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Background Early detection of lung cancer in asymptomatic patients remains challenging, especially for stage I. Considering the substantial interaction with tumor immunogenicity, we hypothesized that lung cancer-associated TCR (LC-aTCR) may serve as potential biomarker in early detection of stage I lung cancer. Methods Individuals who received low-dose computed tomography (LDCT) screening were enrolled in the study. Surgical tissues and peripheral blood specimens were collected and performed with DNA-based T cell repertoire (TCR) sequencing. The motif-based algorithm was used to deconstruct specific lung cancer-associated TCRs (LC-aTCRs). Results A total of 146 individuals participating in the real-world LDCT screening project were enrolled in this study, including 52 patients with pathologically-confirmed stage I lung cancer and 94 non-cancer controls. We developed a motif-based algorithm to define 80 LC-aTCRs in the training cohort. Moreover, in the validation cohort, high sensitivity and specificity was showed in stage I lung cancer with 72% and 91% respectively, and the AUC of the ROC curve was 0.91 (95% CI: 0.85 ∼ 0.96). Conclusion This work provides inspiration for stage I lung cancer detection by using blood TCR profiling data. The combination of TCR-based assay and routine screening deserves further testing in larger cohorts.

Introduction Recent clinical studies have identified tumor mutation burden (TMB) as a promising therapeutic biomarker of anti-tumor immune checkpoint blockade. However, given the relatively slow turnaround time and high expense in measuring TMB, tobacco smoking history (TSH) is an attractive replacement biomarker. The carcinogenic effects of tobacco smoking may be modified by the protective effects of genome stability genes. This study aims to test the associations between tobacco smoking, genome stability gene inactivation, and TMB. Methods Publicly available TSH and DNA somatic alteration data from NSCLC were downloaded from The Cancer Genome Atlas. Correlations and enrichments were calculated with Spearman and Fisher’s exact test methods, respectively. Multivariate modeling of TMB was performed with penalized linear regression. Results 85% of never smokers in adenocarcinomas (LUAD) had low TMB, but a positive TSH was not predictive of hypermutancy. The limited utility of TSH in predicting TMB was reproduced on an independent LUAD dataset. To expand our search for predictors of TMB, we further investigated the contributions of genome stability related genes (GSGs) to TMB. 242/461 (52%) and 300/465 (65%) patients with LUAD and squamous carcinomas (LUSC), respectively, showed evidence of loss of function in at least one of the 182 GSGs. 182 GSGs from 16 pathways were assessed for associations with TMB high tumor status using Fisher’s exact test. We performed univariate gene and pathway enrichments in TMB high tumors and found roles forPOLE, REV3L, and FANCE genes, as well as several key GSG pathways. Conclusions This study comprehensively tested the association between GSG, tobacco smoking, and TMB in NSCLC. In LUAD, never-smoking status was predictive of low TMB, but overall TSH was not an adequate surrogate biomarker for TMB in NSCLC. Furthermore, we identified an association between GSG inactivation and TMB.

This study aimed to evaluate the prognostic and potential therapeutic value of expanded molecular testing of resected early-stage lung ACA.We analyzed 324 patients who underwent lobectomy and lymphadenectomy for clinical Stage III lung ACA between 2011-2017. Molecular testing was routinely performed, first by PCR-based Sanger sequencing and FISH and then expanded to a 20 and then 50-gene next generation sequencing (NGS) panel. The frequency of mutations by testing method and their association with disease-free (DFS) and overall survival (OS) were tested.A total of 241 patients (74.4%) had at least one somatic mutation detected, with KRAS exon 2 (38.1%) and EGFR (17.9%) being the most common. TP53 was the most frequent co-existing mutation. Detection of at least one mutation increased from 49% with selective PCR/FISH testing to 82% with limited NGS/FISH, and 91% with extended NGS/FISH (p0.001). The rate of actionable mutations increased from 18% to 32% and 45% with expansion of molecular testing, respectively (p = 0.001). Using NGS, an additional 10 cases with EGFR mutations, and other rare mutations were found, including BRAF (5.9%), MET (5.6%), ERBB2 (4.1%), PIK3CA (2.3%), and DDR2 (2.1%). The expansion of FISH testing resulted in one additional detection of ROS1 and RET (1%) rearrangement. KRAS mutation was associated with worse DFS (HR 1.87; 95%CI 1.14-3.06) and OS (HR 2.09; 95%CI 1.11-3.92). BRAF mutation detected in NGS tested patients was also associated with decreased DFS (HR3.80; 95%CI 1.46-9.89) and OS (HR 7.37; 95%CI 2.36-22.99) on multivariate analysis.The expansion of molecular testing has resulted in a substantial increase in the detection of potentially therapeutically significant mutations in resected early-stage ACA. KRAS and BRAF mutation status by NGS was prognostic for relapse and survival. These data emphasize opportunities for clinical trials in a growing number surgical ACA patients with available targeted therapies.

