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1.  Genome-Wide Association Study Identifies a Novel Susceptibility Locus at 12q23.1 for Lung Squamous Cell Carcinoma in Han Chinese 
PLoS Genetics  2013;9(1):e1003190.
Adenocarcinoma (AC) and squamous cell carcinoma (SqCC) are two major histological subtypes of lung cancer. Genome-wide association studies (GWAS) have made considerable advances in the understanding of lung cancer susceptibility. Obvious heterogeneity has been observed between different histological subtypes of lung cancer, but genetic determinants in specific to lung SqCC have not been systematically investigated. Here, we performed the GWAS analysis specifically for lung SqCC in 833 SqCC cases and 3,094 controls followed by a two-stage replication in additional 2,223 lung SqCC cases and 6,409 controls from Chinese populations. We found that rs12296850 in SLC17A8-NR1H4 gene region at12q23.1 was significantly associated with risk of lung SqCC at genome-wide significance level [additive model: odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.72–0.84, P = 1.19×10−10]. Subjects carrying AG or GG genotype had a 26% (OR = 0.74, 95% CI = 0.67–0.81) or 32% (OR = 0.68, 95% CI = 0.56–0.83) decreased risk of lung SqCC, respectively, as compared with AA genotype. However, we did not observe significant association between rs12296850 and risk of lung AC in a total of 4,368 cases with lung AC and 9,486 controls (OR = 0.96, 95% CI = 0.90–1.02, P = 0.173). These results indicate that genetic variations on chromosome 12q23.1 may specifically contribute to lung SqCC susceptibility in Chinese population.
Author Summary
Previous genome-wide association studies (GWAS) strongly suggested the importance of genetic susceptibility for lung cancer. However, the studies specific to different histological subtypes of lung cancer were limited. We performed the GWAS analysis specifically for lung squamous cell carcinoma (SqCC) with 570,009 autosomal SNPs in 833 SqCC cases and 3,094 controls and replicated in additional 2,223 lung SqCC cases and 6,409 controls from Chinese populations (822 SqCC cases and 2,243 controls for the first replication stage and 1,401 SqCC cases and 4,166 controls for the second replication stage). We found a novel association at rs12296850 (SLC17A8-NR1H4) on12q23.1. However, rs12296850 didn't show significant association with risk of lung adenocacinoma (AC) in 4,368 lung AC cases and 9,486 controls. These results indicate that genetic variations on chromosome 12q23.1 may specifically contribute to lung SqCC susceptibility in Chinese population.
doi:10.1371/journal.pgen.1003190
PMCID: PMC3547794  PMID: 23341777
2.  Divergent Genomic and Epigenomic Landscapes of Lung Cancer Subtypes Underscore the Selection of Different Oncogenic Pathways during Tumor Development 
PLoS ONE  2012;7(5):e37775.
For therapeutic purposes, non-small cell lung cancer (NSCLC) has traditionally been regarded as a single disease. However, recent evidence suggest that the two major subtypes of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SqCC) respond differently to both molecular targeted and new generation chemotherapies. Therefore, identifying the molecular differences between these tumor types may impact novel treatment strategy. We performed the first large-scale analysis of 261 primary NSCLC tumors (169 AC and 92 SqCC), integrating genome-wide DNA copy number, methylation and gene expression profiles to identify subtype-specific molecular alterations relevant to new agent design and choice of therapy. Comparison of AC and SqCC genomic and epigenomic landscapes revealed 778 altered genes with corresponding expression changes that are selected during tumor development in a subtype-specific manner. Analysis of >200 additional NSCLCs confirmed that these genes are responsible for driving the differential development and resulting phenotypes of AC and SqCC. Importantly, we identified key oncogenic pathways disrupted in each subtype that likely serve as the basis for their differential tumor biology and clinical outcomes. Downregulation of HNF4α target genes was the most common pathway specific to AC, while SqCC demonstrated disruption of numerous histone modifying enzymes as well as the transcription factor E2F1. In silico screening of candidate therapeutic compounds using subtype-specific pathway components identified HDAC and PI3K inhibitors as potential treatments tailored to lung SqCC. Together, our findings suggest that AC and SqCC develop through distinct pathogenetic pathways that have significant implication in our approach to the clinical management of NSCLC.
doi:10.1371/journal.pone.0037775
PMCID: PMC3357406  PMID: 22629454
3.  Gene-expression data integration to squamous cell lung cancer subtypes reveals drug sensitivity 
British Journal of Cancer  2013;109(6):1599-1608.
Background:
Squamous cell lung cancer (SqCC) is the second most common type of lung cancer in the United States. Previous studies have used gene-expression data to classify SqCC samples into four subtypes, including the primitive, classical, secretory and basal subtypes. These subtypes have different survival outcomes, although it is unknown whether these molecular subtypes predict response to therapy.
Methods:
Here, we analysed RNAseq data of 178 SqCC tumour samples and characterised the features of the different SqCC subtypes to define signature genes and pathway alterations specific to each subtype. Further, we compared the gene-expression features of each molecular subtype to specific time points in models of airway development. We also classified SqCC-derived cell lines and their reported therapeutic vulnerabilities.
Results:
We found that the primitive subtype may come from a later stage of differentiation, whereas the basal subtype may be from an early time. Most SqCC cell lines responded to one of five anticancer drugs (Panobinostat, 17-AAG, Irinotecan, Topotecan and Paclitaxel), whereas the basal-type cell line EBC-1 was sensitive to three other drugs (PF2341066, AZD6244 and PD-0325901).
Conclusion:
Compared with the other three subtypes of cell lines, the secretory-type cell lines were significantly less sensitive to the five most effective drugs, possibly because of their low proliferation activity. We provide a bioinformatics framework to explore drug repurposing for cancer subtypes based on the available genomic profiles of tumour samples, normal cell types, cancer cell lines and data of drug sensitivity in cell lines.
doi:10.1038/bjc.2013.452
PMCID: PMC3776976  PMID: 24002593
squamous cell lung cancer subtypes; gene expression; RNAseq; microarray; signature genes; cells of origin; representative cell line; drug sensitivity; classification
4.  Detection of ALK protein expression in lung squamous cell carcinomas by immunohistochemistry 
Background
The echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene rearrangements occur in approximately 5% of lung adenocarcimomas (ACA), leading to ALK overexpression and predicting response to targeted therapy. To the present, few studies have been focused on the expression of ALK protein in lung squamous cell carcinomas (SqCC). Only several cases of lung SqCC were reported expression of ALK protein. No clinical study has been published to explicit the relationship between ALK expression and the response to targeted therapy in SqCC.
