Citations

Abstract Lung cancer accounts for about 27% of the cancer related deaths in the USA annually. Pathologically, it is a very complex disease broadly classified into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLCs are further classified into squamous cell carcinoma, large cell carcinoma and adenocarcinoma. Achaete-scute homolog 1 (ASCL1), an important transcription factor essential in the development of neuroendocrine cells (NE) in lungs is shown to be specifically expressed in lung NE cancers and 10-20% of adenocarcinomas (AD) with NE differentiation (NED), thus suggesting a role in the pathogenesis of these tumors. Our previous study showed that ASCL1 is a regulator of the RET oncogene in AD with NED. RET is a receptor tyrosine kinase with two isoforms in humans: RET9 (short) and RET51 (long). We performed survival analysis to study implications of RET isoforms in ASCL1+ tumors and found that elevated expression of the long RET mRNA was associated with poor survival. Subsequent in vitro experiments demonstrated that treatment with EGF robustly induced phosphorylation of RET in HCC1833 and H1755 cell lines which have high endogenous levels of ASCL1 and RET but not in VMRC-LCD cell line which has high level of ASCL1 but low level of RET. EGF induced phosphorylation of RET was diminished by gefitinib and by EGFR siRNA. Immunoprecipitation results indicated direct binding between EGFR and RET in presence of EGF. Furthermore, a high throughput drug screening found 8 EGFR inhibitors that were 10 - 250 fold more cytotoxic in ASCL1+ compared with ASCL1- AD cells. These results implicate EGFR as a key regulator of RET activation in ASCL1+ AD and suggest that EGFR inhibitors may be therapeutic for this population of patients. Citation Format: Kaustubh N. Bhinge, Yang Lin, Hamed Rahi, Marie Christine Aubry, Aaron Mansfield, Irina Kovtun, Stephen Murphy, Ping Yang, Dennis Wigle, Joanne (Eunhee) Yi, Aqsa Nasir, Simone Terra, Julian Molina, George Vasmatzis, Farhad Kosari. EGFR-mediated activation of RET in ASCL1+ lung adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1129.

Purpose According to the lung cancer staging project, T1a (≤ 2 cm) non–small-cell lung cancer (NSCLC) should be additionally classified into ≤ 1 cm and > 1 to 2 cm groups. This study aimed to investigate the surgical procedure for NSCLC ≤ 1 cm and > 1 to 2 cm. Methods We identified 15,760 patients with T1aN0M0 NSCLC after surgery from the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and lung cancer–specific survival (LCSS) were compared among patients after lobectomy, segmentectomy, or wedge resection. The proportional hazards model was applied to evaluate multiple prognostic factors. Results OS and LCSS favored lobectomy compared with segmentectomy or wedge resection in patients with NSCLC ≤ 1 cm and > 1 to 2 cm. Multivariable analysis showed that segmentectomy and wedge resection were independently associated with poorer OS and LCSS than lobectomy for NSCLC ≤ 1 cm and > 1 to 2 cm. With sublobar resection, lower OS and LCSS emerged for NSCLC > 1 to 2 cm after wedge resection, whereas similar survivals were observed for NSCLC ≤ 1 cm. Multivariable analyses showed that wedge resection is an independent risk factor of survival for NSCLC > 1 to 2 cm but not for NSCLC ≤ 1 cm. Conclusion Lobectomy showed better survival than sublobar resection for patients with NSCLC ≤ 1 cm and > 1 to 2 cm. For patients in whom lobectomy is unsuitable, segmentectomy should be recommended for NSCLC > 1 to 2 cm, whereas surgeons could rely on surgical skills and the patient profile to decide between segmentectomy and wedge resection for NSCLC ≤ 1 cm.