Objectives The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance. Materials and methods We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59–1021 cancer-related genes. Results and conclusion Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.

Activating mutations in the epidermal growth factor receptor (EGFR) gene are exceedingly rare in small cell lung cancer (SCLC). We present two cases of SCLC harboring EGFR mutations, one in an 82 year-old male smoker with a combined SCLC and adenocarcinoma with a novel D855H point mutation in exon 21, and the second in a 68 year-old female never smoker with the L858R point mutation in exon 21. The cases, accompanied by a review of the literature, highlight the importance of integration of clinicopathologic considerations and adherence to recently promulgated Guideline recommendations for molecular testing in lung cancer.

We applied an established and commercially available serum proteomic classifier for survival after treatment with erlotinib (VeriStrat®) in a blinded manner to pre-treatment sera obtained from recurrent advanced NSCLC patients before treatment with the combination of erlotinib plus bevacizumab. We found that VeriStrat® could classify these patients into two groups with significantly better or worse outcomes and may enable rational selection of patients more likely to benefit from this costly and potentially toxic regimen.

Summary RNA interference is a phenomenon whereby small double-stranded RNA knocks down the expression of a sequence-specific gene. Double-stranded siRNA transfection, as currently used, is considered to have transient and low transfection efficiency. We constructed an adenoviral vector-based short hair-pin(sh)RNA system to overcome the limitations of the genetic blockade of IGF-1R, one of most important cancer therapy targets. We constructed three different IGF-1R specific shRNAs (612, 801, and 3425) and generated three ad-shIGF-1Rs using BD Adeno-X™ expression system. We assessed the effect of ad-shIGF-1R on signal transduction, induction of apoptosis, and in vitro tumorigenicity of lung cancer cell lines. Western blot and FACS assays demonstrated that endogenous IGF-1R expression was efficiently suppressed after transduction of lung cancer cell lines with the three different ad-shIGF-1Rs. IGF-1R blockade by ad-shIGF-1R inhibited ligand induced phosphorylation of pAkt and pErk, and ad-shIGF-1R effectively blocked the in vitro tumorigenicity of lung cancer cell lines. Moreover, the transduction of a human lung cancer cell line with ad-IGF-1R(3425) enhanced chemosensitivity to anticancer drugs. We conclude that the adenoviral vector-based approach to the RNA interference of IGF-1R induced effective IGF-1R silencing in lung cancer cell lines as manifested by effective blocking of the downstream pathway of IGF-1R and by an antitumor effect. We believe that this system can be usefully applied to other cancer targets.

The complexities of human cancer have frustrated attempts to understand its genetic underpinnings and explain the unpredictable behavior of individual tumors. Advances in robotics and computer science, as well as the sequence data from the human genome project are now allowing us to begin to glean useful information from the simultaneous analysis of thousands of data elements from hundreds of tumors. Through the sophisticated analysis of patterns in these complex data sets, we are seeing clues that we may be able to predict the behavior of individual tumors as well as to define novel biomarkers and therapeutic targets. In this review, we will discuss the application of these high-throughput technologies for the study of human lung cancer.

Using single-strand conformation polymorphasm we have found two polymorphic sites, AAC to AAT at codon 511 (exon 12) and GCT to GCG at codon 708 (exon 15), in the MCC gene. These sizes and an RsaI polymorphic site in AFC allowed us to study 23 human small cell lung cancer (SCLC) and 7 non-small cell lung cancer samples for allele loss. Of the 23 SCLC samples, 21 (91%) were informative for one or more of these markers, and we found allele loss in more than 80% (17 of 21)