Methods
In this study, we analyzed ALK protein expression with a specific rabbit monoclonal Ig antibody (D5F3 clone) in 207 cases of lung SqCC. The positive cases were confirmed with ALK fluorescence in situ hybridization (FISH) and RT-PCR.
Results
We found that 3 out of 207 (1.4%) cases of lung SqCC were ALK positive detected by IHC staining, which were confirmed by ALK FISH and RT-PCR.
Conclusions
Our results indicate that ALK protein expression is not a rare molecular event in SqCC. Although the frequency of EML4-ALK rearrangements is lower in lung SqCC than that in lung adenocarcinomas, their presence may provide additional treatment options in lung SqCC. The response of SqCC patients with ALK expression to target therapy of crizotinib should be explored.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-014-0109-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-014-0109-2
PMCID: PMC4304180  PMID: 25527865
Anaplastic lymphoma kinase; Lung squamous cell carcinoma; IHC; D5F3 clone
5.  Expression of transcript factors SALL4 and OCT4 in a subset of non-small cell lung carcinomas (NSCLC) 
Background
SALL4 and OCT4 are transcription factors and play essential roles in stem cell development and oncogenesis. However, the expression of these transcription factors has not been well studied in lung cancers. In this study, we evaluated the expression of SALL4 and OCT4 in non-small cell lung carcinomas (NSCLC) by immunochemistry. NSCLC tissue microarrays (TMAs) were constructed with a total of 77 primary lung adenocarcinomas (ADCs) and 90 primary lung squamous cell carcinomas (SqCCs). A mouse monoclonal anti-human SALL4 (1:400 dilution) and a polyclonal anti-human OCT4 (1:200 dilution) antibodies were used. Nuclear staining of SALL4 and OCT4 was scored semi-quantitatively using a three tiered scale. The expressions of SALL4 and OCT4 were correlated with the tumor differentiation, pathological stage, and patients’ clinical information.
Results
In primary ADCs, the stronger expression of SALL4 and OCT4 was 7.8% and 9.1%, respectively. The stronger expression of SALL4 was inversely correlated with tumor differentiations. In primary SqCCs, the stronger expressions of SALL4 and OCT4 were 16.7% and 0%, respectively. The expression of SALL4 is correlated with the expression of OCT4, but inversely correlated with the tumor stage in SqCCs.
Conclusions
We found that both SALL4 and OCT4 were differentially expressed in a subset of primary ADC and SqCC. Our finding suggest that different stem cell markers may be expressed and/or play differential role in different subtypes of NSCLC. The potential role of SALL4 and OCT4 needs to be further investigated in NSCLC.
doi:10.1186/s40247-014-0010-7
PMCID: PMC4201749  PMID: 25346886
Transcription factor SALL4 and OCT4; Immunohistochemistry (IHC); Non-small cell lung cancer (NSCLC); Metastatic NSCLC; Lung cancer biopsy and tissue microarray (TMA)
6.  Prognostic significance of PIK3CA and SOX2 in Asian patients with lung squamous cell carcinoma 
International Journal of Oncology  2014;46(2):505-512.
The recent development of human genome studies has demonstrated the possibility of alteration of several genes as oncogenic driver mutations of lung squamous cell carcinoma (SQCC). FGFR1, PIK3CA and SOX2 genes have been recognized as candidate driver genes of SQCC. The aim of the present study was to evaluate FGFR1, PIK3CA and SOX2 protein expression in SQCC and determine whether the expression of these can be used as prognostic biomarkers. We evaluated the relationships between FGFR1, PIK3CA and SOX2 expression by immunohistochemical analysis and overall survival in lung SQCC patients with stage I–III that originated from China, United States and Japan. FGFR1-positive, PIK3CA-negative and SOX2-positive staining each showed trends toward better survival, although the differences were not statistically significant in a Chinese cohort of 57 patients. Patients with PIK3CA-negative and SOX2-positive staining (PIK3CA−/SOX2+) showed better prognosis compared with those with PIK3CA-positive or SOX2-negative staining in the Chinese cohort (P=0.04). The robustness of PIK3CA−/SOX2+ classification as having prognostic significance was validated in an independent set of 66 Japanese cohort patients (P=0.007). Japanese SQCC patients with stage I were evaluated separately and PIK3CA−/SOX2+ cases had significantly better survival than the group with PIK3CA-positive or SOX2-negative status (P=0.03). In univariate and multivariable Cox proportional hazards models of Asian stage I patients, the PIK3CA−/SOX2+ classification was statistically significantly associated with survival and was an independent prognostic factor. Classification by PIK3CA and SOX2 protein expression is useful for predicting the prognosis of Asian patients with lung SQCC with stage I.
doi:10.3892/ijo.2014.2742
PMCID: PMC4277247  PMID: 25384882
PIK3CA; SOX2; lung squamous cell carcinoma; prognosis
7.  Aberrant DNA Methylation of OLIG1, a Novel Prognostic Factor in Non-Small Cell Lung Cancer 
PLoS Medicine  2007;4(3):e108.
Background
Lung cancer is the leading cause of cancer-related death worldwide. Currently, tumor, node, metastasis (TNM) staging provides the most accurate prognostic parameter for patients with non-small cell lung cancer (NSCLC). However, the overall survival of patients with resectable tumors varies significantly, indicating the need for additional prognostic factors to better predict the outcome of the disease, particularly within a given TNM subset.
Methods and Findings
In this study, we investigated whether adenocarcinomas and squamous cell carcinomas could be differentiated based on their global aberrant DNA methylation patterns. We performed restriction landmark genomic scanning on 40 patient samples and identified 47 DNA methylation targets that together could distinguish the two lung cancer subgroups. The protein expression of one of those targets, oligodendrocyte transcription factor 1 (OLIG1), significantly correlated with survival in NSCLC patients, as shown by univariate and multivariate analyses. Furthermore, the hazard ratio for patients negative for OLIG1 protein was significantly higher than the one for those patients expressing the protein, even at low levels.
Conclusions
Multivariate analyses of our data confirmed that OLIG1 protein expression significantly correlates with overall survival in NSCLC patients, with a relative risk of 0.84 (95% confidence interval 0.77–0.91, p < 0.001) along with T and N stages, as indicated by a Cox proportional hazard model. Taken together, our results suggests that OLIG1 protein expression could be utilized as a novel prognostic factor, which could aid in deciding which NSCLC patients might benefit from more aggressive therapy. This is potentially of great significance, as the addition of postoperative adjuvant chemotherapy in T2N0 NSCLC patients is still controversial.
