Genomic Mutations of Primary and Metastatic Lung Adenocarcinoma in Chinese Patients

Chen, Xinyu; Bu, Qing; Yan, Xuexin; Li, Ye; Yu, Qian; Zhao, Haiping; Zhao, Liang; Zeng, Yanwu; Lu, Leilei; Li, Dong; Ma, Jie

doi:10.1155/2020/6615575

Cited by 14 publications

(10 citation statements)

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“…The library construction and sequencing were performed in the Clinical Laboratory Improvement Amendments (CLIA)/CAP-compliant Molecular Diagnostics Service Laboratory of Shanghai OrigiMed Co., Ltd. Methods were similar to our previous work ( 10 , 11 ). Briefly, the formalin-fixed paraffin-embedded (FFPE) tissues were deparaffinized by heating in a 60°C oven for 1 h. As a control, white blood cells from the paired whole blood samples were separated by centrifugation.…”

Section: Methodsmentioning

confidence: 99%

Gene Mutations Associated With Clinical Characteristics in the Tumors of Patients With Breast Cancer

et al. 2022

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BackgroundClinical characteristics including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) are important biomarkers in the treatment of breast cancer, but how genomic mutations affect their status is rarely studied. This study aimed at finding genomic mutations associated with these clinical characteristics.MethodsThere were 160 patients with breast cancer enrolled in this study. Samples from those patients were used for next-generation sequencing, targeting a panel of 624 pan-cancer genes. Short nucleotide mutations, copy number variations, and gene fusions were identified for each sample. Fisher’s exact test compared each pair of genes. A similarity score was constructed with the resulting P-values. Genes were clustered with the similarity scores. The identified gene clusters were compared to the status of clinical characteristics including ER, PR, HER2, and a family history of cancer (FH) in terms of the mutations in patients.ResultsGene-by-gene analysis found that CCND1 mutations were positively correlated with ER status while ERBB2 and CDK12 mutations were positively correlated with HER2 status. Mutation-based clustering identified four gene clusters. Gene cluster 1 (ADGRA2, ZNF703, FGFR1, KAT6A, and POLB) was significantly associated with PR status; gene cluster 2 (COL1A1, AXIN2, ZNF217, GNAS, and BRIP1) and gene cluster 3 (FGF3, FGF4, FGF19, and CCND1) were significantly associated with ER status; gene cluster 2 was also negatively associated with a family history of cancer; and gene cluster 4 was significantly negatively associated with age. Patients were classified into four corresponding groups. Patient groups 1, 2, 3, and 4 had 24.1%, 36.5%, 38.7%, and 41.3% of patients with an FDA-recognized biomarker predictive of response to an FDA-approved drug, respectively.ConclusionThis study identified genomic mutations positively associated with ER and PR status. These findings not only revealed candidate genes in ER and PR status maintenance but also provided potential treatment targets for patients with endocrine therapy resistance.

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Section: Methodsmentioning

confidence: 99%

Gene Mutations Associated With Clinical Characteristics in the Tumors of Patients With Breast Cancer

et al. 2022

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“…It was indicated that subclonal driver heterogeneity is high between untreated metastases and primary tumors [ 115 ], while in treated metastases the proportion of pre-selected clonal drivers increased dramatically [ 76 , 117 ]. In particular, the treatment induced a significantly higher number of actionable mutations in genes encoding proteins involved in PI3K-AKT and HER/ErbB pathways [ 30 , 76 , 120 ]. As part of treatment pressure, the origin of primary and metastatic niches affects the selection of the clonal alteration repertoire in metastatic lesions [ 13 , 119 , 120 ].…”

Section: Clonality Of Metastasesmentioning

confidence: 99%

“…In particular, the treatment induced a significantly higher number of actionable mutations in genes encoding proteins involved in PI3K-AKT and HER/ErbB pathways [ 30 , 76 , 120 ]. As part of treatment pressure, the origin of primary and metastatic niches affects the selection of the clonal alteration repertoire in metastatic lesions [ 13 , 119 , 120 ]. A pan-cancer evolution study suggested that clonal dissemination exhibits organ specificity, and NSCLC shows a common spreading pattern to lymph nodes, liver, bones and brain; however, the mechanisms underlying colonization tropism remain unclear [ 22 , 81 , 115 , 116 , 121 ].…”

