Lung Adenocarcinoma From East Asian Never-Smokers Is a Disease Largely Defined by Targetable Oncogenic Mutant Kinases

Institute of Biostatistics, Fudan University, Shanghai, Shanghai Shi, China
Journal of Clinical Oncology (Impact Factor: 18.43). 10/2010; 28(30):4616-20. DOI: 10.1200/JCO.2010.29.6038
Source: PubMed


To determine the proportion of lung adenocarcinomas from East Asian never-smokers who harbor known oncogenic driver mutations.
In this surgical series, 52 resected lung adenocarcinomas from never-smokers (< 100 cigarettes in a lifetime) at a single institution (Fudan University, Shanghai, China) were analyzed concurrently for mutations in EGFR, KRAS, NRAS, HRAS, HER2, BRAF, ALK, PIK3CA, TP53 and LKB1.
Forty-one tumors harbored EGFR mutations, three harbored EML4-ALK fusions, two harbored HER2 insertions, and one harbored a KRAS mutation. All mutations were mutually exclusive. Thus, 90% (47 of 52; 95% CI, 0.7896 to 0.9625) of lung adenocarcinomas from never-smokers were found to harbor well-known oncogenic mutations in just four genes. No BRAF, NRAS, HRAS, or LKB1 mutations were detected, while 15 had TP53 mutations. Four tumors contained PIK3CA mutations, always together with EGFR mutations.
To our knowledge, this study represents the first comprehensive and concurrent analysis of major recurrent oncogenic mutations found in a large cohort of lung adenocarcinomas from East Asian never-smokers. Since drugs are now available that target mutant EGFR, HER2, and ALK, respectively, this result indicates that prospective mutation testing in these patients should successfully assign a targeted therapy in the majority of cases.