Christopher Plass and colleagues find thatOLIG1 expression correlates with survival in lung cancer patients and suggest that it could be used in deciding which patients are likely to benefit from more aggressive therapy.
Editors' Summary
Background.
Lung cancer is the commonest cause of cancer-related death worldwide. Most cases are of a type called non-small cell lung cancer (NSCLC). Like other cancers, treatment of NCSLC depends on the “TNM stage” at which the cancer is detected. Staging takes into account the size and local spread of the tumor (its T classification), whether nearby lymph nodes contain tumor cells (its N classification), and whether tumor cells have spread (metastasized) throughout the body (its M classification). Stage I tumors are confined to the lung and are removed surgically. Stage II tumors have spread to nearby lymph nodes and are treated with a combination of surgery and chemotherapy. Stage III tumors have spread throughout the chest, and stage IV tumors have metastasized around the body; patients with both of these stages are treated with chemotherapy alone. About 70% of patients with stage I or II lung cancer, but only 2% of patients with stage IV lung cancer, survive for five years after diagnosis.
Why Was This Study Done?
TNM staging is the best way to predict the likely outcome (prognosis) for patients with NSCLC, but survival times for patients with stage I and II tumors vary widely. Another prognostic marker—maybe a “molecular signature”—that could distinguish patients who are likely to respond to treatment from those whose cancer will inevitably progress would be very useful. Unlike normal cells, cancer cells divide uncontrollably and can move around the body. These behavioral changes are caused by alterations in the pattern of proteins expressed by the cells. But what causes these alterations? The answer in some cases is “epigenetic changes” or chemical modifications of genes. In cancer cells, methyl groups are aberrantly added to GC-rich gene regions. These so-called “CpG islands” lie near gene promoters (sequences that control the transcription of DNA into mRNA, the template for protein production), and their methylation stops the promoters working and silences the gene. In this study, the researchers have investigated whether aberrant methylation patterns vary between NSCLC subtypes and whether specific aberrant methylations are associated with survival and can, therefore, be used prognostically.
What Did the Researchers Do and Find?
The researchers used “restriction landmark genomic scanning” (RLGS) to catalog global aberrant DNA methylation patterns in human lung tumor samples. In RLGS, DNA is cut into fragments with a restriction enzyme (a protein that cuts at specific DNA sequences), end-labeled, and separated using two-dimensional gel electrophoresis to give a pattern of spots. Because methylation stops some restriction enzymes cutting their target sequence, normal lung tissue and lung tumor samples yield different patterns of spots. The researchers used these patterns to identify 47 DNA methylation targets (many in CpG islands) that together distinguished between adenocarcinomas and squamous cell carcinomas, two major types of NSCLCs. Next, they measured mRNA production from the genes with the greatest difference in methylation between adenocarcinomas and squamous cell carcinomas. OLIG1 (the gene that encodes a protein involved in nerve cell development) had one of the highest differences in mRNA production between these tumor types. Furthermore, three-quarters of NSCLCs had reduced or no expression of OLIG1 protein and, when the researchers analyzed the association between OLIG1 protein expression and overall survival in patients with NSCLC, reduced OLIG1 protein expression was associated with reduced survival.
What Do These Findings Mean?
These findings indicate that different types of NSCLC can be distinguished by examining their aberrant methylation patterns. This suggests that the establishment of different DNA methylation patterns might be related to the cell type from which the tumors developed. Alternatively, the different aberrant methylation patterns might reflect the different routes that these cells take to becoming tumor cells. This research identifies a potential new prognostic marker for NSCLC by showing that OLIG1 protein expression correlates with overall survival in patients with NSCLC. This correlation needs to be tested in a clinical setting to see if adding OLIG1 expression to the current prognostic parameters can lead to better treatment choices for early-stage lung cancer patients and ultimately improve these patients' overall survival.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040108.
Patient and professional information on lung cancer, including staging (in English and Spanish), is available from the US National Cancer Institute
The MedlinePlus encyclopedia has pages on non-small cell lung cancer (in English and Spanish)
Cancerbackup provides patient information on lung cancer
CancerQuest, provided by Emory University, has information about how cancer develops (in English, Spanish, Chinese and Russian)
Wikipedia pages on epigenetics (note that Wikipedia is a free online encyclopedia that anyone can edit)
The Epigenome Network of Excellence gives background information and the latest news about epigenetics (in several European languages)
doi:10.1371/journal.pmed.0040108
PMCID: PMC1831740  PMID: 17388669
8.  HPV Analysis in Distinguishing Second Primary Tumors from Lung Metastases in Patients with Head and Neck Squamous Cell Carcinoma 
For patients with head and neck squamous cell carcinoma (HNSqCC), the development of squamous cell carcinoma (SqCC) in the lung may signal a new primary or the onset of metastatic dissemination. Although the distinction influences prognosis and therapy, it may not be straightforward on histological or clinical grounds. Human papillomavirus (HPV) is an etiologic agent for SqCCs arising from the oropharynx, but not for SqCCs arising from other head and neck sites. For patients with HNSqCC who develop a lung SqCC, HPV analysis could be useful in establishing tumor relationships. High risk HPV in-situ hybridization was performed on 54 lung SqCCs from patients with a prior HNSqCC, and on 166 primary lung carcinomas from patients without prior HNSqCC. HPV was detected in 11 of 220 (5%) cases. All HPV-positive cases were from patients with a prior oropharyngeal SqCC. For the paired oropharyngeal and lung SqCCs, HPV status was concordant in 95% of cases. Time from treatment of the HPV-positive oropharyngeal carcinomas to detection of the lung carcinoma ranged from 1 to 97 months (mean 36 months). Two HPV-positive cancers were detected in the lung 8 years after treatment of the oropharyngeal primary. Despite the long interval, E6 sequencing analysis of one of these paired samples confirmed that the tumors harbored the same HPV-16 variant. HPV does not appear to play a role in the development of primary lung cancer. For patients with oropharyngeal SqCC who develop lung SqCCs, HPV analysis may be helpful in clarifying tumor relationships. These relationships may not be obvious on clinical grounds as HPV-related HNSqCC may metastasize long after treatment of the primary tumor.
doi:10.1097/PAS.0b013e3182395c7b
PMCID: PMC3273906  PMID: 22173119
Human papillomavirus; lung carcinoma; oropharyngeal squamous cell carcinoma
9.  Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma 
Cancer research  2013;73(16):5195-5205.