Abstract The aim of this study was to estimate the effect of exposure to secondhand tobacco smoke on the incidence of lung adenocarcinoma in situ/minimally invasive adenocarcinoma (AIS/MIA). Data from seven case–control studies participating in the International Lung Cancer Consortium (ILCCO) were pooled, resulting in 625 cases of AIS/MIA and 7,403 controls, of whom 170 cases and 3,035 controls were never smokers. Unconditional logistic regression was used to estimate adjusted ORs (ORadj) and 95% confidence intervals (CI), controlling for age, sex, race, smoking status (ever/never), and pack-years of smoking. Study center was included in the models as a random-effects intercept term. Ever versus never exposure to secondhand tobacco smoke was positively associated with AIS/MIA incidence in all subjects (ORadj = 1.48; 95% CI, 1.14–1.93) and in never smokers (ORadj = 1.45; 95% CI, 1.00–2.12). There was, however, appreciable heterogeneity of ORadj across studies (P = 0.01), and the pooled estimates were largely influenced by one large study (40% of all cases and 30% of all controls). These findings provide weak evidence for an effect of secondhand tobacco smoke exposure on AIS/MIA incidence. Further studies are needed to assess the impact of secondhand tobacco smoke exposure using the newly recommended classification of subtypes of lung adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 24(12); 1902–6. ©2015 AACR.

Patients with lung cancer report more disease burden and lower spiritual well-being (SWB) compared with other cancer patients. Understanding variables that lessen disease burden and improve SWB is essential. The aim of this study was to explore the relationship between motivational level for physical activity and SWB in patients with lung cancer. Linear regression showed increased SWB as stage of change for physical activity increased (p < 0.0001), even after adjusting for multiple demographic variables.

AbstractMicroRNA‐200 (miR‐200) has emerged as a regulator of the PI3K/AKT pathway and cancer cell growth. It was reported that miR‐200 can activate PI3K/AKT by targeting FOG2 (friend of GATA 2), which directly binds to the p85α regulatory subunit of PI3K. We found that miR‐200 was elevated in early stage lung adenocarcinomas when compared with normal lung tissues, and the expression of miR‐200 promoted the tumor spheroid growth of lung adenocarcinoma cells. We show that AKT activation was essential for such oncogenic action of miR‐200. However, depletion of FOG2 had little effect on AKT activation. By performing a reverse‐phase protein array, we found that miR‐200 not only activated AKT but also concomitantly inactivated S6K and increased IRS‐1, an S6K substrate that is increased on S6K inactivation. Depletion of IRS‐1 partially inhibited the miR‐200‐dependent AKT activation. Taken together, our results suggest that miR‐200 may activate AKT in lung adenocarcinoma cells through a FOG2‐independent mechanism involving IRS‐1. Our findings also provide evidence that increased miR‐200 expression may contribute to early lung tumorigenesis and that AKT inhibitors may be useful for the treatment of miR‐200‐dependent tumor cell growth. © 2015 IUBMB Life, 67(9):720–725, 2015

Abstract Introduction: Pulmonary carcinoid tumors account for up to 5% of all lung malignancies in adults, and comprise 30% of all carcinoid malignancies. They are defined histologically as typical carcinoid (TC) and atypical carcinoid (AC) tumors, and are characterized by neuroendocrine differentiation and the potential to metastasize. Method: We characterized genomic alterations in pulmonary carcinoid tumors using whole genome and exome sequencing in addition to mRNA expression and SNP genotyping from specimens of normal lung, typical and atypical carcinoid, and SCLC. Results: Analysis of the sequencing data identified novel mutations in the pulmonary neuroendocrine tumor spectrum, including KRAS, ABCA9, GALNT10, HSFX1, PTHLH, RANBP2, BRIP1, FXR1, BACE2, NCOR2, DGKI, HERC1, HERC5 and GLI3. Pathway analysis found 45% of the cases to harbor a mutation in genes that are involved in protein-protein interaction with ubiquitin c (UBC) and may therefore play a role in ubiquitin protein degradation pathway. We also identified genes differentially expressed in corresponding regions of copy number variation, 52 of which were linked to ubiquitination pathways in 88% of the samples genotyped. Genes amplified in 15 to 23% of the cases included ITM2A, MAOA, EGR2, HAGH, TSC22D3, NBEA, TCEAL2, and TSPYL2 whereas deleted regions in 15% of the cases implicated CFD, GDI1, IFITM1 and IFITM2. Conclusion: These results suggest that in addition to previously identified pathways, dysregulation of the ubiquitin pathway may contribute to lung carcinoid tumorigenesis and could be exploited for therapeutic purposes. Citation Format: Michael K. Asiedu, Charles L. Thomas, Jie Dong, Prasidda Khadka, Zhifu Sun, Farhad Kosari, Jin Jen, Julian Molina, George Vasmatzis, Marie Christine Aubry, Ping Yang, Dennis Wigle. Genomic alterations modify ubiquitination pathways in pulmonary carcinoid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3895. doi:10.1158/1538-7445.AM2015-3895