Section: Clonality Of Metastasesmentioning

confidence: 99%

“…In particular, studies have shown that clones seeding the brain niche may be clonally distinct from clones seeding other sites [ 13 , 118 ]. Moreover, brain-seeding clones acquire early clonal divergence from primary clones with increased numbers of distinct alterations in PI3K, EGFR, ErbB2 (HER2), ALK, Wnt/b-catenin and EMT signaling pathways, which seems to be crucial in spreading of cancers to the brain [ 13 , 54 , 120 , 127 ]. On the other hand, mutations of major driver genes, including EGFR , KRAS , TP53 , and ALK are highly concordant between primary NSCLC and matched brain metastatic lesions, suggesting that early clonal genomic events during carcinogenesis of NSCLC may be involved in dissemination to the brain [ 116 , 118 , 128 ].…”

Section: Clonality Of Metastasesmentioning

confidence: 99%

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Genetic Clonality as the Hallmark Driving Evolution of Non-Small Cell Lung Cancer

Nicoś

Krawczyk

2022

Cancers

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Data indicate that many driver alterations from the primary tumor of non-small cell lung cancer (NSCLC) are predominantly shared across all metastases; however, disseminating cells may also acquire a new genetic landscape across their journey. By comparing the constituent subclonal mutations between pairs of primary and metastatic samples, it is possible to derive the ancestral relationships between tumor clones, rather than between tumor samples. Current treatment strategies mostly rely on the theory that metastases are genetically similar to the primary lesions from which they arise. However, intratumor heterogeneity (ITH) affects accurate diagnosis and treatment decisions and it is considered the main hallmark of anticancer therapy failure. Understanding the genetic changes that drive the metastatic process is critical for improving the treatment strategies of this deadly condition. Application of next generation sequencing (NGS) techniques has already created knowledge about tumorigenesis and cancer evolution; however, further NGS implementation may also allow to reconstruct phylogenetic clonal lineages and clonal expansion. In this review, we discuss how the clonality of genetic alterations influence the seeding of primary and metastatic lesions of NSCLC. We highlight that wide genetic analyses may reveal the phylogenetic trajectories of NSCLC evolution, and may pave the way to better management of follow-up and treatment.

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“…The library construction, sequencing, and mutation calling were performed by the Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP)compliant Molecular Diagnostics Service Laboratory of Shanghai OrigiMed Co., Ltd. Briefly, library construction from the FFPE (Formalin-fixed, paraffin-embedded) tissues, sequencing, mapping, mutation calling, and annotation followed the previous studies (13,14). FFPE tissues were first sliced into 4µm sections.…”

Section: Dna Sequencing and Genomic Analysismentioning

confidence: 99%

Gene Mutational Clusters in the Tumors of Colorectal Cancer Patients With a Family History of Cancer

et al. 2022

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IntroductionFamily history is a high-risk factor for colorectal cancer (CRC). The risk comes not only from known germline mutations but also from the other family-related mechanisms. Uncovering them would be an important step to improve the diagnosis and treatment of these patients.MethodSamples from 168 patients with advanced CRC were collected and applied to next-generation sequencing of 624 pan-cancer genes. Genomic mutations and significantly mutated genes were identified. Significantly mutated genes and co-mutated genes were used to cluster patients. For each cluster of patients, mutational signatures were extracted. The identified mutational signatures were further validated in the other independent cohort.ResultSignificantly mutated genes including TP53, APC, KRAS, and SMAD4 were found associated with tumor mutational burden and microsatellite instability. LRP1, ACVR2A, and SETBP1 were found co-mutated. Patients with mutations in LRP1, ACVR2A, and SETBP1 tend to have a family history of cancer. Those patients tended to have right-sided tumors with high tumor mutational burden and microsatellite instability. Among them, signature analysis identified two possible etiologies, SBS10a (defective polymerase epsilon exonuclease domain) and SBS6 (defective DNA mismatch repair and microsatellite unstable tumors). These signatures were also found in another independent cohort.ConclusionThe gene cluster (LRP1, ACVR2A, and SETBP1) could be a good biomarker of these patients with a family risk, which was characterized by right-sidedness, high tumor mutational burden, and high microsatellite instability.

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Genomic Mutations of Primary and Metastatic Lung Adenocarcinoma in Chinese Patients

Cited by 14 publications

References 38 publications

Gene Mutations Associated With Clinical Characteristics in the Tumors of Patients With Breast Cancer

Gene Mutations Associated With Clinical Characteristics in the Tumors of Patients With Breast Cancer

Genetic Clonality as the Hallmark Driving Evolution of Non-Small Cell Lung Cancer

Gene Mutational Clusters in the Tumors of Colorectal Cancer Patients With a Family History of Cancer

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