A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SqCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SqCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, which are each observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. Additionally, we report a patient with an FGFR2-mutated oral squamous cell carcinoma who responded to the multi-targeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SqCC.
doi:10.1158/0008-5472.CAN-12-3950
PMCID: PMC3749739  PMID: 23786770
Squamous cell lung cancer; Fibroblast growth factor receptors; tyrosine kinase inhibitors; lung cancer genomics
10.  Role of the extracellular matrix in variations of invasive pathways in lung cancers 
Among the most common features of highly invasive tumors, such as lung adenocarcinomas (AD) and squamous cell carcinomas (SqCC), is the massive degradation of the extracellular matrix. The remarkable qualitative and quantitative modifications of hyaluronidases (HAases), hyaluronan synthases (HAS), E-cadherin adhesion molecules, and the transforming growth factor β (TGF-β) may favor invasion, cellular motility, and proliferation. We examined HAase proteins (Hyal), HAS, E-cadherin, and TGF-β profiles in lung AD subtypes and SqCC obtained from smokers and non-smokers. Fifty-six patients, median age 64 years, who underwent lobectomy for AD (N = 31) and SqCC (N = 25) were included in the study. HAS-1, -2 and -3, and Hyal-1 and -3 were significantly more expressed by tumor cells than normal and stroma cells (P < 0.01). When stratified according to histologic types, HAS-3 and Hyal-1 immunoreactivity was significantly increased in tumor cells of AD (P = 0.01) and stroma of SqCC (P = 0.002), respectively. Tobacco history in patients with AD was significantly associated with increased HAS-3 immunoreactivity in tumor cells (P < 0.01). Stroma cells of SqCC from non-smokers presented a significant association with HAS-3 (P < 0.01). Hyal, HAS, E-cadherin, and TGF-β modulate a different tumor-induced invasive pathway in lung AD subgroups and SqCC. HAases in resected AD and SqCC were strongly related to the prognosis. Therefore, our findings suggest that strategies aimed at preventing high HAS-3 and Hyal-1 synthesis, or local responses to low TGF-β and E-cadherin, may have a greater impact in lung cancer prognosis.
doi:10.1590/1414-431X20122263
PMCID: PMC3854345  PMID: 23314337
Lung cancer; E-cadherin; TGF-β; HAS-1, HAS-2 and HAS-3; Hyal-1 and Hyal-3; Immunohistochemistry; Prognosis and morphometry
11.  Genomics of Squamous Cell Lung Cancer 
The Oncologist  2013;18(6):707-716.
Approximately 30% of patients with non-small cell lung cancer have the squamous cell carcinoma (SQCC) histological subtype. This review discusses key molecular aberrations reported by The Cancer Genome Atlas and other investigators and their potential therapeutic implications for patients with SQCC of lung.
Learning Objectives
Describe important molecular aberrations associated with squamous cell carcinoma.Identify molecular aberrations that may have therapeutic implications.
Approximately 30% of patients with non-small cell lung cancer have the squamous cell carcinoma (SQCC) histological subtype. Although targeted therapies have improved outcomes in patients with adenocarcinoma, no agents are currently approved specifically for use in SQCC. The Cancer Genome Atlas (TCGA) recently published the results of comprehensive genomic analyses of tumor samples from 178 patients with SQCC of the lung. In this review, we briefly discuss key molecular aberrations reported by TCGA and other investigators and their potential therapeutic implications. Carefully designed preclinical and clinical studies based on these large-scale genomic analyses are critical to improve the outcomes of patients with SQCC of lung in the near future.
doi:10.1634/theoncologist.2013-0063
PMCID: PMC4063398  PMID: 23728941
12.  Comprehensive genomic characterization of squamous cell lung cancers 
Nature  2012;489(7417):519-525.
Summary
Lung squamous cell carcinoma (lung SqCC) is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in lung SqCC have not been comprehensively characterized and no molecularly targeted agents have been developed specifically for its treatment. As part of The Cancer Genome Atlas (TCGA), we profiled 178 lung SqCCs to provide a comprehensive landscape of genomic and epigenomic alterations. Lung SqCC is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumor. We found statistically recurrent mutations in 18 genes in including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations were seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2/KEAP1 in 34%, squamous differentiation genes in 44%, PI3K/AKT in 47%, and CDKN2A/RB1 in 72% of tumors. We identified a potential therapeutic target in the majority of tumors, offering new avenues of investigation for lung SqCC treatment.
doi:10.1038/nature11404
PMCID: PMC3466113  PMID: 22960745
13.  Clarifying the spectrum of driver oncogene mutations in biomarker-verified squamous carcinoma of lung: lack of EGFR/KRAS and presence of PIK3CA/AKT1 mutations 
Purpose
There is persistent controversy as to whether EGFR/KRAS mutations occur in pulmonary squamous cell carcinoma (SQCC). We hypothesized that the reported variability may reflect difficulties in the pathologic distinction of true SQCC from adenosquamous carcinoma (AD-SQC) and poorly-differentiated adenocarcinoma (ADC) due to incomplete sampling or morphologic overlap. The recent development of a robust immunohistochemical approach for distinguishing squamous vs glandular differentiation provides an opportunity to reassess EGFR/KRAS and other targetable kinase mutation frequencies in a pathologically homogeneous series of SQCC.
Experimental Design
Ninety-five resected SQCC, verified by immunohistochemistry as ΔNp63+/TTF-1−, were tested for activating mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, AKT1, ERBB2/HER2, and MAP2K1/MEK1. Additionally, all tissue samples from rare patients with the diagnosis of EGFR/KRAS-mutant “SQCC” encountered during5 years of routine clinical genotyping were reassessed pathologically.
Results
The screen of 95biomarker-verified SQCC revealed no EGFR/KRAS (0%; 95%CI 0–3.8%), 4 PIK3CA (4%; 95% CI 1–10%) and 1 AKT1 (1%; 95% CI 0–5.7%) mutations. Detailed morphologic and immunohistochemical reevaluation of EGFR/KRAS-mutant SQCC” identified during clinical genotyping (n=16) resulted in reclassification of 10 (63%)cases as AD-SQC and 5 (31%) cases as poorly-differentiated ADC morphologically mimicking SQCC (i.e. ADC with “squamoid” morphology). One (6%) case had no follow-up.
Conclusions
Our findings suggest that EGFR/KRAS mutations do not occur in pure pulmonary SQCC, and occasional detection of these mutations in samples diagnosed as “SQCC” is due to challenges with the diagnosis of AD-SQC and ADC, which can be largely resolved by comprehensive pathologic assessment incorporating immunohistochemical biomarkers.
doi:10.1158/1078-0432.CCR-11-2109
PMCID: PMC3487403  PMID: 22228640
EGFR; KRAS; TTF-1; p63; squamous cell carcinoma
14.  Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer 
PLoS Medicine  2010;7(12):e1000378.
