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1.  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
2.  Lung Cancer Occurrence in Never-Smokers: An Analysis of 13 Cohorts and 22 Cancer Registry Studies  
PLoS Medicine  2008;5(9):e185.
Background
Better information on lung cancer occurrence in lifelong nonsmokers is needed to understand gender and racial disparities and to examine how factors other than active smoking influence risk in different time periods and geographic regions.
Methods and Findings
We pooled information on lung cancer incidence and/or death rates among self-reported never-smokers from 13 large cohort studies, representing over 630,000 and 1.8 million persons for incidence and mortality, respectively. We also abstracted population-based data for women from 22 cancer registries and ten countries in time periods and geographic regions where few women smoked. Our main findings were: (1) Men had higher death rates from lung cancer than women in all age and racial groups studied; (2) male and female incidence rates were similar when standardized across all ages 40+ y, albeit with some variation by age; (3) African Americans and Asians living in Korea and Japan (but not in the US) had higher death rates from lung cancer than individuals of European descent; (4) no temporal trends were seen when comparing incidence and death rates among US women age 40–69 y during the 1930s to contemporary populations where few women smoke, or in temporal comparisons of never-smokers in two large American Cancer Society cohorts from 1959 to 2004; and (5) lung cancer incidence rates were higher and more variable among women in East Asia than in other geographic areas with low female smoking.
Conclusions
These comprehensive analyses support claims that the death rate from lung cancer among never-smokers is higher in men than in women, and in African Americans and Asians residing in Asia than in individuals of European descent, but contradict assertions that risk is increasing or that women have a higher incidence rate than men. Further research is needed on the high and variable lung cancer rates among women in Pacific Rim countries.
Michael Thun and colleagues pooled and analyzed comprehensive data on lung cancer incidence and death rates among never-smokers to examine what factors other than active smoking affect lung cancer risk.
Editors' Summary
Background.
Every year, more than 1.4 million people die from lung cancer, a leading cause of cancer deaths worldwide. In the US alone, more than 161,000 people will die from lung cancer this year. Like all cancers, lung cancer occurs when cells begin to divide uncontrollably because of changes in their genes. The main trigger for these changes in lung cancer is exposure to the chemicals in cigarette smoke—either directly through smoking cigarettes or indirectly through exposure to secondhand smoke. Eighty-five to 90% of lung cancer deaths are caused by exposure to cigarette smoke and, on average, current smokers are 15 times more likely to die from lung cancer than lifelong nonsmokers (never smokers). Furthermore, a person's cumulative lifetime risk of developing lung cancer is related to how much they smoke, to how many years they are a smoker, and—if they give up smoking—to the age at which they stop smoking.
Why Was This Study Done?
Because lung cancer is so common, even the small fraction of lung cancer that occurs in lifelong nonsmokers represents a large number of people. For example, about 20,000 of this year's US lung cancer deaths will be in never-smokers. However, very little is known about how age, sex, or race affects the incidence (the annual number of new cases of diseases in a population) or death rates from lung cancer among never-smokers. A better understanding of the patterns of lung cancer incidence and death rates among never-smokers could provide useful information about the factors other than cigarette smoke that increase the likelihood of not only never-smokers, but also former smokers and current smokers developing lung cancer. In this study, therefore, the researchers pooled and analyzed a large amount of information about lung cancer incidence and death rates among never smokers to examine what factors other than active smoking affect lung cancer risk.
What Did the Researchers Do and Find?
The researchers analyzed information on lung cancer incidence and/or death rates among nearly 2.5 million self-reported never smokers (men and women) from 13 large studies investigating the health of people in North America, Europe, and Asia. They also analyzed similar information for women taken from cancer registries in ten countries at times when very few women were smokers (for example, the US in the late 1930s). The researchers' detailed statistical analyses reveal, for example, that lung cancer death rates in African Americans and in Asians living in Korea and Japan (but not among Asians living in the US) are higher than those in people of the European continental ancestry group. They also show that men have higher death rates from lung cancer than women irrespective of racial group, but that women aged 40–59 years have a slightly higher incidence of lung cancer than men of a similar age. This difference disappears at older ages. Finally, an analysis of lung cancer incidence and death rates at different times during the past 70 years shows no evidence of an increase in the lung cancer burden among never smokers over time.
What Do These Findings Mean?
Although some of the findings described above have been hinted at in previous, smaller studies, these and other findings provide a much more accurate picture of lung cancer incidence and death rates among never smokers. Most importantly the underlying data used in these analyses are now freely available and should provide an excellent resource for future studies of lung cancer in never smokers.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050185.
The US National Cancer Institute provides detailed information for patients and health professionals about all aspects of lung cancer and information on smoking and cancer (in English and Spanish)
Links to other US-based resources dealing with lung cancer are provided by MedlinePlus (in English and Spanish)
Cancer Research UK provides key facts about the link between lung cancer and smoking and information about all other aspects of lung cancer
doi:10.1371/journal.pmed.0050185
PMCID: PMC2531137  PMID: 18788891
3.  LUNG CANCER IN NEVER SMOKERS: MOLECULAR PROFILES AND THERAPEUTIC IMPLICATIONS 
The majority of lung cancers are caused by long term exposure to the several classes of carcinogens present in tobacco smoke. While a significant fraction of lung cancers in never smokers may also be attributable to tobacco, many such cancers arise in the absence of detectable tobacco exposure, and may follow a very different cellular and molecular pathway of malignant transformation. Recent studies summarized here suggest that lung cancers arising in never smokers have a distinct natural history, profile of oncogenic mutations, and response to targeted therapy. The majority of molecular analyses of lung cancer have focused on genetic profiling of pathways responsible for metabolism of primary tobacco carcinogens. Limited research has been conducted evaluating familial aggregation and genetic linkage of lung cancer, particularly among never smokers in whom such associations might be expected to be strongest. Data emerging over the past several years demonstrates that lung cancers in never smokers are much more likely to carry activating mutations of the Epidermal Growth Factor Receptor (EGFR), a key oncogenic factor and direct therapeutic target of several newer anti-cancer drugs. EGFR mutant lung cancers may represent a distinct class of lung cancers, enriched in the never smoking population, and less clearly linked to direct tobacco carcinogenesis. These insights followed initial testing and demonstration of efficacy of EGFR-targeted drugs. Focused analysis of molecular carcinogenesis in lung cancers in never smokers is needed, and may provide additional biologic insight with therapeutic implications for lung cancers in both ever smokers and never smokers.
doi:10.1158/1078-0432.CCR-09-0377
PMCID: PMC2950319  PMID: 19755392
4.  Integrative Genomic Analyses Identify BRF2 as a Novel Lineage-Specific Oncogene in Lung Squamous Cell Carcinoma 
PLoS Medicine  2010;7(7):e1000315.
William Lockwood and colleagues show that the focal amplification of a gene, BRF2, on Chromosome 8p12 plays a key role in squamous cell carcinoma of the lung.
Background
Traditionally, non-small cell lung cancer is treated as a single disease entity in terms of systemic therapy. Emerging evidence suggests the major subtypes—adenocarcinoma (AC) and squamous cell carcinoma (SqCC)—respond differently to therapy. Identification of the molecular differences between these tumor types will have a significant impact in designing novel therapies that can improve the treatment outcome.
Methods and Findings
We used an integrative genomics approach, combing high-resolution comparative genomic hybridization and gene expression microarray profiles, to compare AC and SqCC tumors in order to uncover alterations at the DNA level, with corresponding gene transcription changes, which are selected for during development of lung cancer subtypes. Through the analysis of multiple independent cohorts of clinical tumor samples (>330), normal lung tissues and bronchial epithelial cells obtained by bronchial brushing in smokers without lung cancer, we identified the overexpression of BRF2, a gene on Chromosome 8p12, which is specific for development of SqCC of lung. Genetic activation of BRF2, which encodes a RNA polymerase III (Pol III) transcription initiation factor, was found to be associated with increased expression of small nuclear RNAs (snRNAs) that are involved in processes essential for cell growth, such as RNA splicing. Ectopic expression of BRF2 in human bronchial epithelial cells induced a transformed phenotype and demonstrates downstream oncogenic effects, whereas RNA interference (RNAi)-mediated knockdown suppressed growth and colony formation of SqCC cells overexpressing BRF2, but not AC cells. Frequent activation of BRF2 in >35% preinvasive bronchial carcinoma in situ, as well as in dysplastic lesions, provides evidence that BRF2 expression is an early event in cancer development of this cell lineage.
