The landscape of germline mutations and the relationship with tumor mutation burden in Chinese patients with lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10522-10522
Author(s):  
Jian Shi ◽  
Rongfeng Liu ◽  
Guanglei Huang ◽  
Lixing Wang ◽  
Baoen Shan ◽  
...  

10522 Background: Lung cancer is one of the most common types of cancer, ranking the first in the incidence and mortality of malignant tumors in the world and China. Although studies have been reported that genetic susceptibility to lung cancer is associated with certain germline mutations, the relationship between lung cancer risk and inherited genetic factors remains relatively elusive. However, the effect of germline mutation on TMB in lung cancer has not been explored. Herein, DNA genomic profiling was performed through NGS with a 539-gene panel to explore the germline mutations and the relationship with TMB in Chinese patients with lung cancer. Methods: We retrospectively analyzed the germline mutations through a comprehensive 539-gene profiling of 3541 Chinese patients with lung cancer. 539-gene panel contained germline mutations in 90 hereditary tumor-associated genes. We screened out the pathogenic and likely pathogenic germline mutations according to the standards and guidelines for the interpretation of sequence variants of The American College of Medical Genetics and Genomics (ACMG), and picked out there is no records in Clinvar database and no literature report. TMB of tissue or blood ctDNA in 3541 patients were further analyzed in with pathogenic mutations (P group), with likely pathogenic mutations (LP group), and no germline mutations group (Non-P group). The difference in TMB was analyzed via the Wilcoxon sign test. Results: In 3541 patients with lung cancer, 177 (4.999%) patients were identified harboring pathogenic or likely pathogenic germline mutations, in which 78 P group and 99 LP group, the rest 3364 were Non-P group. The highest prevalence of germline mutation was found in BRCA2 (0.565%), ATM (0.339%), MUTYH (0.282%), and BRCA1 (0.254%). In 177 patients with pathogenic or likely pathogenic germline mutations, 67 mutations were recorded as UNK (unknow) in Clinvar database and no literature report. The media TMB of tissue in P group, LP group and Non-P group were 5.149, 5.535 and 5.547 respectively. The media TMB of blood ctDNA in P group, LP group and Non-P group were 4.257, 3.945 and 4.483 respectively. There was no statistical difference in TMB between P and Non-P groups (tissue p = 0.98; ctDNA p = 0.5). Conclusions: In our study, we firstly identified 67 novel germline mutations and studied on the relationship between germline mutations and TMB in lung cancer, which expanded the understanding of germline mutations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1530-1530
Author(s):  
Jiaojiao Zhou ◽  
Kun Zhang ◽  
Xuan Zhu ◽  
Mei Deng ◽  
Meng Luo ◽  
...  

1530 Background: PALB2 (Partner and Localizer of BRCA2) is recently recognized as a breast cancer predisposition gene, which plays a critical role in genome maintenance via interacting with BRCA1/2 and RAD51 when DNA break. Germline loss-of-function mutations in PALB2 lead to increased breast cancer risk. Since the germline mutation frequency of PALB2 is much less than BRCA1/2, the distinct mutation spectrum of PALB2 is still obscure. Therefore, we assessed the mutational frequency, spectrum and predictors of the PALB2 gene in a sequential series of Chinese breast cancer patients from our Research DNA Bank, to verify the utility of PALB2 genetic testing in Chinese population. Methods: We examined Chinese breast cancer cases (n = 2279) who agreed to participate in research DNA banking, recruited from 1990 through 2016. To identify the mutations, complete coding sequence and intron–exon boundaries of PALB2 were screened with Next Generation Sequencing. Personal and family histories were synchronously collected for mutation identification. Results: Among the 2279 breast cancer patients, 307 patients were familial breast cancer cases and the rest 1972 patients were sporadic breast cancer cases. PALB2 mutation carriers accounted for 7.8% (n = 24) and 4.8% (n = 95) in familial and sporadic breast cancer cohort separately. In total, 31 missense, 4 nonsense, 3 frameshift, 3 splicing and 1 codon mutations of PALB2 were identified in this study. Among the pathologic variants, PALB2 c.1744C > T, c.2748+1G > A, c.2749-1G > C, c.3114-1G > A were newly identified in sporadic breast cancer, and c.3271delC newly found in familial breast cancer. Based on in silico analysis, a total of 6 potential damaging missense variants were novelly found in this study, among which the PALB2 c.3035C > T was detected in both sporadic and familial breast cancer. Conclusions: Our data presents the germline mutation status of PALB2 in Chinese patients with breast cancer, suggesting that loss-of-function germline mutations of PALB2 are important in both familial and sporadic breast cancer. Clinically, this information may be helpful in genetic counseling of breast cancer patients with PALB2 germline mutation.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3119-3119
Author(s):  
Zhiye Zhang ◽  
Yaqing Wu ◽  
Ningning Luo ◽  
Qin Zhang ◽  
Tiantian Han ◽  
...  