David Mangelsdorf and colleagues show that nuclear receptor expression is strongly associated with clinical outcomes of lung cancer patients, and this expression profile is a potential prognostic signature for lung cancer patient survival time, particularly for individuals with early stage disease.
Background
The identification of prognostic tumor biomarkers that also would have potential as therapeutic targets, particularly in patients with early stage disease, has been a long sought-after goal in the management and treatment of lung cancer. The nuclear receptor (NR) superfamily, which is composed of 48 transcription factors that govern complex physiologic and pathophysiologic processes, could represent a unique subset of these biomarkers. In fact, many members of this family are the targets of already identified selective receptor modulators, providing a direct link between individual tumor NR quantitation and selection of therapy. The goal of this study, which begins this overall strategy, was to investigate the association between mRNA expression of the NR superfamily and the clinical outcome for patients with lung cancer, and to test whether a tumor NR gene signature provided useful information (over available clinical data) for patients with lung cancer.
Methods and Findings
Using quantitative real-time PCR to study NR expression in 30 microdissected non-small-cell lung cancers (NSCLCs) and their pair-matched normal lung epithelium, we found great variability in NR expression among patients' tumor and non-involved lung epithelium, found a strong association between NR expression and clinical outcome, and identified an NR gene signature from both normal and tumor tissues that predicted patient survival time and disease recurrence. The NR signature derived from the initial 30 NSCLC samples was validated in two independent microarray datasets derived from 442 and 117 resected lung adenocarcinomas. The NR gene signature was also validated in 130 squamous cell carcinomas. The prognostic signature in tumors could be distilled to expression of two NRs, short heterodimer partner and progesterone receptor, as single gene predictors of NSCLC patient survival time, including for patients with stage I disease. Of equal interest, the studies of microdissected histologically normal epithelium and matched tumors identified expression in normal (but not tumor) epithelium of NGFIB3 and mineralocorticoid receptor as single gene predictors of good prognosis.
Conclusions
NR expression is strongly associated with clinical outcomes for patients with lung cancer, and this expression profile provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease. This study highlights the potential use of NRs as a rational set of therapeutically tractable genes as theragnostic biomarkers, and specifically identifies short heterodimer partner and progesterone receptor in tumors, and NGFIB3 and MR in non-neoplastic lung epithelium, for future detailed translational study in lung cancer.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lung cancer, the most common cause of cancer-related death, kills 1.3 million people annually. Most lung cancers are “non-small-cell lung cancers” (NSCLCs), and most are caused by smoking. Exposure to chemicals in smoke causes changes in the genes of the cells lining the lungs that allow the cells to grow uncontrollably and to move around the body. How NSCLC is treated and responds to treatment depends on its “stage.” Stage I tumors, which are small and confined to the lung, are removed surgically, although chemotherapy is also sometimes given. Stage II tumors have spread to nearby lymph nodes and are treated with surgery and chemotherapy, as are some stage III tumors. However, because cancer cells in stage III tumors can be present throughout the chest, surgery is not always possible. For such cases, and for stage IV NSCLC, where the tumor has spread around the body, patients are treated with chemotherapy alone. About 70% of patients with stage I and II NSCLC but only 2% of patients with stage IV NSCLC survive for five years after diagnosis; more than 50% of patients have stage IV NSCLC at diagnosis.
Why Was This Study Done?
Patient responses to treatment vary considerably. Oncologists (doctors who treat cancer) would like to know which patients have a good prognosis (are likely to do well) to help them individualize their treatment. Consequently, the search is on for “prognostic tumor biomarkers,” molecules made by cancer cells that can be used to predict likely clinical outcomes. Such biomarkers, which may also be potential therapeutic targets, can be identified by analyzing the overall pattern of gene expression in a panel of tumors using a technique called microarray analysis and looking for associations between the expression of sets of genes and clinical outcomes. In this study, the researchers take a more directed approach to identifying prognostic biomarkers by investigating the association between the expression of the genes encoding nuclear receptors (NRs) and clinical outcome in patients with lung cancer. The NR superfamily contains 48 transcription factors (proteins that control the expression of other genes) that respond to several hormones and to diet-derived fats. NRs control many biological processes and are targets for several successful drugs, including some used to treat cancer.
What Did the Researchers Do and Find?
The researchers analyzed the expression of NR mRNAs using “quantitative real-time PCR” in 30 microdissected NSCLCs and in matched normal lung tissue samples (mRNA is the blueprint for protein production). They then used an approach called standard classification and regression tree analysis to build a prognostic model for NSCLC based on the expression data. This model predicted both survival time and disease recurrence among the patients from whom the tumors had been taken. The researchers validated their prognostic model in two large independent lung adenocarcinoma microarray datasets and in a squamous cell carcinoma dataset (adenocarcinomas and squamous cell carcinomas are two major NSCLC subtypes). Finally, they explored the roles of specific NRs in the prediction model. This analysis revealed that the ability of the NR signature in tumors to predict outcomes was mainly due to the expression of two NRs—the short heterodimer partner (SHP) and the progesterone receptor (PR). Expression of either gene could be used as a single gene predictor of the survival time of patients, including those with stage I disease. Similarly, the expression of either nerve growth factor induced gene B3 (NGFIB3) or mineralocorticoid receptor (MR) in normal tissue was a single gene predictor of a good prognosis.
What Do These Findings Mean?
These findings indicate that the expression of NR mRNA is strongly associated with clinical outcomes in patients with NSCLC. Furthermore, they identify a prognostic NR expression signature that provides information on the survival time of patients, including those with early stage disease. The signature needs to be confirmed in more patients before it can be used clinically, and researchers would like to establish whether changes in mRNA expression are reflected in changes in protein expression if NRs are to be targeted therapeutically. Nevertheless, these findings highlight the potential use of NRs as prognostic tumor biomarkers. Furthermore, they identify SHP and PR in tumors and two NRs in normal lung tissue as molecules that might provide new targets for the treatment of lung cancer and new insights into the early diagnosis, pathogenesis, and chemoprevention of lung cancer.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000378.
