Using Genomics to Differentiate Multiple Primaries From Metastatic Lung Cancer

Murphy, Stephen J.; Harris, Frances; Kosari, Farhad; Terra, Simone; Nasir, Aqsa; Johnson, Sarah H.; Serla, Vishnu; Smadbeck, James B.; Halling, Geoffrey C.; Karagouga, Giannoula; Sukov, William R.; Leventakos, Konstantinos; Yang, Ping; Peikert, Tobias; Mansfield, Aaron S.; Wigle, Dennis A.; Yi, Eunhee S.; Kipp, Benjamin R.; Vasmatzis, George; Aubry, Marie Christine

doi:10.1016/j.jtho.2019.05.008

Cited by 66 publications

(52 citation statements)

References 47 publications

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“…Additionally, some other challenges remain for a wider use of LSTS, including strict technological requirements, high cost, and long turnaround period. Moreover, because of the existence of negative results and common mutation sharing, its utility in making a distinction between MP and IM is limited 20 . In this study, no mutations were detected in one patient, which means that the 520 gene panel was uninformative in 2.8% of the cases.…”

Section: Discussionmentioning

confidence: 99%

“…As reported in previous studies, the molecular spectrum of independent clones is quite different, and the lesions with great similarity in the mutation spectrum tend to be IMs 7 , 17 , 18 . To date, somatic mutations in several major driver genes 12 , targeted sequencing for dozens of genes 13 – 15 , loss of heterozygosity 19 , and chromosomal rearrangements 20 have been applied to discriminate MPs from IMs. Although these manners provide valuable information about tumor clonal relationships, the number of genes in the test method may affect the differential diagnosis of MLCs.…”

Section: Introductionmentioning

confidence: 99%

“…Although these manners provide valuable information about tumor clonal relationships, the number of genes in the test method may affect the differential diagnosis of MLCs. A larger gene panel could enhance the efficiency of lineage calling and the sensitivity of differentiated diagnosis 20 , 21 . Most recently, whole-exome sequencing (WES) and whole-genome sequencing (WGS) have also been proposed to delineate the clonal relationships among different tumors 7 , 16 .…”

Section: Introductionmentioning

confidence: 99%

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Application of large-scale targeted sequencing to distinguish multiple lung primary tumors from intrapulmonary metastases

Duan

Peng

et al. 2020

Sci Rep

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The effective differentiation between multiple primary lung tumors (MPs) and intrapulmonary metastases (IMs) in patients is imperative to discover the exact disease stage and to select the most appropriate treatment. In this study, the authors was to evaluate the efficacy and validity of large-scale targeted sequencing (LSTS) as a supplement to estimate whether multifocal lung cancers (MLCs) are primary or metastatic. Targeted sequencing of 520 cancer-related oncogenes was performed on 36 distinct tumors from 16 patients with MPs. Pairing analysis was performed to evaluate the somatic mutation pattern of MLCs in each patient. A total of 25 tumor pairs from 16 patients were sequenced, 88% (n = 22) of which were classified as MPs by LSTS, consistent with clinical diagnosis. One tumor pair from a patient with lymph node metastases had highly consistent somatic mutation profiles, thus predicted as a primary-metastatic pair. In addition, some matched mutations were observed in the remaining two paired ground-glass nodules (GGNs) and classified as high-probability IMs by LSTS. Our study revealed that LSTS can potentially facilitate the distinction of MPs from IMs. In addition, our results provide new genomic evidence of the presence of cancer invasion in GGNs, even pure GGNs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Application of large-scale targeted sequencing to distinguish multiple lung primary tumors from intrapulmonary metastases

Duan

Peng

et al. 2020

Sci Rep

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“…First, the same genetic mutation should occur in morphologically different lesions [20] . Another problem is the heterogeneity of mutations in primary tumors and metastatic lesions, particularly EGFR and KRAS, with misclassi cation ranging from 0 to 45% [21][22] .…”