3119 Background: Li-Fraumeni syndrome (LFS, OMIM #151623) is an autosomal dominant cancer predisposition syndrome. Typical LFS tumors comprise adrenocortical carcinomas, sarcoma, breast cancer and central nervous system tumors. LFS is also associated with an increased risk of a multitude of other common types of cancer, such as prostate cancer, lung cancer, gastric cancer, colorectal cancer, ovarian cancer, melanoma, etc. TP53 germline mutations are the most common gene with LFS. Germline mutations of CHEK2 have been identified as another predisposing gene and associated with a range of cancer types. However, the pattern of TP53 and CHEK2 germline mutations in malignant tumors remains unknown. Methods: We identified 8535 malignant solid tumors patients without selecting age or family history in a retrospective cohort. Germline mutations were categorized based on ACMG (American College of Medical Genetics and Genomics) guidelines in pathogenicity. The patients were divided into three groups, P group (with pathogenic mutations), LP group (with likely-pathogenic mutations) and Non_P group (neither pathogenic nor likely-pathogenic mutation). Statistical significance was defined as P-value less than 0.05. Results: A total of 461 (461/8535) patients carried TP53 or CHEK2 germline mutations were identified, in which 15 patients with pathogenic mutations and 17 patients with likely-pathogenic mutations. One patient with lung cancer in LP group carried TP53 homozygous mutation ( p. Ser215Ile), and the remaining 31 patients all carried heterozygous mutations. Among these 31 carriers, 16 (51.6%) carried nonsense or missense mutations (10 for nonsense and 6 for missense mutations). 3 patients in the P group carried CHEK2 p. Y139* (one liver cancer patient and two lung cancer patients) were identified. The median age of group P, LP and Non_P was 55 (39 for TP53, 61 for CHEK2), 63 (52 for TP53, 66 for CHEK2) and 59, respectively. Somatic mutation analysis found no significant difference in tumor mutation burden (TMB) among three groups. The SNV/INDEL mutation frequency of LRP1B in the P or LP group was significantly lower than the Non_P group. Conclusions: Our data showed that 0.375% (32/8535) malignant solid tumor patients carried TP53 (16/8535) or CHEK2 (16/8535) germline pathogenic or likely-pathogenic mutations. The relationship between germline mutations and cancer susceptibility will be studied in the future.[Table: see text]


2021 ◽  
Vol 11 ◽  
Author(s):  
Xinqing Lin ◽  
Muyun Peng ◽  
Quanfang Chen ◽  
Mingming Yuan ◽  
Rongrong Chen ◽  
...  

BackgroundEpidemiological surveys have suggested that lung cancer has inherited susceptibility and shows familial aggregation. However, the distribution and prevalence of epidermal growth factor receptor (EGFR) germline variants and their roles in lung cancer genetic predisposition in Chinese population remain to be elucidated.MethodsIn this study, EGFR germline and somatic variants were retrospectively reviewed from the next-generation sequencing results of 31,906 patients with lung cancer. Clinical information was also collected for patients with confirmed EGFR germline mutations.ResultsA total of 22 germline EGFR variants were identified in 64 patients with lung cancer, accounting for 0.2% of the total cases studied. Five patients were diagnosed as multiple primary carcinomas. Family history was documented in 31.3% (20/64) of patients, 55% of which were diagnosed as lung cancer. G863D was the most frequent EGFR germline mutation, followed by P848L, D1014N, and K757R. Somatic EGFR-sensitive mutations were identified in 51.6% of patients with germline EGFR mutations. The proportion of L858R mutation, exon 19 deletion, and rare sensitive mutation was 50%, 17.6%, and 32.4%, respectively. D1014N and T790M mutations were common in young patients. The family members of patients with P848L, R776H, V769M, and V774M mutations were more commonly diagnosed with cancers. A total of 19 patients were confirmed to have received EGFR tyrosine kinase inhibitors (TKIs), but the response to EGFR-TKIs differed among patients with different EGFR mutations.ConclusionChinese patients with lung cancer harbored unique and dispersive EGFR germline mutations and showed unique clinical and genetic characteristics, with varied response patterns to EGFR-TKI treatment.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e12013-e12013
Author(s):  
Rong Li ◽  
Ming Tian ◽  
Meili Ma ◽  
Jun Pei ◽  
Yiyi Song ◽  
...  