Conclusions
This is the first study, to our knowledge, to show that the focal amplification of a gene in Chromosome 8p12, plays a key role in squamous cell lineage specificity of the disease. Our data suggest that genetic activation of BRF2 represents a unique mechanism of SqCC lung tumorigenesis through the increase of Pol III-mediated transcription. It can serve as a marker for lung SqCC and may provide a novel target for therapy.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lung cancer is the commonest cause of cancer-related death. Every year, 1.3 million people die from this disease, which is mainly caused by smoking. Most cases of lung cancer are “non-small cell lung cancers” (NSCLCs). Like all cancers, NSCLC starts when cells begin to divide uncontrollably and to move round the body (metastasize) because of changes (mutations) in their genes. These mutations are often in “oncogenes,” genes that, when activated, encourage cell division. Oncogenes can be activated by mutations that alter the properties of the proteins they encode or by mutations that increase the amount of protein made from them, such as gene amplification (an increase in the number of copies of a gene). If NSCLC is diagnosed before it has spread from the lungs (stage I disease), it can be surgically removed and many patients with stage I NSCLC survive for more than 5 years after their diagnosis. Unfortunately, in more than half of patients, NSCLC has metastasized before it is diagnosed. This stage IV NSCLC can be treated with chemotherapy (toxic chemicals that kill fast-growing cancer cells) but only 2% of patients with stage IV lung cancer are alive 5 years after diagnosis.
Why Was This Study Done?
Traditionally, NSCLC has been regarded as a single disease in terms of treatment. However, emerging evidence suggests that the two major subtypes of NSCLC—adenocarcinoma and squamous cell carcinoma (SqCC)—respond differently to chemotherapy. Adenocarcinoma and SqCC start in different types of lung cell and experts think that for each cell type in the body, specific combinations of mutations interact with the cell type's own unique characteristics to provide the growth and survival advantage needed for cancer development. If this is true, then identifying the molecular differences between adenocarcinoma and SqCC could provide targets for more effective therapies for these major subtypes of NSCLC. Amplification of a chromosome region called 8p12 is very common in NSCLC, which suggests that an oncogene that drives lung cancer development is present in this chromosome region. In this study, the researchers investigate this possibility by looking for an amplified gene in the 8p12 chromosome region that makes increased amounts of protein in lung SqCC but not in lung adenocarcinoma.
What Did the Researchers Do and Find?
The researchers used a technique called comparative genomic hybridization to show that focal regions of Chromosome 8p are amplified in about 40% of lung SqCCs, but that DNA loss in this region is the most common alteration in lung adenocarcinomas. Ten genes in the 8p12 chromosome region were expressed at higher levels in the SqCC samples that they examined than in adenocarcinoma samples, they report, and overexpression of five of these genes correlated with amplification of the 8p12 region in the SqCC samples. Only one of the genes—BRF2—was more highly expressed in squamous carcinoma cells than in normal bronchial epithelial cells (the cell type that lines the tubes that take air into the lungs and from which SqCC develops). Artificially induced expression of BRF2 in bronchial epithelial cells made these normal cells behave like tumor cells, whereas reduction of BRF2 expression in squamous carcinoma cells made them behave more like normal bronchial epithelial cells. Finally, BRF2 was frequently activated in two early stages of squamous cell carcinoma—bronchial carcinoma in situ and dysplastic lesions.
What Do These Findings Mean?
Together, these findings show that the focal amplification of chromosome region 8p12 plays a role in the development of lung SqCC but not in the development of lung adenocarcinoma, the other major subtype of NSCLC. These findings identify BRF2 (which encodes a RNA polymerase III transcription initiation factor, a protein that is required for the synthesis of RNA molecules that help to control cell growth) as a lung SqCC-specific oncogene and uncover a unique mechanism for lung SqCC development. Most importantly, these findings suggest that genetic activation of BRF2 could be used as a marker for lung SqCC, which might facilitate the early detection of this type of NSCLC and that BRF2 might provide a new target for therapy.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000315.
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 (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)
doi:10.1371/journal.pmed.1000315
PMCID: PMC2910599  PMID: 20668658
5.  Quantified smoking status and non-small cell lung cancer stage at presentation: analysis of a North Indian cohort and a systematic review of literature 
Journal of Thoracic Disease  2012;4(5):474-484.
Background: There are variable observations in published literature regarding smoking status and stage of lung cancer (LC) with positive, negative and no associations being reported. In particular, data regarding the association of quantified smoking status (QSS) with non-small cell lung cancer (NSCLC) stage at the time of diagnosis is limited. In India, bidi - the hand rolled form of tobacco wrapped in the dried tendu leaf - is the most common smoking product. The current study was conducted to assess stage differences, if any, based upon QSS, among newly diagnosed LC patients.
Methods
A systematic review of English literature was performed for previous publications that had assessed NSCLC stage differences in relation to QSS. Collected data on demographic and disease characteristics of 654 LC patients presenting to the authors’ institute was also analyzed. Smoking index (SI) was used for QSS and was defined as number of bidis and cigarettes smoked per day multiplied by years smoked. Patients were categorized as never-smokers [Group I, n=151]; light/moderate smokers (SI=1-300) [Group II, n=202] and heavy smokers (SI ≥301) [Group III, n=301]. Multivariate logistic regression analysis (LRA) was performed to derive adjusted odds ratios (ORs) and 95% confidence intervals (CIs).
Results
Among the 520 NSCLC patients, mean [standard deviation (SD)] age in groups I, II and III was 54.5 (12.5), 58.6 (9.9) and 61.2 (9.4) years respectively (P<0.001). Percentage of males in the three groups was 48.1%, 88.0%, and 97.9% (P<0.001). Age and gender differences between groups I, II and III were also significant among 134 small cell lung cancer patients with mean (SD) ages of 44.0 (10.6), 55.7 (10.3) and 58.9 (9.3) years (P<0.001) and percentage of males being 50.0%, 90.4% and 95.5% respectively (P<0.001). Among NSCLC patients, distribution in groups I, II and III respectively of squamous (28.1%, 50.0% and 57.9%) and non-squamous histologies (59.3%, 37.3% and 27.2%) differed significantly (P<0.001). Stage distribution observed for NSCLC patients in groups I, II and III respectively was as follows: stages I-IIIA (8.1%, 19.3 and 18.7%), stage IIIB (24.4%, 34.7% and 42.1%) and stage IV (67.4%, 46.0% and 39.1%). The difference was statistically significant (P<0.001). Differences remained significant (P<0.001) for presence of extrathoracic disease [ETD] (41.5%, 28.0% and 16.6%). On multivariate LRA, SI ≥301 was the only variable that was independently associated with both advanced stage (IIIB-IV) [OR=0.25 (95% CI=0.11-0.61)] and ETD [OR=0.29 (95% CI=0.16-0.53)] at presentation.
Conclusions
Among newly diagnosed NSCLC patients in North India, significant differences exist, based upon SI, for disease stage. Heavy smoking was independently associated with lower odds of having advanced stage as well as with lower odds of having ETD at the time of diagnosis. This observation of the current study however requires confirmation by larger prospective studies.
doi:10.3978/j.issn.2072-1439.2012.05.11
PMCID: PMC3461078  PMID: 23050111
Non-small cell lung cancer; stage; smoking index; systematic review; extrathoracic disease
6.  Evaluation of the Lung Cancer Risks at Which to Screen Ever- and Never-Smokers: Screening Rules Applied to the PLCO and NLST Cohorts 
PLoS Medicine  2014;11(12):e1001764.
Martin Tammemägi and colleagues evaluate which risk groups of individuals, including nonsmokers and high-risk individuals from 65 to 80 years of age, should be screened for lung cancer using computed tomography.
Please see later in the article for the Editors' Summary
Background
Lung cancer risks at which individuals should be screened with computed tomography (CT) for lung cancer are undecided. This study's objectives are to identify a risk threshold for selecting individuals for screening, to compare its efficiency with the U.S. Preventive Services Task Force (USPSTF) criteria for identifying screenees, and to determine whether never-smokers should be screened. Lung cancer risks are compared between smokers aged 55–64 and ≥65–80 y.