Section: Discussionmentioning

confidence: 99%

Morphological and Genetic Heterogeneity of Synchronous Multifocal Lung Adenocarcinoma in a Chinese Cohort

Zhu

Cao

Shen

et al. 2020

Preprint

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Background: Synchronous multifocal lung cancer (SMLC) is seen with increasing frequency in clinical practice globally. Because of innate variation in clinical management and outcome, it is vital to distinguish properly between synchronous multifocal primary lung cancer (SMPLC) and intrapulmonary metastasis (IM). The pathologic features and principal classification criteria of multifocal lung cancer remain unclear. Methods: We have collected a unique cohort of Chinese patients with SMLC, and fully explored the morphologic, immunohistochemical, and molecular features of the disease. Twenty-one SMLC patients with a total of 50 tumors were included in our study. The pathological features presented by these cases were analyzed, including tumor location, tumor size, pathological types, predominant pattern of adenocarcinoma, and immunohistochemical staining. We undertook molecular testing of nine driver oncogenes associated with lung cancer, including EGER, KRAS, BRAF, NRAS, ALK, ROS1, RET, HER2, and PIK3CA. Results: According to Martini-Melamed classification and refined standard, 8 and 17 cases were considered as SMPLC respectively. Gene mutations were identified in 18 tumors (36%). There were 12 patients had different gene mutations. Conclusions: We demonstrate that conventional morphological assessment is not sufficient to establish clearly the clonal relationship of SMPLC. Instead the evaluation of histological subtypes, including non-mucinous adherent components, is required. Multiplex genotypic analysis may also prove a useful additional tool.

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“…These alterations could stem from EGFR-mutated tumor cells but also from tumor clones lacking EGFR mutation. Furthermore, recent studies have uncovered that in patients with multiple pulmonary nodules, which represent up to 10% of all lung cancers, a sizeable quota are independent tumors, which disclose a completely different genetic makeup [19,20].…”

Section: Discussionmentioning

confidence: 99%

Detection of Loss of Heterozygosity in cfDNA of Advanced EGFR- or KRAS-Mutated Non-Small-Cell Lung Cancer Patients

Boldrin

Nardo

Zulato

et al. 2019

IJMS

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Liquid biopsy is currently approved for management of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients. However, one unanswered question is whether the rate of cell-free DNA (cfDNA)-negative samples is due to technical limitations rather than to tumor genetic characteristics. Using four microsatellite markers that map specific chromosomal loci often lost in lung cancer, we conducted a pilot study to investigate whether other alterations, such as loss of heterozygosity (LOH), could be detected in EGFR-negative cfDNA. We analyzed EGFR-mutated NSCLC patients (n = 24) who were positive or negative for EGFR mutations in cfDNA and compared the results with a second cohort of 24 patients bearing KRAS-mutated cancer, which served as a representative control population not exposed to targeted therapy. The results showed that in EGFR-negative post-tyrosine-kinase-inhibitor (TKI) cfDNAs, LOH frequency was significantly higher than in both pre- and post-TKI EGFR-positive cfDNAs. By contrast, no association between KRAS status in cfDNA and number of LOH events was found. In conclusion, our study indicates the feasibility of detecting LOH events in cfDNA from advanced NSCLC and suggests LOH analysis as a new candidate molecular assay to integrate mutation-specific assays.

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Using Genomics to Differentiate Multiple Primaries From Metastatic Lung Cancer

Cited by 66 publications

References 47 publications

Application of large-scale targeted sequencing to distinguish multiple lung primary tumors from intrapulmonary metastases

Application of large-scale targeted sequencing to distinguish multiple lung primary tumors from intrapulmonary metastases

Morphological and Genetic Heterogeneity of Synchronous Multifocal Lung Adenocarcinoma in a Chinese Cohort

Detection of Loss of Heterozygosity in cfDNA of Advanced EGFR- or KRAS-Mutated Non-Small-Cell Lung Cancer Patients

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