e12013 Background: Vitamin D and its receptor (VDR) have been implicated in lung cancer incidence and mortality. Here we assess the relationships between VDR single nucleotide polymorphisms (SNPs) (FokI, BsmI, ApaI, Taq, Cdx2) and lung cancer incidence in Chinese patients. Methods: Genomic DNA was extracted from peripheral blood samples. Five VDR SNPs (FokI, BsmI, ApaI, Taq, Cdx2) were detected by polymerase chain reaction. Genotype analysis was conducted using mass spectrograph. Results: A total of 67 lung cancer patients and 72 healthy controls participated in the study. There were more males and current smokers among the lung cancer patients than among healthy controls. Lung cancer patients were much older than controls. Age and smoking status were included in the equation for predicting disease status. The CC-AA (Apa1-Cdx2) and the CC-AA-CC (ApaI-Cdx2- FokI) haplotypes were associated with higher lung cancer incidence. The rs1544410 (BsmI) and rs731236 (TaqI) were not associated with higher lung cancer incidence, but they were associated with rs797523 (ApaI). Conclusions: There is a significant correlation between certain VDR SNPs (FokI, ApaI, Cdx2) and lung cancer incidence in Chinese people.


2020 ◽  
Author(s):  
Jun Yang ◽  
Hua Zhong ◽  
Qinghui Yang ◽  
Jian Yu ◽  
Cailing Jin ◽  
...  

Abstract Background: Lung cancer is one of the most common causes of cancer death among all the malignancies worldwide. Evidences suggest that the incidence and mortality of lung cancer has been on the rise. MicroRNA-449a (miR-449a) as one important member of microRNAs, has been demonstrated acting as a tumor suppressor in lung cancer. In this study, we sought to assess the relationship between miR-449a expression level and diagnostic value of lung cancer.Methods: In this present research, quantitative Real-Time PCR was applied to detect the miR-449a expression in 116 lung cancer patients and 41 healthy volunteers. The diagnostic value of miR-449a in lung cancer patients was determined by receiver operating characteristic (ROC) curve.Results: MiR-449a was significantly down-regulated in lung cancer patients compared with healthy control (P<0.05). In addition, miR-449a expression was associated with sex (P=0.004), tumor size (P=0.000), TNM stage (P=0.006) and metastasis (P=0.036). However, there was no correlation with age, smoking history and histological type of lung cancer patients (all P>0.05). In the ROC analysis, the results showed that the area under the ROC curve (AUC) was 0.902 with the sensitivity of 94.8% and specificity of 78.0%, and the optimum cutoff value was 2.255.Conclusion: MiR-449a expression was down-regulated in lung cancer patients, and it could be an efficient diagnostic biomarker in lung cancer patients.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15522-e15522
Author(s):  
Hongxia Li ◽  
Qianqian Duan ◽  
Yuan Tan

e15522 Background: In recently years, although CRC morbidity and mortality can be mitigated through appropriate screening and surveillance, the incidence rate of colorectal cancer (CRC) younger than 50 years old increased annually. Limited studies have investigated the underpinnings driving CRC development in Chinese younger population. In our study, we aim to explore the comprehensive mutational profile of Chinese CRC patients old (>50) and young (≤50) diagnosed with CRC. Methods: Targeted sequencing with a 539 cancer-related genes panel was performed on 235 patients diagnosed with CRC. We investigate the landscape and difference of old and young CRC somatic and germline mutations in our Chinese cohort and compare with TCGA CRC cohort (N = 592). Results: Analysis revealed an overall 20.9% (49/235) mutation detection rate of young CRC in our Chinese cohort, which is higher than TCGA cohort (13.9%, 82/592). In our cohort, all Chinese young CRC patients can detect mutation and median mutation count is 10 mutations which is similar to old CRC patients (11 mutations). Comparing high frequency somatic mutations (young group with top 20), we found that BRCA2 mutation in young CRC group is significantly higher than old group (18.4% vs 7.0%, P = 0.025). In TCGA cohort, there is no difference between two groups with top 20 mutations and frequency of BRCA2 is 13.4% (11/82) in young CRC. For germline mutation, 12.29% (29/236) patients in our Chinese cohort harbored pathogenic and likely pathogenic (P/LP) germline mutations and 24.1% (7/29) CRC with P/LP germline mutations is young patients. In these seven P/LP mutation young patients, three patients have MMR gene mutation, two patients harbor ATM mutation, one patient has APC and another has SLX4 mutation. Moreover, young CRC have higher frequency MSI-H than old CRC patients (28.6% vs 18.2%). Conclusions: Our study has identified that young CRC patients account for a higher proportion in Chinese population and BRAC2 mutation may be an important factor in the early development of colorectal tumors in younger patients. In addition, our results also support the role of MSI statues in tumor oncogenesis in Chinese patients with early-onset CRC, indicating the need to include a more comprehensive germline mutation and genetic screening in our population.