Methods and Findings
Applying the PLCOm2012 model, a model based on 6-y lung cancer incidence, we identified the risk threshold above which National Lung Screening Trial (NLST, n = 53,452) CT arm lung cancer mortality rates were consistently lower than rates in the chest X-ray (CXR) arm. We evaluated the USPSTF and PLCOm2012 risk criteria in intervention arm (CXR) smokers (n = 37,327) of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). The numbers of smokers selected for screening, and the sensitivities, specificities, and positive predictive values (PPVs) for identifying lung cancers were assessed. A modified model (PLCOall2014) evaluated risks in never-smokers. At PLCOm2012 risk ≥0.0151, the 65th percentile of risk, the NLST CT arm mortality rates are consistently below the CXR arm's rates. The number needed to screen to prevent one lung cancer death in the 65th to 100th percentile risk group is 255 (95% CI 143 to 1,184), and in the 30th to <65th percentile risk group is 963 (95% CI 291 to −754); the number needed to screen could not be estimated in the <30th percentile risk group because of absence of lung cancer deaths. When applied to PLCO intervention arm smokers, compared to the USPSTF criteria, the PLCOm2012 risk ≥0.0151 threshold selected 8.8% fewer individuals for screening (p<0.001) but identified 12.4% more lung cancers (sensitivity 80.1% [95% CI 76.8%–83.0%] versus 71.2% [95% CI 67.6%–74.6%], p<0.001), had fewer false-positives (specificity 66.2% [95% CI 65.7%–66.7%] versus 62.7% [95% CI 62.2%–63.1%], p<0.001), and had higher PPV (4.2% [95% CI 3.9%–4.6%] versus 3.4% [95% CI 3.1%–3.7%], p<0.001). In total, 26% of individuals selected for screening based on USPSTF criteria had risks below the threshold PLCOm2012 risk ≥0.0151. Of PLCO former smokers with quit time >15 y, 8.5% had PLCOm2012 risk ≥0.0151. None of 65,711 PLCO never-smokers had PLCOm2012 risk ≥0.0151. Risks and lung cancers were significantly greater in PLCO smokers aged ≥65–80 y than in those aged 55–64 y. This study omitted cost-effectiveness analysis.
Conclusions
The USPSTF criteria for CT screening include some low-risk individuals and exclude some high-risk individuals. Use of the PLCOm2012 risk ≥0.0151 criterion can improve screening efficiency. Currently, never-smokers should not be screened. Smokers aged ≥65–80 y are a high-risk group who may benefit from screening.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Lung cancer is the most commonly occurring cancer in the world and the most common cause of cancer-related deaths. Like all cancers, lung cancer occurs when cells acquire genetic changes that allow them to grow uncontrollably and to move around the body (metastasize). The most common trigger for these genetic changes in lung cancer is exposure to cigarette smoke. Symptoms of lung cancer include a persistent cough and breathlessness. If lung cancer is diagnosed when it is confined to the lung (stage I), the tumor can often be removed surgically. Stage II tumors, which have spread into nearby lymph nodes, are usually treated with surgery plus chemotherapy or radiotherapy. For more advanced lung cancers that have spread throughout the chest (stage III) or the body (stage IV), surgery is rarely helpful and these tumors are treated with chemotherapy and radiotherapy alone. Overall, because most lung cancers are not detected until they are advanced, less than 17% of people diagnosed with lung cancer survive for five years.
Why Was This Study Done?
Screening for lung cancer—looking for early disease in healthy people—could save lives. In the US National Lung Screening Trial (NLST), annual screening with computed tomography (CT) reduced lung cancer mortality by 20% among smokers at high risk of developing cancer compared with screening with a chest X-ray. But what criteria should be used to decide who is screened for lung cancer? The US Preventive Services Task Force (USPSTF), for example, recommends annual CT screening of people who are 55–80 years old, have smoked 30 or more pack-years (one pack-year is defined as a pack of cigarettes per day for one year), and—if they are former smokers—quit smoking less than 15 years ago. However, some experts think lung cancer risk prediction models—statistical models that estimate risk based on numerous personal characteristics—should be used to select people for screening. Here, the researchers evaluate PLCOm2012, a lung cancer risk prediction model based on the incidence of lung cancer among smokers enrolled in the US Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). Specifically, the researchers use NLST and PLCO screening trial data to identify a PLCOm2012 risk threshold for selecting people for screening and to compare the efficiency of the PLCOm2012 model and the USPSTF criteria for identifying “screenees.”
What Did the Researchers Do and Find?
By analyzing NLST data, the researchers calculated that at PLCOm2012 risk ≥0.0151, mortality (death) rates among NLST participants screened with CT were consistently below mortality rates among NLST participants screened with chest X-ray and that 255 people with a PLCOm2012 risk ≥0.0151 would need to be screened to prevent one lung cancer death. Next, they used data collected from smokers in the screened arm of the PLCO trial to compare the efficiency of the PLCOm2012 and USPSTF criteria for identifying screenees. They found that 8.8% fewer people had a PLCOm2012 risk ≥0.0151 than met USPSTF criteria for screening, but 12.4% more lung cancers were identified. Thus, using PLCOm2012 improved the sensitivity and specificity of the selection of individuals for lung cancer screening over using UPSTF criteria. Notably, 8.5% of PLCO former smokers with quit times of more than 15 years had PLCOm2012 risk ≥0.0151, none of the PLCO never-smokers had PLCOm2012 risk ≥0.0151, and the calculated risks and incidence of lung cancer were greater among PLCO smokers aged ≥65–80 years than among those aged 55–64 years.
What Do These Findings Mean?
Despite the absence of a cost-effectiveness analysis in this study, these findings suggest that the use of the PLCOm2012 risk ≥0.0151 threshold rather than USPSTF criteria for selecting individuals for lung cancer screening could improve screening efficiency. The findings have several other important implications. First, these findings suggest that screening may be justified in people who stopped smoking more than 15 years ago; USPSTF currently recommends that screening stop once an individual's quit time exceeds 15 years. Second, these findings do not support lung cancer screening among never-smokers. Finally, these findings suggest that smokers aged ≥65–80 years might benefit from screening, although the presence of additional illnesses and reduced life expectancy need to be considered before recommending the provision of routine lung cancer screening to this section of the population.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001764.
The US National Cancer Institute provides information about all aspects of lung cancer for patients and health-care professionals, including information on lung cancer screening (in English and Spanish)
Cancer Research UK also provides detailed information about lung cancer and about lung cancer screening
The UK National Health Service Choices website has a page on lung cancer that includes personal stories
MedlinePlus provides links to other sources of information about lung cancer (in English and Spanish)
Information about the USPSTF recommendations for lung cancer screening is available
doi:10.1371/journal.pmed.1001764
PMCID: PMC4251899  PMID: 25460915
7.  Cooperative Regulation of Non-Small Cell Lung Carcinoma by Nicotinic and Beta-Adrenergic Receptors: A Novel Target for Intervention 
PLoS ONE  2012;7(1):e29915.
Lung cancer is the leading cause of cancer death; 80–85% of lung cancer cases are non-small cell lung cancer (NSCLC). Smoking is a documented risk factor for the development of this cancer. Although nicotine does not have the ability to initiate carcinogenic events, recent studies have implicated nicotine in growth stimulation of NSCLC. Using three NSCLC cell lines (NCI-H322, NCI-H441 and NCI-H1299), we identified the cooperation of nicotinic acetylcholine receptors (nAChRs) and β-adrenergic receptors (β-ARs) as principal regulators of these effects. Proliferation was measured by thymidine incorporation and MTT assays, and Western blots were used to monitor the upregulation of the nAChRs and activation of signaling molecules. Noradrenaline and GABA were measured by immunoassays. Nicotine-treated NSCLC cells showed significant induction of the α7nAChR and α4nAChR, along with significant inductions of p-CREB and p-ERK1/2 accompanied by increases in the stress neurotransmitter noradrenaline, which in turn led to the observed increase in DNA synthesis and cell proliferation. Effects on cell proliferation and signaling proteins were reversed by the α7nAChR antagonist α-BTX or the β-blocker propranolol. Nicotine treatment also down-regulated expression of the GABA synthesizing enzyme GAD 65 and the level of endogenous GABA, while treatment of NSCLC cells with GABA inhibited cell proliferation. Interestingly, GABA acts by reducing β-adrenergic activated cAMP signaling. Our findings suggest that nicotine-induced activation of this autocrine noradrenaline-initiated signaling cascade and concomitant deficiency in inhibitory GABA, similar to modulation of these neurotransmitters in the nicotine-addicted brain, may contribute to the development of NSCLC in smokers. Our data suggest that exposure to nicotine either by tobacco smoke or nicotine supplements facilitates growth and progression of NSCLC and that pharmacological intervention by β blocker may lower the risk for NSCLC development among smokers and could be used to enhance the clinical outcome of standard cancer therapy.
doi:10.1371/journal.pone.0029915
PMCID: PMC3257239  PMID: 22253823
8.  A Gene Expression Signature Predicts Survival of Patients with Stage I Non-Small Cell Lung Cancer 
PLoS Medicine  2006;3(12):e467.
Background
Lung cancer is the leading cause of cancer-related death in the United States. Nearly 50% of patients with stages I and II non-small cell lung cancer (NSCLC) will die from recurrent disease despite surgical resection. No reliable clinical or molecular predictors are currently available for identifying those at high risk for developing recurrent disease. As a consequence, it is not possible to select those high-risk patients for more aggressive therapies and assign less aggressive treatments to patients at low risk for recurrence.