Download full-text


Available from: Hongbin Ji, Mar 23, 2015
29 Reads
  • Source
    • "However, the sensitivity of sequencing results is affected by the relatively low quality of FFPE samples, in which DNA is degraded and artificially mutated. The mutation rate of well known driver genes is lower than previous studies using high quality snap-frozen samples [20], [21], and the artificial mutations appeared in hTERT 5′ promoter region. Though consecutive samples with complete survival data are not always available, our study provided the mutation spectrum and prognostic association of these genetic alterations with available sample and techniques. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Targeting activating oncogenic driver mutations in lung adenocarcinoma has led to prolonged survival in patients harboring these specific genetic alterations. The prognostic value of these mutations has not yet been elucidated. The prevalence of recently uncovered non-coding somatic mutation in promoter region of TERT gene is also to be validated in lung cancer. The purpose of this study is to show the prevalence, association with clinicalpathological features and prognostic value of these factors. Methods In a cohort of patients with non-small cell lung cancer (NSCLC) (n = 174, including 107 lung adenocarcinoma and 67 lung squamous cell carcinoma), EGFR, KRAS, HER2 and BRAF were directly sequenced in lung adeoncarcinoma, ALK fusions were screened using FISH (Fluorescence in situ Hybridization).TERT promoter region was sequenced in all of the 174 NSCLC samples. Associations of these somatic mutations and clinicopathological features, as well as prognostic factors were evaluated. Results EGFR, KRAS, HER2, BRAF mutation and ALK fusion were mutated in 25.2%, 6.5%, 1.9%, 0.9% and 3.7% of lung adenocarcinomas. No TERT promoter mutation was validated by reverse-sided sequencing. Lung adenocarcinoma with EGFR and KRAS mutations showed no significant difference in Disease-free Survival (DFS) and Overall Survival (OS). Cox Multi-variate analysis revealed that only N stage and HER2 mutation were independent predictors of worse overall survival (HR = 1.653, 95% CI 1.219–2.241, P = 0.001; HR = 12.344, 95% CI 2.615–58.275, P = 0.002). Conclusions We have further confirmed that TERT promoter mutation may only exist in a very small fraction of NSCLCs. These results indicate that dividing lung adenocarcinoma into molecular subtypes according to oncogenic driver mutations doesn't predict survival difference of the disease.
    PLoS ONE 09/2014; 9(9):e107276. DOI:10.1371/journal.pone.0107276 · 3.23 Impact Factor
  • Source
    • "Comprehensive mutational analyses of EGFR, KRAS, ALK, and HER2 were performed in lung adenocarcinomas as previously described.12–14 Briefly, ribonucleic acid was extracted as per standard protocol after frozen tissues were dissected into TRIzol® (Life Technologies, Carlsbad, CA, USA), and was reverse transcribed into complementary deoxyribonucleic acid (cDNA). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The clinicopathologic characteristics of tumors expressing programmed death (PD-1) ligands (PD-Ls) PD-L1 or PD-L2 and their associations with common driver mutations in lung adenocarcinoma are not clearly defined, despite the progression of anti-PD-1/PD-L1 immunotherapy. PD-L1 and PD-L2 expression was measured by immunohistochemistry in 143 surgically resected lung adenocarcinomas and was correlated with clinical variables, histologic subtypes, and the mutational status of EGFR, KRAS, HER2, and ALK. Positive PD-L1 expression was significantly associated with more advanced T status, N status, and pathologic stage. Histologically, lung adenocarcinomas with positive PD-L1 staining were less likely to be adenocarcinoma in situ or minimally invasive adenocarcinoma and more likely to have solid predominant subtype. Both PD-L1 expression (odds ratio =1.984, 95% confidence interval =1.010-3.894; P=0.047) and PD-L2 expression (odds ratio =2.328, 95% confidence interval =1.201-4.512; P=0.012) were independent predictors of poor overall survival. When the combined PD-L expression and pathologic stage were used together to predict overall survival, the concordance index increased to 0.763, and the Akaike information criteria value decreased to 356.08. We defined the clinicopathologic features of lung adenocarcinomas with high expression of PD-L1 and PD-L2. We further demonstrated the role of PD-L expression as a useful prognostic marker for lung adenocarcinoma.
    OncoTargets and Therapy 04/2014; 7:567-73. DOI:10.2147/OTT.S59959 · 2.31 Impact Factor
  • Source
    • "For lung adenocarcinomas, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been approved for treatment of tumors carrying EGFR gene mutations, and crizotinib for tumors with anaplastic lymphoma kinase (ALK) gene rearrangements [7], [8], [9], [10]. Clinical trials are ongoing in subgroups of patients harboring specific molecular alterations such as BRAF, PIK3CA or KRAS activating mutations [11], [12], [13]. Therefore, the number of predictive biomarkers to be assessed for novel targeted drugs entering into clinical practice is expected to rapidly increase [2], [10], [14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Identification of driver mutations in lung adenocarcinoma has led to development of targeted agents that are already approved for clinical use or are in clinical trials. Therefore, the number of biomarkers that will be needed to assess is expected to rapidly increase. This calls for the implementation of methods probing the mutational status of multiple genes for inoperable cases, for which limited cytological or bioptic material is available. Cytology specimens from 38 lung adenocarcinomas were subjected to the simultaneous assessment of 504 mutational hotspots of 22 lung cancer-associated genes using 10 nanograms of DNA and Ion Torrent PGM next-generation sequencing. Thirty-six cases were successfully sequenced (95%). In 24/36 cases (67%) at least one mutated gene was observed, including EGFR, KRAS, PIK3CA, BRAF, TP53, PTEN, MET, SMAD4, FGFR3, STK11, MAP2K1. EGFR and KRAS mutations, respectively found in 6/36 (16%) and 10/36 (28%) cases, were mutually exclusive. Nine samples (25%) showed concurrent alterations in different genes. The next-generation sequencing test used is superior to current standard methodologies, as it interrogates multiple genes and requires limited amounts of DNA. Its applicability to routine cytology samples might allow a significant increase in the fraction of lung cancer patients eligible for personalized therapy.
    PLoS ONE 11/2013; 8(11):e80478. DOI:10.1371/journal.pone.0080478 · 3.23 Impact Factor
Show more