2021 ◽  
Vol 11 ◽  
Author(s):  
Jie Yang ◽  
Hefei Li ◽  
Ben Li ◽  
Wei Li ◽  
Qiang Guo ◽  
...  

IntroductionEmerging evidence has suggested that inherited factors are also involved in lung cancer development. However, most studies focused on well-elucidated cancer predisposition genes, the majority of which are tumor suppressor genes. The profile of germline mutations in oncogenic driver genes remains unrevealed, which might also provide potential clinical implications for lung cancer management.MethodsSequencing data from 36,813 unselected lung cancer patients who underwent somatic mutation profiling were retrospectively reviewed. All recruited patients had matched white blood cell samples sequenced in parallel using a capture-based panel including eight key lung cancer driver genes (epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), MET proto-oncogene, receptor tyrosine kinase (MET), Kirsten rat sarcoma viral oncogene homolog (KRAS), Erb-B2 receptor tyrosine kinase 2(ERBB2), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), ret proto-oncogene (RET), and B-Raf proto-oncogene, serine/threonine kinase (BRAF)). Likely pathogenic/pathogenic (LP/P) variants were called according to the classification criteria of the American College of Medical Genetics and Genomics. Variants of uncertain significance (VUS) located in the kinase domains of driver genes and occurring recurrently (n ≥3) were also included for further analyses.ResultsSeven different LP/P variants in EGFR, MET, or RET were identified in 0.03% of lung cancer patients (n = 14) and 25 different VUS in the kinase domains of seven driver genes (except KRAS) were found with a prevalence of 0.3% (n = 117).Collectively, germline mutations were most frequently seen in ROS1 (n = 31, 0.084%), followed by MET (n = 23, 0.062%), EGFR (n = 22, 0.06%), ALK (n = 22, 0.06%) and RET (n = 17, 0.046%). LP/P variants and VUS fell the most commonly in EGFR (n = 10, 72%) and ROS1 (n = 31, 26%), respectively. Of the 10 patients with EGFR LP/P germline mutation, 70% also acquired somatic EGFR driver mutation exon21 p.L858R or exon19 deletion at baseline; while the three patients with pathogenic germline RET mutation displayed distinct baseline somatic profiles of rare EGFR mutation or KRAS exon2 p.G12C. We discovered 11 germline mutations that also occurred somatically, including four LP/P variants and seven VUS.ConclusionWe present the first study to systemically characterize the germline mutation in oncogenic driver genes in a large cohort of unselected patients with lung cancers.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13007-e13007 ◽  
Author(s):  
Wenfeng Fang ◽  
Xiuyu Cai ◽  
Huaqiang Zhou ◽  
Yinguang Wang ◽  
Yaxiong Zhang ◽  
...  