Methods and Findings
In this study, we applied a meta-analysis of datasets from seven different microarray studies on NSCLC for differentially expressed genes related to survival time (under 2 y and over 5 y). A consensus set of 4,905 genes from these studies was selected, and systematic bias adjustment in the datasets was performed by distance-weighted discrimination (DWD). We identified a gene expression signature consisting of 64 genes that is highly predictive of which stage I lung cancer patients may benefit from more aggressive therapy. Kaplan-Meier analysis of the overall survival of stage I NSCLC patients with the 64-gene expression signature demonstrated that the high- and low-risk groups are significantly different in their overall survival. Of the 64 genes, 11 are related to cancer metastasis (APC, CDH8, IL8RB, LY6D, PCDHGA12, DSP, NID, ENPP2, CCR2, CASP8, and CASP10) and eight are involved in apoptosis (CASP8, CASP10, PIK3R1, BCL2, SON, INHA, PSEN1, and BIK).
Conclusions
Our results indicate that gene expression signatures from several datasets can be reconciled. The resulting signature is useful in predicting survival of stage I NSCLC and might be useful in informing treatment decisions.
Meta-analysis of several lung cancer gene expression studies yields a set of 64 genes whose expression profile is useful in predicting survival of patients with early-stage lung cancer and possibly informing treatment decisions.
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) and are mainly caused by smoking. Like other cancers, how NSCLC is treated depends on the “stage” at which it is detected. Stage IA NSCLCs are small and confined to the lung and can be removed surgically; patients with slightly larger stage IB tumors often receive chemotherapy after surgery. In stage II NSCLC, cancer cells may be present in lymph nodes near the tumor. Surgery plus chemotherapy is the usual treatment for this stage and for some stage III NSCLCs. However, in this stage, the tumor can be present throughout the chest and surgery is not always possible. For such cases and in stage IV NSCLC, where the tumor has spread throughout the body, patients are treated with chemotherapy alone. The stage at which NSCLC is detected also determines how well patients respond to treatment. Those who can be treated surgically do much better than those who can't. So, whereas only 2% of patients with stage IV lung cancer survive for 5 years after diagnosis, about 70% of patients with stage I or II lung cancer live at least this long.
Why Was This Study Done?
Even stage I and II lung cancers often recur and there is no accurate way to identify the patients in which this will happen. If there was, these patients could be given aggressive chemotherapy, so the search is on for a “molecular signature” to help identify which NSCLCs are likely to recur. Unlike normal cells, cancer cells divide uncontrollably and can move around the body. These behavioral differences are caused by changes in their genetic material that alter their patterns of RNA transcription and protein expression. In this study, the researchers have investigated whether data from several microarray studies (a technique used to catalog the genes expressed in cells) can be pooled to construct a gene expression signature that predicts the survival of patients with stage I NSCLC.
What Did the Researchers Do and Find?
The researchers took the data from seven independent microarray studies (including a new study of their own) that recorded gene expression profiles related to survival time (less than 2 years and greater than 5 years) for stage I NSCLC. Because these studies had been done in different places with slightly different techniques, the researchers applied a statistical tool called distance-weighted discrimination to smooth out any systematic differences among the studies before identifying 64 genes whose expression was associated with survival. Most of these genes are involved in cell adhesion, cell motility, cell proliferation, and cell death, all processes that are altered in cancer cells. The researchers then developed a statistical model that allowed them to use the gene expression and survival data to calculate risk scores for nearly 200 patients in five of the datasets. When they separated the patients into high and low risk groups on the basis of these scores, the two groups were significantly different in terms of survival time. Indeed, the gene expression signature was better at predicting outcome than routine staging. Finally, the researchers validated the gene expression signature by showing that it predicted survival with more than 85% accuracy in two independent datasets.
What Do These Findings Mean?
The 64 gene expression signature identified here could help clinicians prepare treatment plans for patients with stage I NSCLC. Because it accurately predicts survival in patients with adenocarcinoma or squamous cell cancer (the two major subtypes of NSCLC), it potentially indicates which of these patients should receive aggressive chemotherapy and which can be spared this unpleasant treatment. Previous attempts to establish gene expression signatures to predict outcome have used data from small groups of patients and have failed when tested in additional patients. In contrast, this new signature seems to be generalizable. Nevertheless, its ability to predict outcomes must be confirmed in further studies before it is routinely adopted by oncologists for treatment planning.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030467.
US National Cancer Institute information on lung cancer for patients and health professionals.
MedlinePlus encyclopedia entries on small-cell and non-small-cell lung cancer.
Cancer Research UK, information on patients about all aspects of lung cancer.
Wikipedia pages on DNA microarrays and expression profiling (note that Wikipedia is a free online encyclopedia that anyone can edit).
doi:10.1371/journal.pmed.0030467
PMCID: PMC1716187  PMID: 17194181
9.  The changing epidemiology of smoking and lung cancer histology. 
Environmental Health Perspectives  1995;103(Suppl 8):143-148.
In 1950, the first large-scale epidemiological studies demonstrated that lung cancer is causatively associated with cigarette smoking, a finding subsequently confirmed by the Royal College of Physicians in London, the U.S. Surgeon General, and the World Health Organization. Although cigarette consumption has gradually decreased in the United States from a high of about 3800 cigarettes per adult per year in 1965 to about 2800 cigarettes in 1993, death from lung cancer has reached a high among males at the rate of 74.9/100,000/year and among females at the rate of 28.5. However, in the younger cohorts, the lung cancer death rate is decreasing in both men and women. In this overview we discuss the steeper increase during recent decades of lung adenocarcinoma incidence compared with squamous cell carcinoma of the lung. In 1950, the ratio of these two major types of lung cancer in males was about 1:18; today it is about 1:1.2-1.4. This overview discusses two concepts that are regarded as contributors to this change in the histological types of lung cancer. One factor is the decrease in average nicotine and tar delivery of cigarettes from about 2.7 and 38 mg in 1955 to 1.0 and 13.5 mg in 1993, respectively. Other major factors for the reduced emission of smoke relate to changes in the composition of the cigarette tobacco blend and general acceptance of cigarettes with filter tips; the latter constitute 97% of all cigarettes currently sold. However, smokers of low-yield cigarettes compensate for the low delivery of nicotine by inhaling the smoke more deeply and by smoking more intensely; such smokers may be taking up to 5 puffs/min with puff volumes up to 55 ml. Under these conditions, the peripheral lung is exposed to increased amounts of smoke carcinogens that are suspected to lead to lung adenocarcinoma. Among the important changes in the composition of the tobacco blend of the U.S. cigarette is a significant increase in nitrate content (0.5% to 1.2-1.5%), which raises the yields of nitrogen oxides and N-nitrosamines in the smoke. Furthermore, the more intense smoking by the consumers of low-yield cigarettes increases N-nitrosamines in the smoke 2- to 3-fold. Among the N-nitrosamines is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a powerful lung carcinogen in animals that is exclusively formed from nicotine. This organ-specific tobacco-specific nitrosamine (TSNA) induces adenocarcinoma of the lung. All of these factors, the more intense smoking, the deeper inhalation of the smoke, and the increased yields of N-nitrosamines in the smoke of low-yield cigarettes, are considered major contributors to the drastic increase in lung adenocarcinoma among cigarette smokers in recent years. This overview also discusses the differences in the major lung cancer types in female compared with male smokers as well as the likely underlying factors for increased lung cancer risk among African Americans compared with that among white Americans. Although the only sure way to prevent smoking-related diseases is giving up the tobacco habit, there must be a measure of protection for those who cannot accomplish this. Therefore, setting upper permissible limits of tar levels for the smoke of U.S. cigarettes, similar to strategies already taken in Western Europe, should be considered.
PMCID: PMC1518964  PMID: 8741774
10.  LUNG CANCER IN NEVER SMOKERS: CLINICAL EPIDEMIOLOGY AND ENVIRONMENTAL RISK FACTORS 
More than 161,000 lung cancer deaths are projected to occur in the U.S. in 2008. Of these, an estimated 10–15% will be caused by factors other than active smoking, corresponding to 16,000–24,000 deaths annually. Thus lung cancer in never smokers would rank among the most common causes of cancer mortality in the U.S. if considered to be a separate category. Slightly more than half of the lung cancers caused by factors other than active smoking occur in never smokers. As summarized in the accompanying article, lung cancers that occur in never smokers differ from those that occur in smokers in their molecular profile and response to targeted therapy. These recent laboratory and clinical observations highlight the importance of defining the genetic and environmental factors responsible for the development of lung cancer in never-smokers. This article summarizes available data on the clinical epidemiology of lung cancer in never smokers, and the several environmental risk factors that population-based research has implicated in the etiology of these cancers. Primary factors closely tied to lung cancer in never smokers include exposure to known and suspected carcinogens including radon, second-hand tobacco smoke, and other indoor air pollutants. Several other exposures have been implicated. However, a large fraction of lung cancers occurring in never-smokers cannot be definitively associated with established environmental risk factors, highlighting the need for additional epidemiologic research in this area.
doi:10.1158/1078-0432.CCR-09-0376
PMCID: PMC3170525  PMID: 19755391
11.  Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts 
PLoS Medicine  2014;11(4):e1001631.
Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia.
Please see later in the article for the Editors' Summary
Background
Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest.
Methods and Findings
We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan—accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37–1.51) and 1.48-fold (1.38–1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%–17.2%) and 3.3% (2.6%–4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000–1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.
Conclusions
Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, more than 5 million smokers die from tobacco-related diseases. Tobacco smoking is a major risk factor for cardiovascular disease (conditions that affect the heart and the circulation), respiratory disease (conditions that affect breathing), lung cancer, and several other types of cancer. All told, tobacco smoking kills up to half its users. The ongoing global “epidemic” of tobacco smoking and tobacco-related diseases initially affected people living in the US and other Western countries, where the prevalence of smoking (the proportion of the population that smokes) in men began to rise in the early 1900s, peaking in the 1960s. A similar epidemic occurred in women about 40 years later. Smoking-related deaths began to increase in the second half of the 20th century, and by the 1990s, tobacco smoking accounted for a third of all deaths and about half of cancer deaths among men in the US and other Western countries. More recently, increased awareness of the risks of smoking and the introduction of various tobacco control measures has led to a steady decline in tobacco use and in smoking-related diseases in many developed countries.
Why Was This Study Done?
Unfortunately, less well-developed tobacco control programs, inadequate public awareness of smoking risks, and tobacco company marketing have recently led to sharp increases in the prevalence of smoking in many low- and middle-income countries, particularly in Asia. More than 50% of men in many Asian countries are now smokers, about twice the prevalence in many Western countries, and more women in some Asian countries are smoking than previously. More than half of the world's billion smokers now live in Asia. However, little is known about the burden of tobacco-related mortality (deaths) in this region. In this study, the researchers quantify the risk of total and cause-specific mortality associated with tobacco use among adults aged 45 years or older by undertaking a pooled statistical analysis of data collected from 21 Asian cohorts (groups) about their smoking history and health.
What Did the Researchers Do and Find?
For their study, the researchers used data from more than 1 million participants enrolled in studies undertaken in Bangladesh, India, mainland China, Japan, the Republic of Korea, Singapore, and Taiwan (which together account for 71% of Asia's total population). Smoking prevalences among male and female participants were 65.1% and 7.1%, respectively. Compared with never-smokers, ever-smokers had a higher risk of death from any cause in pooled analyses of all the cohorts (adjusted hazard ratios [HRs] of 1.44 and 1.48 for men and women, respectively; an adjusted HR indicates how often an event occurs in one group compared to another group after adjustment for other characteristics that affect an individual's risk of the event). Compared with never smoking, ever smoking was associated with a higher risk of death due to cardiovascular disease, cancer (particularly lung cancer), and respiratory disease among Asian men and among East Asian women. Moreover, the researchers estimate that, in the countries included in this study, tobacco smoking accounted for 15.8% of all deaths among men and 3.3% of deaths among women in 2004—a total of about 1.5 million deaths, which scales up to 2 million deaths for the population of the whole of Asia. Notably, in 2004, tobacco smoking accounted for 60.5% of lung-cancer deaths among Asian men and 16.7% of lung-cancer deaths among East Asian women.
What Do These Findings Mean?
These findings provide strong evidence that tobacco smoking is associated with a substantially raised risk of death among adults aged 45 years or older throughout Asia. The association between smoking and mortality risk in Asia reported here is weaker than that previously reported for Western countries, possibly because widespread tobacco smoking started several decades later in most Asian countries than in Europe and North America and the deleterious effects of smoking take some years to become evident. The researchers note that certain limitations of their analysis are likely to affect the accuracy of its findings. For example, because no data were available to estimate the impact of secondhand smoke, the estimate of deaths attributable to smoking is likely to be an underestimate. However, the finding that nearly 45% of the global deaths from active tobacco smoking occur in Asia highlights the urgent need to implement comprehensive tobacco control programs in Asia to reduce the burden of tobacco-related disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001631.
The World Health Organization provides information about the dangers of tobacco (in several languages) and about the WHO Framework Convention on Tobacco Control, an international instrument for tobacco control that came into force in February 2005 and requires parties to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes; its 2013 report on the global tobacco epidemic is available
The US Centers for Disease Control and Prevention provides detailed information about all aspects of smoking and tobacco use
The UK National Health Services Choices website provides information about the health risks associated with smoking
MedlinePlus has links to further information about the dangers of smoking (in English and Spanish)
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking
Smokefree.gov, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
doi:10.1371/journal.pmed.1001631
PMCID: PMC3995657  PMID: 24756146
12.  Impact of Neuro-Psychological Factors on Smoking-Associated Lung Cancer 
Cancers  2014;6(1):580-594.
Smoking has been extensively documented as a risk factor for all histological types of lung cancer and tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons reproducibly cause lung cancer in laboratory rodents. However, the most common lung cancer, non-small cell lung cancer (NSCLC), frequently develops in never smokers and is particularly common in women and African Americans, suggesting that factors unrelated to smoking significantly impact this cancer. Recent experimental investigations in vitro and in animal models have shown that chronic psychological stress and the associated hyperactive signaling of stress neurotransmitters via β-adrenergic receptors significantly promote the growth and metastatic potential of NSCLC. These responses were caused by modulation in the expression and sensitization state of nicotinic acetylcholine receptors (nAChRs) that regulate the production of stress neurotransmitters and the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Similar changes in nAChR-mediated neurotransmitter production were identified as the cause of NSCLC stimulation in vitro and in xenograft models by chronic nicotine. Collectively, these data suggest that hyperactivity of the sympathetic branch of the autonomic nervous system caused by chronic psychological stress or chronic exposure to nicotinic agonists in cigarette smoke significantly contribute to the development and progression of NSCLC. A recent clinical study that reported improved survival outcomes with the incidental use of β-blockers among patients with NSCLC supports this interpretation.
doi:10.3390/cancers6010580
PMCID: PMC3980616  PMID: 24633083
smoking; non-small cell lung cancer; nicotinic receptors; β-adrenergic receptors; sympathicus hyperactivity; psychological stress
13.  Relation between smoking history and gene expression profiles in lung adenocarcinomas 
BMC Medical Genomics  2012;5:22.
Background
Lung cancer is the worldwide leading cause of death from cancer. Tobacco usage is the major pathogenic factor, but all lung cancers are not attributable to smoking. Specifically, lung cancer in never-smokers has been suggested to represent a distinct disease entity compared to lung cancer arising in smokers due to differences in etiology, natural history and response to specific treatment regimes. However, the genetic aberrations that differ between smokers and never-smokers’ lung carcinomas remain to a large extent unclear.
Methods
Unsupervised gene expression analysis of 39 primary lung adenocarcinomas was performed using Illumina HT-12 microarrays. Results from unsupervised analysis were validated in six external adenocarcinoma data sets (n=687), and six data sets comprising normal airway epithelial or normal lung tissue specimens (n=467). Supervised gene expression analysis between smokers and never-smokers were performed in seven adenocarcinoma data sets, and results validated in the six normal data sets.
Results
Initial unsupervised analysis of 39 adenocarcinomas identified two subgroups of which one harbored all never-smokers. A generated gene expression signature could subsequently identify never-smokers with 79-100% sensitivity in external adenocarcinoma data sets and with 76-88% sensitivity in the normal materials. A notable fraction of current/former smokers were grouped with never-smokers. Intriguingly, supervised analysis of never-smokers versus smokers in seven adenocarcinoma data sets generated similar results. Overlap in classification between the two approaches was high, indicating that both approaches identify a common set of samples from current/former smokers as potential never-smokers. The gene signature from unsupervised analysis included several genes implicated in lung tumorigenesis, immune-response associated pathways, genes previously associated with smoking, as well as marker genes for alveolar type II pneumocytes, while the best classifier from supervised analysis comprised genes strongly associated with proliferation, but also genes previously associated with smoking.
