Introduction: Multiple oncogene fusions beyond ALK receptor tyrosine kinase (ALK), RET, and ROS1 fusion has been described in lung cancer, especially in lung adenocarcinomas without common oncogenic mutations. Molecular inhibitors have been developed and proved effective for patients whose tumors harbor these novel alterations. Methods: A consecutive series of surgically resected lung adenocarcinomas were collected and profiled using an enrichment strategy to detect nine common oncogenic driver mutations and fusions concerning EGFR, KRAS, HER2, BRAF, MET, ALK, RET, ROS1, and FGFR. Driver-negative cases were further analyzed by a comprehensive RNA-based next-generation sequencing (NGS) fusion assay for novel fusions. Results: In total, we profiled 1681 lung adenocarcinomas, among which 255 cases were common driver-negative. One hundred seventy-seven cases had sufficient tissue for NGS fusions screening, which identified eight novel fusions. NRG1 fusions occurred in 0.36% of all lung adenocarcinoma cases (6 of 1681 cases), including 4 CD74-NRG1-positive cases, 1 RBPMS-NRG1-positive case, and 1 novel ITGB1-NRG1-positive case. Furthermore, another 2 novel fusions were also detected, including 1 EGFR-SHC1 fusion and 1 CD47-MET fusion, both of which were in-frame and retained the functional domain of the corresponding kinases. No fusion event was detected for NTRK, KRAS, BRAF or HER2 genes in this cohort. Detailed clinicopathologic data showed that invasive mucous adenocarcinoma (three of eight cases) and acinar-predominant adenocarcinoma (three of eight cases) were the most prevalent pathologic subtypes among novel fusions. Conclusions: Fusions affecting NRG1, EGFR, and MET were detected in 0.48% of unselected lung adenocarcinomas, and NRG1 fusions ranked the most prevalent fusions in common driver-negative lung adenocarcinomas from Chinese population. RNA-based NGS fusion assay was an optional method for screening actionable fusions in common driver-negative cases. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Introduction: Mosaic loss of chromosome Y (mLOY) is the most commonly detectable mosaic chromosomal event in cancers; however, its underlying relationship with tumorigenesis is still unclear. Methods: We conducted a mendelian randomization study to systematically investigate the effect of mLOY on lung cancer based on a published genome-wide association study and inferred the causal relationship between mLOY and lung cancer. Kaplan-Meier and Cox regression analyses were used to evaluate the effect of mLOY on lung cancer prognosis. Results: We discovered that genetically defined mLOY was a protective factor against lung cancer development in nonsmokers but not in smokers (lifelong nonsmokers: OR = 0.80, 95% confidence interval [CI]: 0.69-0.93, p = 4.03 x 10(-3); smokers: OR = 0.96, 95% CI: 0.89-1.04, p = 2.90 x 10(-1), p(Heterogeneity) = 3.83 x 10(-2)). A U-shaped curve between the copy number level of chromosome Y and lung cancer risk was fitted (p for linearity Wald = 8.81 x 10(-10)) to support the idea that heavy mLOY caused by acquired damaging environmental factors may have effects on lung cancer that are different from those of genetically defined mLOY, whereas genetically predicted mLOY was linearly associated with a decreased lung cancer risk (p for linearity Wald = 0.15). In addition, increased genetically defined mLOY was also significantly associated with a better outcome of lung cancer (HR = 0.86, 95% CI: 0.75-0.98, p = 2.03 x 10(-2)). Conclusions: In summary, we propose a "two-sides" model: "natural" mLOY reduces the risk and ensures a better prognosis of lung cancer, although the effect can be abolished by an aberrant loss of chromosome Y caused by environmental risk factors. Our results reveal a complex relationship between mLOY and lung cancer and provide important implications for the prevention of lung cancer. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Introduction: Adjuvant gefitinib therapy prolonged disease-free survival in patients with resected early-stage EGFR-mutation positive NSCLC in the ADJUVANT study (CTONG 1104). However, treatment failure patterns after gefitinib therapy are less well characterized. Methods: Overall, 222 stage N1-N2, EGFR-mutant NSCLC patients received gefitinib or vinorelbine plus cisplatin (VP) treatment. Tumor recurrences or metastases occurring during follow-up were defined as treatment failure; sites and data of first treatment failure were recorded. A post hoc analysis of treatment failure patterns which was estimated by Kaplan-Meier and hazard rate curves in modified intention-to-treat patients was conducted. Results: There were 114 recurrences and 10 deaths before recurrence across 124 progression events. Spatial distribution analysis showed that the first metastasis site was most frequently the central nervous system in the gefitinib group (29 of 106 [27.4%]), extracranial metastases were most frequent in the VP group (32 of 87 [36.8%]). Temporal distribution analysis showed lower tumor recurrence with gefitinib than with VP 0 to 21 months post-surgery. However, recurrence with gefitinib showed a constant rate of increase 12 months post-surgery. The first peak of extracranial metastasis appeared during 9 to 15 months with VP and 24 to 30 months with gefitinib. The highest peak for central nervous system metastases post-surgery occurred after 12 to 18 months with VP and 24 to 36 months with gefitinib. Conclusions: Adjuvant gefitinib showed advantages over VP chemotherapy in treatment failure patterns especially in extracranial metastasis. Adjuvant tyrosine kinas inhibitors may be considered as a treatment option in resected stage N1-N2 EGFR-mutant NSCLC but longer duration should be explored. (C) 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.