The Nuclear Receptor Signaling Atlas (NURSA) is consortium of scientists sponsored by the US National Institutes of Health that provides scientific reagents, datasets, and educational material on nuclear receptors and their co-regulators to the scientific community through a Web-based portal
The Cancer Prevention and Research Institute of Texas (CPRIT) provides information and resources to anyone interested in the prevention and treatment of lung and other cancers
The US National Cancer Institute provides detailed information for patients and professionals about all aspects of lung cancer, including information on non-small-cell carcinoma and on tumor markers (in English and Spanish)
Cancer Research UK also provides information about lung cancer and information on how cancer starts
MedlinePlus has links to other resources about lung cancer (in English and Spanish)
Wikipedia has a page on nuclear receptors (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1000378
PMCID: PMC3001894  PMID: 21179495
15.  Differential expression of the TFIIIB subunits Brf1 and Brf2 in cancer cells 
Background
RNA polymerase (pol) III transcription is specifically elevated in a variety of cancers and is a target of regulation by a variety of tumor suppressors and oncogenes. Accurate initiation by RNA pol III is dependent on TFIIIB. In higher eukaryotes, two forms of TFIIIB have been characterized. TFIIIB required for proper initiation from gene internal RNA pol III promoters is comprised of TBP, Bdp1, and Brf1. Proper initiation from gene external RNA pol III promoters requires TBP, Bdp1, and Brf2. We hypothesized that deregulation of RNA polymerase III transcription in cancer may be a consequence of altered TFIIIB expression
Results
Here, we report: (1) the TFIIIB subunits Brf1 and Brf2 are differentially expressed in a variety of cancer cell lines: (2) the Brf1 and Brf2 promoters differ in activity in cancer cell lines, and (3) VAI transcription is universally elevated, as compared to U6, in breast, prostate and cervical cancer cells.
Conclusion
Deregulation of TFIIIB-mediated transcription may be an important step in tumor development. We demonstrate that Brf1 and Brf2 mRNA are differentially expressed in a variety of cancer cells and that the Brf2 promoter is more active than the Brf1 promoter in all cell lines tested. We also demonstrate, that Brf1-dependent VAI transcription was significantly higher than the Brf2-dependent U6 snRNA transcription in all cancer cell lines tested. The data presented suggest that Brf2 protein expression levels correlate with U6 promoter activity in the breast, cervical and prostate cell lines tested. Interestingly, the Brf1 protein levels did not vary considerably in HeLa, MCF-7 and DU-145 cells, yet Brf1 mRNA expression varied considerably in breast, prostate and cervical cancer cell lines tested. Thus, Brf1 promoter activity and Brf1 protein expression levels did not correlate well with Brf1-dependent transcription levels. Taken together, we reason that deregulation of Brf1 and Brf2 expression could be a key mechanism responsible for the observed deregulation of RNA pol III transcription in cancer cells.
doi:10.1186/1471-2199-9-74
PMCID: PMC2533013  PMID: 18700021
16.  Immunohistochemical demonstration of alteration of β-catenin during tumor metastasis by different mechanisms according to histology in lung cancer 
The protein β-catenin exhibits a dual function in cells, by acting as a major structural component of cell-cell adherens junctions and as a central signaling molecule in the Wnt signaling pathway. However, how the regulation of β-catenin expression during tumor metastasis in non-small cell lung cancer (NSCLC) varies according to histological type remains unclear. To investigate the regulatory mechanism of β-catenin on tumor metastasis, the present study compared the expression of Wnt1, β-catenin and E-cadherin in 41 primary NSCLC tumors and their corresponding metastatic lesions by immunohistochemistry. Altered expression of β-catenin was more frequent in the metastatic tumors (34/41, 82.9%) than in the corresponding primary tumors (24/41, 58.5%; P<0.05). There were 12 cases [nine of adenocarcinoma (ADC) and three of squamous cell carcinoma (SqCC)] that revealed discordant β-catenin expression between the primary tumors and the corresponding metastatic lesions. Of these, 11 cases (11/12, 91.7%; nine ADCs and two SqCCs) demonstrated acquired β-catenin alterations in the metastatic lesions. Subgroup analysis of these nine ADCs revealed that six cases (6/9, 66.7%) were accompanied by E-cadherin loss but no Wnt1 overexpression. Subgroup analysis of the three SqCCs revealed discordant β-catenin expression. Two cases (2/3, 66.7%) demonstrated acquired β-catenin expression during metastatic progression with Wnt1 overexpression but no change in E-cadherin expression. One case of SqCC revealed normal β-catenin expression in the metastasis although the expression was aberrant in the primary tumor. The results of the present study revealed that the changes in β-catenin expression occurred during tumor metastasis by different mechanisms, depending on histological type. The alterations in β-catenin expression may be regulated by a cadherin-catenin system in ADCs with reduced membranous expression of E-cadherin, but mediated by Wnt1 overexpression in SqCCs with cytoplasmic or nuclear transition types.
doi:10.3892/etm.2014.2095
PMCID: PMC4280991  PMID: 25574191
β-catenin; wnt1; E-cadherin; lung cancer
17.  Arsenic-related DNA copy-number alterations in lung squamous cell carcinomas 
British Journal of Cancer  2010;103(8):1277-1283.
Background:
Lung squamous cell carcinomas (SqCCs) occur at higher rates following arsenic exposure. Somatic DNA copy-number alterations (CNAs) are understood to be critical drivers in several tumour types. We have assembled a rare panel of lung tumours from a population with chronic arsenic exposure, including SqCC tumours from patients with no smoking history.
Methods:
Fifty-two lung SqCCs were analysed by whole-genome tiling-set array comparative genomic hybridisation. Twenty-two were derived from arsenic-exposed patients from Northern Chile (10 never smokers and 12 smokers). Thirty additional cases were obtained for comparison from North American smokers without arsenic exposure. Twenty-two blood samples from healthy individuals from Northern Chile were examined to identify germline DNA copy-number variations (CNVs) that could be excluded from analysis.
Results:
We identified multiple CNAs associated with arsenic exposure. These alterations were not attributable to either smoking status or CNVs. DNA losses at chromosomes 1q21.1, 7p22.3, 9q12, and 19q13.31 represented the most recurrent events. An arsenic-associated gain at 19q13.33 contains genes previously identified as oncogene candidates.
Conclusions:
Our results provide a comprehensive approach to molecular characteristics of the arsenic-exposed lung cancer genome and the non-smoking lung SqCC genome. The distinct and recurrent arsenic-related alterations suggest that this group of tumours may be considered as a separate disease subclass.
doi:10.1038/sj.bjc.6605879
PMCID: PMC2967055  PMID: 20842114
arsenic; lung squamous cell carcinoma; never smokers; copy-number alterations; copy-number variation; CGH
18.  Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors for Chinese patients with squamous cell carcinoma of lung harboring EGFR mutation 
Journal of Thoracic Disease  2013;5(5):585-592.