Conclusions
Based on gene expression profiling, we demonstrate that never-smokers can be identified with high sensitivity in both tumor material and normal airway epithelial specimens. Our results indicate that tumors arising in never-smokers, together with a subset of tumors from smokers, represent a distinct entity of lung adenocarcinomas. Taken together, these analyses provide further insight into the transcriptional patterns occurring in lung adenocarcinoma stratified by smoking history.
doi:10.1186/1755-8794-5-22
PMCID: PMC3447685  PMID: 22676229
Lung cancer; Smoking; Gene expression analysis; Adenocarcinoma; EGFR; Never-smokers; Immune response
14.  Notch signaling contributes to lung cancer clonogenic capacity in vitro but may be circumvented in tumorigenesis in vivo 
Molecular cancer research : MCR  2011;9(12):1746-1754.
The Notch signaling pathway is a critical embryonic developmental regulatory pathway that has been implicated in oncogenesis. In non-small cell lung cancer (NSCLC), recent evidence suggests that Notch signaling may contribute to maintenance of a cancer stem or progenitor cell compartment required for tumorigenesis. We explored whether intact Notch signaling is required for NSCLC clonogenic and tumorigenic potential in vitro and in vivo using a series of genetically modified model systems. In keeping with previous observations, we find that Notch3 in particular is upregulated in human lung cancer lines, and that down regulation of Notch signaling using a selective γ-secretase inhibitor (MRK-003) is associated with decreased proliferation and clonogenic capacity in vitro. We demonstrate that this phenotype is rescued with the expression of NICD3, a constitutively active cleaved form of Notch3 not affected by γ-secretase inhibition. Using an inducible LSL-KRASG12D model of lung cancer in vivo, we demonstrate a transient upregulation of Notch pathway activity in early tumor precursor lesions. However, a more rigorous test of the requirement for Notch signaling in lung oncogenesis, crossing the LSL-KRASG12D mouse model with a transgenic with a similarly inducible global dominant negative suppressor of Notch activity, LSL-DNMAML (dominant negative mastermind-like), reveals no evidence of Notch pathway requirement for lung tumor initiation or growth in vivo. Distinct Notch family members may have different, and potentially opposing, activities in oncogenesis, and targeted inhibition of individual Notch family members may be a more effective anti-cancer strategy than global pathway suppression.
doi:10.1158/1541-7786.MCR-11-0286
PMCID: PMC3243765  PMID: 21994468
15.  Lungs don’t forget: Comparison of the KRAS and EGFR mutation profile and survival of “collegiate smokers” and never smokers with advanced lung cancers 
HYPOTHESIS
We hypothesize that among patients with lung cancers the KRAS/EGFR mutation profile and overall survival of “collegiate smokers” (former smokers who smoked between 101 lifetime cigarettes and 5 pack years) are distinct from those of never smokers and former smokers with ≥ 15 pack years.
METHODS
We collected age, sex, stage, survival, and smoking history for patients evaluated from 2004 to 2009 with advanced stage lung cancers and known KRAS/EGFR status. Mutation profile and overall survival were compared using Fisher’s exact test and log-rank test, respectively.
RESULTS
Data were available for 852 patients with advanced stage lung cancers with known KRAS/EGFR status. 6% were “collegiate smokers”, 36% were never smokers, and 30% were former smokers with ≥ 15 pack years. The mutation profile of “collegiate smokers” (15% KRAS mutations, 27% EGFR mutations) was distinct from those of never smokers (p < .001) and former smokers with ≥ 15 pack years (p < .001)and not significantly different from those of former smokers with 5 to 15 pack years (p = 0.9). Median overall survival for “collegiate smokers” was 25 months, compared to 32 months for never smokers (p = 0.4), 33 months for former smokers with 5–15 pack years (p = 0.48),and 21 months for former smokers with ≥ 15 pack years (p = 0.63).
CONCLUSIONS
“Collegiate smokers” with advanced stage lung cancers represent a distinct subgroup of patients with a higher frequency of KRAS mutations and lower frequency of EGFR mutations compared to never smokers. These observations reinforce the recommendation for routine mutation testing for all patients with lung cancers and that no degree of tobacco exposure is safe.
doi:10.1097/JTO.0b013e31827914ea
PMCID: PMC3534987  PMID: 23242442
Collegiate Smokers; non-small cell lung cancers; epidermal growth factor receptor mutation; KRAS mutation
16.  The accumulated evidence on lung cancer and environmental tobacco smoke. 
BMJ : British Medical Journal  1997;315(7114):980-988.
OBJECTIVE: To estimate the risk of lung cancer in lifelong non-smokers exposed to environmental tobacco smoke. DESIGN: Analysis of 37 published epidemiological studies of the risk of lung cancer (4626 cases) in non-smokers who did and did not live with a smoker. The risk estimate was compared with that from linear extrapolation of the risk in smokers using seven studies of biochemical markers of tobacco smoke intake. MAIN OUTCOME MEASURE: Relative risk of lung cancer in lifelong non-smokers according to whether the spouse currently smoked or had never smoked. RESULTS: The excess risk of lung cancer was 24% (95% confidence interval 13% to 36%) in non-smokers who lived with a smoker (P < 0.001). Adjustment for the effects of bias (positive and negative) and dietary confounding had little overall effect; the adjusted excess risk was 26% (7% to 47%). The dose-response relation of the risk of lung cancer with both the number of cigarettes smoked by the spouse and the duration of exposure was significant. The excess risk derived by linear extrapolation from that in smokers was 19%, similar to the direct estimate of 26%. CONCLUSION: The epidemiological and biochemical evidence on exposure to environmental tobacco smoke, with the supporting evidence of tobacco specific carcinogens in the blood and urine of non-smokers exposed to environmental tobacco smoke, provides compelling confirmation that breathing other people's tobacco smoke is a cause of lung cancer.
PMCID: PMC2127653  PMID: 9365295
17.  Aldehyde dehydrogenase activity selects for lung adenocarcinoma stem cells dependent on Notch signaling 
Cancer research  2010;70(23):9937-9948.
Aldehyde dehydrogenase (ALDH) is a candidate marker for lung cancer cells with stem cell-like properties. Immunohistochemical staining of a large panel of primary non-small cell lung cancer (NSCLC) samples for the ALDH1A1, ALDH3A1 and CD133 revealed a significant correlation between ALDH1A1 (but not ALDH3A1 or CD133) expression and poor prognosis in patients including those with stage I and N0 disease. Flow cytometric analysis of a panel of lung cancer cell lines and patient tumors revealed most NSCLCs contain a subpopulation of cells with elevated ALDH activity, and that this activity is associated with ALDH1A1 expression. Isolated ALDH+ lung cancer cells were observed to be highly tumorigenic and clonogenic as well as capable of self-renewal compared to their ALDH− counterparts. Expression analysis of sorted cells revealed elevated Notch pathway transcript expression in ALDH+ cells. Suppression of the Notch pathway by treatment with either a gamma-secretase inhibitor or stable expression of shRNA against NOTCH3 resulted in a significant decrease in ALDH+ lung cancer cells, commensurate with a reduction in tumor cell proliferation and clonogenicity. Taken together, these findings indicate that ALDH selects for a subpopulation of self-renewing NSCLC stem-like cells with increased tumorigenic potential, that NSCLCs harboring tumor cells with ALDH1A1 expression have inferior prognosis, and that ALDH1A1 and CD133 identify different tumor subpopulations. Therapeutic targeting of the Notch pathway reduces this ALDH+ component, implicating Notch signaling in lung cancer stem cell maintenance.
doi:10.1158/0008-5472.CAN-10-0881
PMCID: PMC3058307  PMID: 21118965
Lung cancer; cancer stem cells; ALDH; Notch; self renewal
18.  The relation between smokeless tobacco and cancer in Northern Europe and North America. A commentary on differences between the conclusions reached by two recent reviews 
BMC Cancer  2009;9:256.
Background
Smokeless tobacco is an alternative for smokers who want to quit but require nicotine. Reliable evidence on its effects is needed. Boffetta et al. and ourselves recently reviewed the evidence on cancer, based on Scandinavian and US studies. Boffetta et al. claimed a significant 60–80% increase for oropharyngeal, oesophageal and pancreatic cancer, and a non-significant 20% increase for lung cancer, data for other cancers being "too sparse". We found increases less than 15% for oesophageal, pancreatic and lung cancer, and a significant 36% increase for oropharyngeal cancer, which disappeared in recent studies. We found no association with stomach, bladder and all cancers combined, using data as extensive as that for oesophageal, pancreatic and lung cancer. We explain these differences.
Methods
For those cancers Boffetta et al. considered, we compared the methods, studies and risk estimates used in the two reviews.
