RU002), National Natural Science Foundation of China (No.82072566), Peking University People's Hospital Research and Development Funds (RS2019-01) and Daxuesheng Chuangxin Shiyan Project of Peking University Health Science Center.Declaration of Interest: Wendy Wu, Wenjie Liu, Hao Yang, Airong Yang and Xueying Zhang are the employee of Berry Oncology Corporation. The other authors declare that they have no competing interests.Ethical Approval: All procedures were approved by the Medical Ethics Committee (2019PHB058-02) of the Peking University People’s Hospital. Informed consent was obtained from all enrolled participants prior to participation.
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