Abstract Recently, Wilson et al. (doi:10.1038/onc.2013.396) found that EYA4 was frequently inactivated biallelically in sporadic lung cancer, displays tumor suppressor gene-like properties and affects DNA repair, and that 5 of 17 common SNPs in this 0.3Mb region showed nominal association to familial lung cancer (FLC, p&lt;0.05) although these associations are not genome-wide significant after correction for multiple testing.. However, this is an interesting candidate gene for FLC risk because it is located on chromosome 6q in a region where we previously showed evidence of linkage to FLC (PMID: 15272417, 20215501). Here, we sequenced 75 individuals from our 9 most strongly 6q-linked families, using Illumina technology and a custom Agilent kit to capture 37Mb of chromosome 6 from 130Mb to 167Mb. We closely examined a region around EYA4, between 133Mb and 135Mb. This region contains a number of other genes in addition to EYA4, including the Vanin cluster; ribosomal protein S12; the tumor suppressor gene TCF21 and its antisense RNA TARID which directs methylation and activation of TCF21; solute carriers SLC18B1 and SLC2A12 and the serum/glucocorticoid regulated kinase SGK1. To detect sharing of variants among affecteds in each family while allowing for phenocopies, singlepoint affected-only linkage analysis was performed on lung cancer affection status for all sequence variants using the Elston-Stewart algorithm implemented in the R package paramlink assuming penetrance of 0.01, 0.1 and 0.1 for dd/Dd/DD and a disease allele (D) frequency of 0.01, at a recombination fraction (theta) of 0. The highest total LOD score (summed over all 9 families) in the entire 37Mb targeted region was not near EYA4. In only one family was there any variant in EYA4 that appeared on the linked haplotype with close to the highest family-specific LOD score: Family 30 had a LOD of 0.6514 at several EYA4 variants (max LOD across region 0.6519). However, many variants across the region had similar LODs. In the remaining families, all EYA4 variants had LODs much lower than the maximum family-specific LOD score in the region. Thus, EYA4 variants are unlikely to explain our 6q linkage peak in these 6q-linked families. The second highest total LOD score for the entire 37Mb targeted region was found near EYA4 at 133.9Mb (LOD = 3.82), in the middle of the TARID antisense RNA gene. This variant appears to be entirely novel, as it is not present in any of the online variant databases, such as NHLBI's ESP or 1000 Genomes. In two families, the family LOD score at this locus was at or close to the highest in the region: in Family 44 the LOD score was 1.206 (max LOD across entire region 1.207) and in Family 35 the LOD score was 0.3958 (max LOD across region 0.3959). Therefore this variant in the TARID antisense RNA is a candidate in some of our families most strongly linked to chromosome 6q. Citation Format: Joan E. Bailey-Wilson, Claire L. Simpson, Susan M. Pinney, Mariza de Andrade, Colette Gaba, Ping Yang, Ming You, Elena Y. Kupert, Ann G. Schwartz, Diptasri Mandal, Christopher I. Amos, Marshall W. Anderson. Evaluation of EYA4 as a candidate risk locus in familial lung cancer families linked to 6q. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2757. doi:10.1158/1538-7445.AM2015-2757