Results
One major reason for the difference is our more consistent approach in choosing between study-specific never smoker and combined smoker/non-smoker estimates. Another is our use of derived as well as published estimates. We included more studies, and avoided estimates for data subsets. Boffetta et al. also included some clearly biased or not smoking-adjusted estimates. For pancreatic cancer, their review included significantly increased never smoker estimates in one study and combined smoker/non-smoker estimates in another, omitting a combined estimate in the first study and a never smoker estimate in the second showing no increase. For oesophageal cancer, never smoker results from one study showing a marked increase for squamous cell carcinoma were included, but corresponding results for adenocarcinoma and combined smoker/non-smoker results for both cell types showing no increase were excluded. For oropharyngeal cancer, Boffetta et al. included a markedly elevated estimate that was not smoking-adjusted, and overlooked the lack of association in recent studies.
Conclusion
When conducting meta-analyses, all relevant data should be used, with clear rules governing the choice between alternative estimates. A systematic meta-analysis using pre-defined procedures and all relevant data gives a lower estimate of cancer risk from smokeless tobacco (probably 1–2% of that from smoking) than does the previous review by Boffetta et al.
doi:10.1186/1471-2407-9-256
PMCID: PMC3087330  PMID: 19638246
19.  Progesterone and estrogen receptor expression and activity in human non-small cell lung cancer 
Steroids  2011;76(9):910-920.
Lung cancer is the most common cause of cancer mortality in male and female patients in the US. Although it is clear that tobacco smoking is a major cause of lung cancer, about half of all women with lung cancer worldwide are never-smokers. Despite a declining smoking population, the incidence of non-small cell lung cancer (NSCLC), the predominant form of lung cancer, has reached epidemic proportions particularly in women. Emerging data suggest that factors other than tobacco, namely endogenous and exogenous female sex hormones, have a role in stimulating NSCLC progression. Aromatase, a key enzyme for estrogen biosynthesis, is expressed in NSCLC. Clinical data show that women with high levels of tumor aromatase (and high intratumoral estrogen) have worse survival than those with low aromatase. The present and previous studies also reveal significant expression and activity of estrogen receptors (ERα, ERβ) in both extranuclear and nuclear sites in most NSCLC. We now report further on the expression of progesterone receptor (PR) transcripts and protein in NSCLC. PR transcripts were significantly lower in cancerous as compared to non-malignant tissue. Using immunohistochemistry, expression of PR was observed in the nucleus and/or extranuclear compartments in the majority of human tumor specimens examined. Combinations of estrogen and progestins administered in vitro cooperate in promoting tumor secretion of vascular endothelial growth factor and, consequently, support tumor-associated angiogenesis. Further, dual treatment with estradiol and progestin increased the numbers of putative tumor stem/progenitor cells. Thus, ER- and/or PR-targeted therapies may offer new approaches to manage NSCLC.
doi:10.1016/j.steroids.2011.04.015
PMCID: PMC3129425  PMID: 21600232
Progesterone; Estrogen; Steroid hormone receptor; Non-small cell lung cancer; VEGF; Progenitor cells; Cancer stem cells; Angiogenesis
20.  Driver Mutations Determine Survival in Smokers and Never Smokers with Stage IIIB/IV Lung Adenocarcinomas 
Cancer  2012;118(23):5840-5847.
Background
We previously demonstrated that stage IIIB/IV non-small cell lung cancer (NSCLC) never smokers lived 50% longer than former/current smokers. This observation persisted after adjusting for age, performance status, and gender. We hypothesized that smoking-dependent differences in the distribution of driver mutations might explain differences in prognosis between these subgroups.
Methods
We reviewed 293 never smokers and 382 former/current smokers with lung adenocarcinoma who underwent testing for EGFR and KRAS mutations and rearrangements in ALK between 2009 and 2010. Clinical outcomes and patient characteristics were collected. Survival probabilities were estimated using the Kaplan-Meier method. Group comparison was performed with log-rank tests and Cox proportional hazards methods.
Results
While the overall incidence of these mutations was nearly identical (55% never smokers vs. 57% current/former smokers, p=0.48), there were significant differences in the distribution of mutations between these groups: EGFR mutations- 37% never smokers vs. 14% former/current smokers (p<0.0001); KRAS mutations- 4% never smokers vs. 43% former/current smokers (p<0.0001); ALK rearrangements- 12% never smokers vs. 2% former/current smokers (p<0.0001). Among never smokers and former/current smokers, prognosis differed significantly by genotype. Patients harboring KRAS mutations demonstrated the poorest survival. Smoking status, however, had no influence on survival within each genotype.
Conclusion
Never smokers and former/current smokers with lung adenocarcinomas are not homogeneous subgroups. Each is made up of individuals whose tumors have a unique distribution of driver mutations which are associated with different prognoses, irrespective of smoking history.
doi:10.1002/cncr.27637
PMCID: PMC3424296  PMID: 22605530
non-small cell lung cancer; adenocarcinoma; EGFR; KRAS; ALK; never smoker
21.  Characterizing the Impact of Smoking and Lung Cancer on the Airway Transcriptome Using RNA-Seq 
Cigarette smoke creates a molecular field of injury in epithelial cells that line the respiratory tract. We hypothesized that transcriptome sequencing (RNA-Seq) will enhance our understanding of the field of molecular injury in response to tobacco smoke exposure and lung cancer pathogenesis by identifying gene expression differences not interrogated or accurately measured by microarrays. We sequenced the high-molecular-weight fraction of total RNA (>200 nt) from pooled bronchial airway epithelial cell brushings (n = 3 patients per pool) obtained during bronchoscopy from healthy never smoker (NS) and current smoker (S) volunteers and smokers with (C) and without (NC) lung cancer undergoing lung nodule resection surgery. RNA-Seq libraries were prepared using 2 distinct approaches, one capable of capturing non-polyadenylated RNA (the prototype NuGEN Ovation RNA-Seq protocol) and the other designed to measure only polyadenylated RNA (the standard Illumina mRNA-Seq protocol) followed by sequencing generating approximately 29 million 36 nt reads per pool and approximately 22 million 75 nt paired-end reads per pool, respectively. The NuGEN protocol captured additional transcripts not detected by the Illumina protocol at the expense of reduced coverage of polyadenylated transcripts, while longer read lengths and a paired-end sequencing strategy significantly improved the number of reads that could be aligned to the genome. The aligned reads derived from the two complementary protocols were used to define the compendium of genes expressed in the airway epithelium (n = 20,573 genes). Pathways related to the metabolism of xenobiotics by cytochrome P450, retinol metabolism, and oxidoreductase activity were enriched among genes differentially expressed in smokers, whereas chemokine signaling pathways, cytokine–cytokine receptor interactions, and cell adhesion molecules were enriched among genes differentially expressed in smokers with lung cancer. There was a significant correlation between the RNA-Seq gene expression data and Affymetrix microarray data generated from the same samples (P < 0.001); however, the RNA-Seq data detected additional smoking- and cancer-related transcripts whose expression was were either not interrogated by or was not found to be significantly altered when using microarrays, including smoking-related changes in the inflammatory genes S100A8 and S100A9 and cancer-related changes in MUC5AC and secretoglobin (SCGB3A1). Quantitative real-time PCR confirmed differential expression of select genes and non-coding RNAs within individual samples. These results demonstrate that transcriptome sequencing has the potential to provide new insights into the biology of the airway field of injury associated with smoking and lung cancer. The measurement of both coding and non-coding transcripts by RNA-Seq has the potential to help elucidate mechanisms of response to tobacco smoke and to identify additional biomarkers of lung cancer risk and novel targets for chemoprevention.
doi:10.1158/1940-6207.CAPR-11-0212
PMCID: PMC3694393  PMID: 21636547
22.  Health Effects of High Radon Environments in Central Europe: Another Test for the LNT Hypothesis? 
Among the various “natural laboratories” of high natural or technical enhanced natural radiation environments in the world such as Kerala (India), Brazil, Ramsar (Iran), etc., the areas in and around the Central European Ore Mountains (Erzgebirge) in the southern parts of former East Germany, but also including parts of Thuringia, northern Bohemia (now Czech Republic), and northeastern Bavaria, are still relatively little known internationally.
Although this area played a central role in the history of radioactivity and radiation effects on humans over centuries, most of the valuable earlier results have not been published in English or quotable according to the current rules in the scientific literature and therefore are not generally known internationally. During the years 1945 to 1989, this area was one of the world’s most important uranium mining areas, providing the former Soviet Union with 300,000 tons of uranium for its military programs. Most data related to health effects of radon and other carcinogenic agents on miners and residents became available only during the years after German reunification. Many of the studies are still unpublished, or more or less internal reports.