Objective
Epidermal growth factor receptor (EGFR) mutation mostly occurred in lung adenocarcinoma, rarely in squamous cell carcinoma (SQCC). EGFR mutation rate in SQCC varied in previous reports, and the efficacy of EGFR tyrosine kinase inhibitors (TKIs) in SQCC harboring EGFR mutation has not yet been fully evaluated. The aim of this study was to investigate the efficacy EGFR-TKIs for Chinese patients with SQCC of lung harboring EGFR mutation.
Patients and methods
Two cohorts of patients were analyzed. The first cohort included 146 consecutive post-operation SQCC patients from January 2008 to October 2012. The second cohort included 63 patients with advanced SQCC receiving EGFR-TKIs treatment. EGFR mutation analysis was performed with Real-time PCR method. The pathologic diagnosis was validated with immunohistochemistry (IHC) for patients harboring activated EGFR mutation. And the efficacy of EGFR-TKIs in squamous cell carcinoma of lung (SQCC) was evaluated in patients with activated EGFR mutations.
Results
In the first cohort, 146 resected patients, EGFR mutations were detected in 3 patients, with the mutation rate of 2.0%. In cohort two, 63 patients treated with EGFR-TKIs, 15 patients possessed activated EGFR mutations. The response rate and disease control rate in these patients was 26.7% and 66.7% respectively. 5 patients had disease control over 6 months. The progression free survival (PFS) in EGFR-mutated patients was 3.9 months.
Conclusions
In Chinese SQCC patients, EGFR mutation rate was extremely low. EGFR-TKIs seemed to be less effective in EGFR-mutated SQCC patients, but some patients could still obtain benefit from EGFR-TKIs. To identify this part of patients, further study was warranted in the future.
doi:10.3978/j.issn.2072-1439.2013.09.15
PMCID: PMC3815724  PMID: 24255770
Squamous cell carcinoma of lung (SQCC); immunohistochemistry (IHC); epidermal growth factor receptor mutation (EGFR mutation); epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs)
19.  Low levels of p27 in association with deregulated p53-pRb protein status enhance tumor proliferation and chromosomal instability in non-small cell lung carcinomas. 
Molecular Medicine  2001;7(6):418-429.
BACKGROUND: Down-regulation or overexpression of the cyclin-dependent kinase inhibitor p27 have been observed in a range of malignancies, including lung cancer. To further elucidate the role of the molecule in tumor growth regulation, we evaluated p27 expression in a series of non-small cell lung carcinomas (NSCLCs), and examined its relation with histology, kinetic parameters, ploidy, and overall survival. We extended our investigation into the association of p27 levels with the presence of Ki-ras mutations, as well as with the expression status of p53 and pRb in tumor cells. MATERIAL AND METHODS: p27, p53, and pRb status were immunohistochemically evaluated in a total of 69 NSCLCs. In situ assays were employed to assess the kinetic parameters (Ki-67 immunohistochemistry for proliferation index, Tdt-mediated dUTP nick end labeling assay for apoptotic index). The ploidy status of the tumors was assessed after staining nuclei with the Feulgen procedure, and the presence of Ki-ras mutations was examined by restriction fragment length polymorphisms. All possible associations were assessed with a series of statistical methods. RESULTS: Immunoreactivity for p27 was observed in the entire series of specimens, with the mean percentage of positive cells being 33%. Adenocarcinomas (AdCs) exhibited higher p27 levels compared to squamous cell carcinomas (SqCCs) (p < 0.01). An inverse correlation was established between p27 expression and proliferation index (PI) (r = -0.834, p < 0.01) but not with apoptotic index (AI), whereas aneuploid tumors were characterized by lower p27 levels than diploid ones (p < 0.01). No difference in p27 immunostaining was observed with regard to the presence of Ki-ras mutations, whereas aberrant p53 and/or pRb expression patterns were associated with p27 underexpression (p < 0.01 for p53 status, p < 0.05 regarding pRb levels, and p < 0.01 for a combined deregulation of both proteins). Two or more alterations in the p27/p53/pRb protein network (i.e., p27 levels lower than the estimated mean value, overexpressed p53, and/or aberrant pRb) were associated with increased PI and aneuploidy (p < 0.001 and p < 0.01, respectively). A powerful trend was found between p27 expression and overall survival (p = 0.066). CONCLUSIONS: Our findings confirm the heterogeneity between AdCs and SqCCs, and are suggestive of an increased proliferative activity in NSCLCs underexpressing p27. Furthermore, our analysis supports the concept of p27 forming a functionally compact network with p53 and pRb, which is actively involved in the regulation of cellular proliferation and chromosomal stability.
PMCID: PMC1950049  PMID: 11474135
20.  Impact of Histopathological Diagnosis with Ancillary Immunohistochemical Studies on Lung Cancer Subtypes Incidence and Survival: A Population-Based Study 
Journal of Cancer Epidemiology  2011;2011:275758.
Purpose. The aim of this study was to assess the impact of immunohistochemical- (IHC-) studies on incidence and survival of lung cancer histotypes. Patients and Methods. Lung cancers occurred in southern Switzerland between 1996 and 2010 were selected by the Ticino Cancer Registry and categorised into adenocarcinoma (AC), squamous-cell-carcinoma (SqCC), small-cell-carcinoma (SmCC), and large-cell carcinoma/non-small-cell lung cancer (LCC/NSCLC). Incidence rates, annual-percentage-change (APC), and two-year overall survival (OS) (follow-up: 31.12.2010) were performed. Results. 2467 cases were selected: 997 (40.4%) AC; 522 (21.2%) LCC/NSCLC, 378 (15.3%) SmCC, and 570 (23.1%) SqCC. Trend-analysis showed significant increase in AC (APC: 4.6; 95% CI: 3.1; 6.0) and decrease of LCC/NSCLC, with significant joinpoint in 2003 (APC: −14.7; 95% CI: −21.6; −7.1). Improved OS and decreased OS were detected in SqCC and LCC/NSCLC, respectively. Conclusions. This study highlights that diagnosis with ancillary immunohistochemical studies will change incidence and survival of precisely defined lung cancer subtypes. It calls attention to the need for cautious interpretation of studies and clinical trials, where the diagnosis was based on histology unaccompanied by IHC studies, and to the need of standardised diagnostic procedures.
doi:10.1155/2011/275758
PMCID: PMC3255178  PMID: 22253626
21.  Targeted therapy for squamous cell lung cancer 
Lung cancer management  2012;1(4):293-300.