e13007 Background: Germline mutations in BRCA1/2 (BReast CAncer genes 1 and 2), which are targets for PARP inhibitors in breast and ovarian cancer, have been previously identified in patients with non-small cell lung cancer (NSCLC). However, its prevalence and clinical outcomes to targeted therapy in NSCLC still remains unknown. Methods: We conducted a retrospective review of 9,324 Chinese NSCLC patients who underwent targeted next-generation sequencing (NGS) during 2015/11/01 and 2018/10/31. Patients with BRCA1/2 somatic and germline mutations were identified. We summarized their prevalence and explored their co-existing driver mutations. Then we initially reviewed the response to PARP-inhibitor targeted therapy in patient with BRCA2 germline mutation. Results: 459 (4.9%) patients are BRCA1/2 positive (germline/somatic mutation). Most patients are diagnosed with LUAD (372, 81.1%), with a median age of 63 years (range: 2-101). Slightly more male patients were carrying BRCA1/2 mutations (59.9%, 275 out of 459). The prevalence of BRCA1 and BRCA2 somatic mutations was similar (145, 1.56% vs. 169, 1.81%, p = 0.19). BRCA2 germline mutation was more common in lung cancer than BRCA1 germline mutation (148, 1.59% vs. 20, 0.21%, p < 0.0001). When specified to the common driver gene mutation subgroups, the prevalence of BRCA2 germline mutation is similar to the entire population (EGFR 1.79%; ALK 1.74%; KRAS 2.05%; BRAF 2.86%; ERBB2 0.93%; p > 0.05). K2729N is the most common BRCA2 germline mutation (41, 27.7%), followed by C315S (26, 17.6%), V2109I (12, 8.1%), R2108C (11, 7.4%), I2490T (10, 6.8%), T582P (5, 3.4%). About 20% patients with BRCA2 germline mutation carried at least one concomitant mutations of DNA repair genes, including MLH1, MLH3, MSH6, CHEK2, BARD1, BLM, BRCA1, MUTYH, RAD50, RECQL4 and XRCC1. One 56-year-old male LUAS patient, with germline BRCA2 rs80359490 frameshift deletion mutation (p.S1722Yfs*4), received the targeted therapy with PARP inhibitor Olaparib after multi lines therapies. This patient showed a great PR response to Olaparib, with a PFS of at least 6 months. Conclusions: BRCA1/2 germline mutations were rare in Chinese NSCLC patients. Patients with BRCA2 germline mutations might benefit from PARP-inhibitor treatment.


2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13594-e13594
Author(s):  
Lele Song ◽  
Mengyuan Liu ◽  
Xinyi Liu ◽  
Suo Peisu ◽  
Tanxiao Huang ◽  
...  

e13594 Background: Germline variations may contribute to lung cancer susceptibility besides environmental factors. The susceptibility of germline mutations and their correlation with somatic mutations has not been systematically investigated in lung cancer patients. Methods: Germline mutations from 1090 lung cancer patients were analyzed with a 58-gene NGS panel containing known hereditary cancer-related genes, and were categorized based on ACMG guidelines in pathogenicity, and the corresponding somatic mutations were analyzed using a 605-gene NGS panel containing known cancer-related genes. Results: Genetic susceptibility was found in 4.5% of lung cancer patients, in which 14 patients with pathogenic mutations and 35 patients with likely-pathogenic mutations were identified. Significantly stronger family history was found with the pathogenic group than other groups. Pathogenic mutations fell most commonly in BRCA2 (6/14), followed by CHEK2 (3/14) and ATM (2/14). Likely-pathogenic mutations fell most commonly in NTRK1 mutations (4/35) and EXT2 mutations (4/35), followed by BRIP1 (3/35) and PALB2 (3/35). These genes are involved in DNA repair (BRCA1 and BRCA2, BLM, RAD50, BRIP1, MLH3), cell cycle regulation (such as CHEK2, ATM, NTRK1 and EPCAM) and tumor suppressor (such as PALB2). The overall odds ratio (OR) value of the pathogenic group was 17.93 (95% CI: 9.74 to 33.01), and was 15.86 (95% CI: 5.999 to 133.2) for the likely-pathogenic group, suggesting that the pathogenic or the likely-pathogenic germline mutations as a whole were risk factors for lung cancer. Somatic mutation analysis revealed no significant difference in TMB among the groups, although a trend of lower TMB in the pathogenic group was found. The SNV/INDEL mutation rate of TP53 in the pathogenic group was significantly lower. Pathway enrichment analysis found no significant difference in aberrant pathways among the groups. Conclusions: 4.5% of patients carrying germline variants may be linked to increased susceptibility to lung cancer. The susceptibility is mainly reflected in family history and morbidity risk without significant influence on aberrant pathways.


2020 ◽  
Vol 4 (4(13)) ◽  
pp. 31-50
Author(s):  
Shiyu Zhang ◽  

Over the past decade, bilateral relations between China and Russia have attracted the attention of the whole world. As neighbors and rapidly developing countries, China and Russia are becoming increasingly important in the international arena. The strategic partnership and interaction between China and Russia occupy a significant place in the politics of both countries. Cooperation is developing dynamically in various fields, primarily in politics. After 2012, a change of government took place in China and Russia, which brought new changes to international relations. Studying the involvement of the media in this process can clarify their impact on international relations, in particular, their role in the relationship between China and Russia.


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