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Comprehensive profiling and quantitation of oncogenic mutations in non small-cell lung carcinoma using single molecule amplification and re-sequencing technology.

ABSTRACT: Activating and resistance mutations in the tyrosine kinase domain of several oncogenes are frequently associated with non-small cell lung carcinoma (NSCLC). In this study we assessed the frequency, type and abundance of EGFR, KRAS, BRAF, TP53 and ALK mutations in tumour specimens from 184 patients with early and late stage disease using single molecule amplification and re-sequencing technology (SMART). Based on modelling of EGFR mutations, the detection sensitivity of the SMART assay was at least 0.1%. Benchmarking EGFR mutation detection against the gold standard ARMS-PCR assay, SMART assay had a sensitivity and specificity of 98.7% and 99.0%. Amongst the 184 samples, EGFR mutations were the most prevalent (59.9%), followed by KRAS (16.9%), TP53 (12.7%), EML4-ALK fusions (6.3%) and BRAF (4.2%) mutations. The abundance and types of mutations in tumour specimens were extremely heterogeneous, involving either monoclonal (51.6%) or polyclonal (12.6%) mutation events. At the clinical level, although the spectrum of tumour mutation(s) was unique to each patient, the overall patterns in early or advanced stage disease were relatively similar. Based on these findings, we propose that personalized profiling and quantitation of clinically significant oncogenic mutations will allow better classification of patients according to tumour characteristics and provide clinicians with important ancillary information for treatment decision-making.

SUBMITTER: Zhang S

PROVIDER: S-EPMC5226597 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Comprehensive profiling and quantitation of oncogenic mutations in non small-cell lung carcinoma using single molecule amplification and re-sequencing technology.

Zhang Shirong S Xia Bing B Jiang Hong H Wang Limin L Xu Rujun R Shi Yanbin Y Zhang Jianguang J Xu Mengnan M Cram David S DS Ma Shenglin S

Oncotarget 20160801 31

Activating and resistance mutations in the tyrosine kinase domain of several oncogenes are frequently associated with non-small cell lung carcinoma (NSCLC). In this study we assessed the frequency, type and abundance of EGFR, KRAS, BRAF, TP53 and ALK mutations in tumour specimens from 184 patients with early and late stage disease using single molecule amplification and re-sequencing technology (SMART). Based on modelling of EGFR mutations, the detection sensitivity of the SMART assay was at lea ...[more]

PMID: 27409166

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Project description:BackgroundAldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na(+) conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined.Materials and methodsThe coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers.ResultsG151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005).DiscussionEither of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

Project description: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.

Dataset Information

Comprehensive profiling and quantitation of oncogenic mutations in non small-cell lung carcinoma using single molecule amplification and re-sequencing technology.

Publications

Comprehensive profiling and quantitation of oncogenic mutations in non small-cell lung carcinoma using single molecule amplification and re-sequencing technology.

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