SUMMARY
Lung squamous cell carcinoma (SqCC) is the second most common subtype of non-small-cell lung cancer and leads to 40,000–50,000 deaths per year in the USA. Management of non-small-cell lung cancer has dramatically changed over the past decade with the introduction of targeted therapeutic agents for genotypically selected individuals with lung adenocarcinoma. These agents lead to improved outcomes, and it has now become the standard of care to perform routine molecular genotyping of lung adenocarcinomas. By contrast, progress in lung SqCC has been modest, and there has yet to be a successful demonstration of targeted therapy in this disease. Here, we review exciting work from ongoing genomic characterization and biomarker validation efforts that have nominated several likely therapeutic targets in lung SqCCs. These studies suggest that targeted therapies are likely to be successful in the treatment of lung SqCCs and should be further explored in both preclinical models and in clinical trials.
doi:10.2217/lmt.12.40
PMCID: PMC3744181  PMID: 23956794
22.  EGFR-Targeted Therapy for Non-Small Cell Lung Cancer: Focus on EGFR Oncogenic Mutation 
The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR molecular testing, as well as for testing of other oncogenes such as EML4-ALK and KRAS. Actually, the value of EGFR expressed in patients with NSCLC in predicting a benefit in terms of survival from treatment with an epidermal growth factor receptor targeted therapy is still in debate, while there is a convincing evidence on the predictive role of the EGFR mutational status with regard to the response to tyrosine kinase inhibitors (TKIs).
This is a literature overview on the state-of-the-art of EGFR oncogenic mutation in NSCLC. It is designed to highlight the preclinical rationale driving the molecular footprint assessment, the progressive development of a specific pharmacological treatment and the best method to identify those NSCLC who would most likely benefit from treatment with EGFR-targeted therapy. This is supported by the belief that a rationale for the prioritization of specific regimens based on patient-tailored therapy could be closer than commonly expected.
doi:10.7150/ijms.4609
PMCID: PMC3575628  PMID: 23423768
EGFR targeted therapy; NSCLC; advanced; mutation; TKIs; resistance.
23.  Cigarette smoking and lung cancer – relative risk estimates for the major histological types from a pooled analysis of case-control studies 
Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. Using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age-adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% CI 74.8-143.2) for SqCC, 111.3 (95% CI 69.8-177.5) for SCLC, and 21.9 (95% CI 16.6-29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI 31.5-124.6), 108.6 (95% CI 50.7-232.8), and 16.8 (95% CI 9.2-30.6), respectively. Whereas ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.
doi:10.1002/ijc.27339
PMCID: PMC3296911  PMID: 22052329
cigarette smoking; lung cancer; relative risk characterization; tobacco smoke; stem cells
24.  Increased SOX2 Gene Copy Number Is Associated with FGFR1 and PIK3CA Gene Gain in Non-Small Cell Lung Cancer and Predicts Improved Survival in Early Stage Disease 
PLoS ONE  2014;9(4):e95303.
Background
We aimed to investigate prevalence and prognostic role of SOX2, PIK3CA, FGFR1 and BRF2 gene gain in patients with surgically resected non-small cell lung cancer (NSCLC).
Methods
SOX2, PIK3CA, FGFR1 and BRF2 gene copy number was assessed by fluorescence in situ hybridization (FISH) in arrayed tissue cores from 447 resected NSCLCs.
Results
Increased gene copy number (FISH+) for SOX2, PIK3CA, FGFR1 and BRF2 was observed in 23.6%, 29.2%, 16.6% and 14.9% of cases, respectively. FISH+ status for each gene was significantly associated with smoking history, squamous cell carcinoma (SCC) histology, and increased copy number of the other studied genes. Multivariate analysis of overall survival indicated increased SOX2 gene copy number (P = 0.008), stage I-II (P<0.001), and adenocarcinoma or SCC histology (P = 0.016) as independent, favorable prognostic factors. A statistically significant interaction was observed between stage and SOX2 gene status (P = 0.021), indicating that the prognostic impact of SOX2 gene gain differs across stages and is limited to patients with stage I-II disease (HR 0.44, 95% CI: 0.25–0.77; P = 0.004, adjusted for histology).
Conclusions
Increased SOX2 gene copy number is an independent and favorable prognostic factor in surgically resected, early stage NSCLC, regardless of histology. SOX2, PIK3CA, FGFR1 and BRF2 gene gains are likely to occur concurrently, with potentially relevant implications for the development of new therapeutic strategies.
doi:10.1371/journal.pone.0095303
PMCID: PMC3988173  PMID: 24736592
25.  Tumor budding is a significant indicator of a poor prognosis in lung squamous cell carcinoma patients 
Molecular Medicine Reports  2012;6(5):937-943.
Lung cancer is a leading cause of cancer mortality worldwide and patients occasionally develop local recurrence or distant metastasis soon after curative resection. Reports of new therapeutic strategies for lung squamous cell carcinoma (SqCC) are extremely rare, while selective anticancer therapy has been reported for lung adenocarcinoma. The aim of this study was to identify clinicopathological prognostic factors for SqCC. We analyzed tumor budding and infiltrative patterns (INF) in 103 cases of surgically-resected SqCC. Tumor infiltrative patterns were classified into three groups (INFa, b and c) and INFc was infiltrative growth at the tumor invasive front. The cases with an INFc component [INFc(+)]were significantly associated with venous invasion (P=0.014) and the scirrhous stromal type (P<0.001). The overall survival rate of patients with INFc(+) was significantly lower than that of patients without the INFc component [INFc(−); P=0.003]. Tumor budding was defined as a single cancer cell or a small nest of up to four cancer cells within stromal tissue. The cases with tumor budding [Bud(+)] were significantly associated with lymph node metastasis (P=0.001), lymphatic invasion (P=0.002), INFc(+) (P<0.001) and the scirrhous stromal type (P=0.014). Patients with the Bud(+) type had a lower overall survival rate than patients with the Bud(−) type (P<0.001). Multivariate analysis demonstrated that tumor budding [hazard ratio (HR), 2.766; 95% confidence interval (CI), 1.497–5.109] and lymph node metastasis (HR, 1.937; 95% CI, 1.097–3.419) were independent predictors of mortality. In conclusion, tumor budding is a significant indicator of a high malignant potential and poor prognosis in SqCC of the lung.
doi:10.3892/mmr.2012.1048
PMCID: PMC3493086  PMID: 22940760
lung cancer; squamous cell carcinoma; patient prognosis; tumor budding

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