By now, substantial studies have been performed on the previously unavailable data about the miners and the population, providing valuable insights that are, to a large degree, in disagreement with the opinion of various international bodies assuming an increase of lung cancer risk in the order of 10% for each 100 Bq/m3 (or doubling for 1000 Bq/m3), even for small residential radon concentrations. At the same time, other studies focusing on never-smokers show little or no effects of residential radon exposures. Experiments in medical clinics using radon on a large scale as a therapeutic against various rheumatic and arthritic disease demonstrated in randomized double-blind studies the effectiveness of such treatments.
The main purpose of this review is to critically examine, including some historical references, recent results primarily in three areas, namely the possible effects of the inhalation of very high radon concentrations on miners; the effect of increased residential radon concentrations on the population; and the therapeutic use of radon. With many of the results still evolving and/or under intense discussion among the experts, more evidence is emerging that radon, which has been inhaled at extremely high concentrations in the multimillion Bq/m3 range by many of older miners (however, with substantial confounders, and large uncertainties in retrospective dosimetry), was perhaps an important but not the dominating factor for an increase in lung cancer rates. Other factors such as smoking, inhalation of quartz and mineral dust, arsenic, nitrous gases, etc. are likely to be more serious contributors to increased miner lung cancer rates. An extrapolation of miner data to indoor radon situations is not feasible.
Concerning indoor radon studies, the by far dominating effect of smoking on the lung cancer incidence makes the results of some studies, apparently showing a positive dose-response relationship, questionable. According to recent studies in several countries, there are no, or beneficial, residential radon effects below about 600 to 1000 Bq/m3 (the extensive studies in the U.S., in particular by B. Cohen, and the discussions about these data, will not be part of this review, because they have already been discussed in detail in the U.S. literature). As a cause of lung cancer, radon seems to rank — behind active and passive smoking, and probably also air pollution in densely populated and/or industrial areas (diesel exhaust soot, etc.) — as a minor contributor in cases of extremely high residential radon levels, combined with heavy smoking of the residents.
As demonstrated in an increasing number of randomized double-blind clinical studies for various painful inflammatory joint diseases such as rheumatism, arthritic problems, and Morbus Bechterew, radon treatments are beneficial, with the positive effect lasting until at least 6 months after the normally 3-week treatment by inhalation or bathes. Studies on the mechanism of these effects are progressing. In other cases of extensive use of radon treatment for a wide spectrum of various diseases, for example, in the former Soviet Union, the positive results are not so well established. However, according to a century of radon treatment experience (after millenniums of unknown radon therapy), in particular in Germany and Austria, the positive medical effects for some diseases far exceed any potential detrimental health effects.
The total amount of available data in this field is too large to be covered in a brief review. Therefore, less known — in particular recent — work from Central Europe has been analyzed in an attempt to summarize new developments and trends. This includes cost/benefit aspects of radon reduction programs. As a test case for the LNT (linear non-threshold) hypothesis and possible biopositive effects of low radiation exposures, the data support a nonlinear human response to low and medium-level radon exposures.
PMCID: PMC2651614  PMID: 19330110
radon; radiation risks; LNT hypothesis; lung cancer; radon balneology
23.  Clinicopathological and Demographical Characteristics of Non-Small Cell Lung Cancer Patients with ALK Rearrangements: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(6):e100866.
Objective
This meta-analysis aimed to comprehensively examine the relationship between the clinicopathological and demographical characteristics and ALK rearrangements in patients with non-small cell lung cancer (NSCLC).
Methods and Main Findings
In total, 62 qualified articles including 1178 ALK rearranged cases from 20541 NSCLC patients were analyzed, and the data were extracted independently by two investigators. NSCLC patients with ALK rearrangements tended to be younger than those without (mean difference: −7.16 years; 95% confidence interval (95% CI): −9.35 to −4.96; P<0.00001), even across subgroups by race. Compared with female NSCLC patients, the odds ratio (OR) of carrying ALK rearrangements was reduced by 28% (95% CI: 0.58–0.90; P = 0.004) in males, and this reduction was potentiated in Asians, yet in opposite direction in Caucasians. Likewise, smokers were less likely to have ALK rearrangements than never-smokers (OR = 0.33; 95% CI: 0.25–0.44; P<0.00001), even in race-stratified subgroups. Moreover, compared with NSCLC patients with tumor stage IV, ALK rearrangements were underrepresented in those with tumor stage I–III (OR = 0.58; 95% CI: 0.44–0.78; P = 0.0002). Patients with lung adenocarcinomas had a significantly higher rate of ALK rearrangements (7.2%) than patients with non-adenocarcinoma (2.0%) (OR = 2.25; 95% CI: 1.54–3.27; P<0.0001).
Conclusion
Our findings demonstrate that ALK rearrangements tended to be present in NSCLC patients with no smoking habit, younger age and tumor stage IV. Moreover, race, age, gender, smoking status, tumor stage and histology might be potential sources of heterogeneity.
doi:10.1371/journal.pone.0100866
PMCID: PMC4069179  PMID: 24959902
24.  The Natural Tumor Suppressor Protein Maspin and Potential Application in Non Small Cell Lung Cancer 
Current pharmaceutical design  2010;16(16):1877-1881.
The grim prognosis of lung cancer, that has an overall 10–15% survival at 5 years, remains in the US the leading cause of cancer mortality, providing a compelling rationale for studying the molecular basis of this malignancy. Surmising the common, general association with smoking, lung cancers differ at the microscopic, anatomical, epidemiological and clinical level and harbor complex genetic and epigenetic alterations. Currently, lung cancer is divided into small cell lung carcinoma (SCLC) and non small cell lung carcinoma (NSCLC) for the purpose of clinical management. NSCLC constitutes 80–85% of lung cancers and is further divided into histological subtypes such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, etc.
The ultimate goal for lung cancer research is to develop a strategy to block the tumor progression and improve the prognosis of lung cancer. This goal can realistically be achieved only when the biological complexity of this disease is taken into account. To this end, identification and understanding of molecular markers that are mechanistically involved in tumor progression are needed. Our recent studies suggest histological subtype-dependent distinct correlations between the expression and/or subcellular localization of tumor suppressive maspin with the progression and prognosis of NSCLC. Maspin is an epithelial specific member of the serine protease inhibitor (serpin) superfamily but recently identified as an endogenous inhibitor of histone deacetylase 1 (HDAC1). This novel biochemical activity coincides with a consensus emerged recently from the evidence that nuclear maspin confers better differentiated epithelial phenotypes, decreased tumor angiogenesis, increased tumor sensitivity to drug-induced apoptosis, and a more favorable prognosis. In the current review, we discuss the evidence that maspin may be a marker that stratifies the progression and prognosis of different subtypes of NSCLC.
PMCID: PMC2908495  PMID: 20337574
lung cancer; molecular marker; prognosis; histological subtypes; histone deacetylase 1; natural HDAC inhibitor; subcellular localization; differential expression; drug discovery
25.  Family history of lung cancer in never smokers with non-small-cell lung cancer and its association with tumors harboring EGFR mutations 
INTRODUCTION
Inherited susceptibility to lung cancer is understudied. Never smokers are an important subgroup of patients enriched for tumors harboring oncogene aberrations in the EGFR and ALK genes. We aimed to better characterize the incidence of family history of lung cancer among never smokers with NSCLC.
METHODS
Clinicopathologic data, tumor genotype, family history of cancer, and specifically family history of lung cancer from 230 consecutive never smokers was retrospectively compiled and analyzed.
RESULTS
In our cohort, the median age was 56 years, 67% were women, 75% were white, 59% had advanced NSCLC and 87% had adenocarcinoma histology. In these tumors, 98/230 (42%) had an EGFR mutation, 17/155 (11%) had KRAS mutations and 27/127 (21%) had an ALK translocation. Family history of any cancer was common (57%) and specific family history of lung cancer was present in 42/230 cases (18%). The percentage of cases with family history of lung cancer was higher in the EGFR mutated versus EGFR wild-type NSCLCs. Out of the cases with a family history of any cancer, 22/53 (41.5%) EGFR mutated, 1/5 (20%) KRAS mutated and 3/19 (15.5%) ALK translocated cohorts had a family history of lung cancer. The ratio of family history of lung cancer to family history of cancer was significantly higher in the EGFR mutated cohort when compared to the ALK translocated plus KRAS mutated cohorts (p=0.039).
CONCLUSIONS
Family history of lung cancer is common in never smokers with NSCLC, and there seems to be a particular link in families in which the proband has an EGFR mutated tumor when compared to ALK translocated or KRAS mutated tumors. Further study of families with EGFR-mutated NSCLC may yield insights into the pathogenesis of this tumor type.
doi:10.1016/j.lungcan.2012.12.002
PMCID: PMC3566317  PMID: 23273562
lung cancer; non-small-cell lung cancer; family history; never smokers; epidermal growth factor receptor; EGFR; anaplastic lymphoma kinase; ALK; KRAS

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