Major Histological Types Research Articles

Involvement of aryl hydrocarbon receptor signaling in the development of small cell lung cancer induced by HPV E6/E7 oncoproteins

BackgroundLung cancers consist of four major types that and for clinical-pathological reasons are often divided into two broad categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). All major histological types of lung cancer are associated with smoking, although the association is stronger for SCLC and squamous cell carcinoma than adenocarcinoma. To date, epidemiological studies have identified several environmental, genetic, hormonal and viral factors associated with lung cancer risk. It has been estimated that 15-25% of human cancers may have a viral etiology. The human papillomavirus (HPV) is a proven cause of most human cervical cancers, and might have a role in other malignancies including vulva, skin, oesophagus, head and neck cancer. HPV has also been speculated to have a role in the pathogenesis of lung cancer. To validate the hypothesis of HPV involvement in small cell lung cancer pathogenesis we performed a gene expression profile of transgenic mouse model of SCLC induced by HPV-16 E6/E7 oncoproteins.MethodsGene expression profile of SCLC has been performed using Agilent whole mouse genome (4 × 44k) representing ~ 41000 genes and mouse transcripts. Samples were obtained from two HPV16-E6/E7 transgenic mouse models and from littermate's normal lung. Data analyses were performed using GeneSpring 10 and the functional classification of deregulated genes was performed using Ingenuity Pathway Analysis (Ingenuity® Systems, http://www.ingenuity.com).ResultsAnalysis of deregulated genes induced by the expression of E6/E7 oncoproteins supports the hypothesis of a linkage between HPV infection and SCLC development. As a matter of fact, comparison of deregulated genes in our system and those in human SCLC showed that many of them are located in the Aryl Hydrocarbon Receptor Signal transduction pathway.ConclusionsIn this study, the global gene expression of transgenic mouse model of SCLC induced by HPV-16 E6/E7 oncoproteins led us to identification of several genes involved in SCLC tumor development. Furthermore, our study reveled that the Aryl Hydrocarbon Receptor Signaling is the primarily affected pathway by the E6/E7 oncoproteins expression and that this pathway is also deregulated in human SCLC. Our results provide the basis for the development of new therapeutic approaches against human SCLC.

CpG Island Methylation According to the Histologic Patterns of Early Gastric Adenocarcinoma

BACKGROUNDAlthough the importance of aberrant DNA methylation in the development of gastric adenocarcinoma has been described, the mechanism of pathogenesis has not been revealed yet. We quantitatively analyzed methylation of four CpG islands and one repetitive DNA element, according to the histologic features of adenocarcinoma with precursor lesions.METHODSWe divided the cases as adenocarcinoma with intestinal type precursors (type A, n=19 cases) and adenocarcinoma with diffuse type precursors (type B, n=19 cases). We micro-dissected tumor cells and matched non-neoplastic gastric mucosa from the hematoxylin and eosin-stained slides.RESULTSA total of 20 CpG sites of long interspersed nucleotide element-1 (LINE1), RAR-related orphan receptor alpha (RORA), Kruppel-like factor 7 (KLF7), mutL homolog 1 (MLH1), MINT25, and CD133 were analyzed. Methylation was determined by bisulfate-pyro-sequencing, and hypomethylation of LINE1 and CD133 was noted in the tumors, compared to the levels in the non-neoplastic gastric mucosa (p=0.014 and p=0.015, respectively). A statistically different methylation pattern of CpG sites at CD133 and KLF7 was noted only in type B lesions, compared to that in matched non-neoplastic gastric mucosa (p=0.027 and p=0.043, respectively).CONCLUSIONSGiven that aberrant methylation occurs in a relatively early phase of carcinogenesis, different patterns of methylation may determine the carcinoma phenotype. However, further large-scale study is required to clarify the significance of this difference.

A Clinicopathological Study of Thyroid Cancers at King Edward Medical University / Mayo Hospital, Lahore

Abstract Objective: The study was conducted to determine the frequency and clinicopathological aspects of various types of thyroid cancers in patients presenting with goitres and thyroid nodules. Study Design: Descriptive cross sectional study. Place and Duration of Study: It was an 11 year ret-rospective study commencing from January 2000 to December 2010 conducted at the Department of Patho-logy, King Edward Medical University, Lahore, Pakis-tan. Materials and Methods: Clinical data and Histopa-thology Reports of 2785 thyroid surgical specimens referred from the Surgical Units of Mayo Hospital, La-hore were reviewed and malignant cases were retri-eved for inclusion in this study. Patients from both sexes and all age groups were included. Results: Reports of a total of 2785 thyroid specimens were reviewed, out of which 170 cases (6.10%) were found to be thyroid cancers. These comprised of 130 cancers (76.47%) in females and 40 cases (23.52%) in males giving a female to male ratio of 3.25:1. Patients ranged in age from 8 years to 90 years. Papillary Car-cinoma was the commonest thyroid cancer comprising of 116 cases (68.23%), followed by Follicular Carci-noma which constituted of 24 cases (14.11%). Medul-lary Thyroid Carcinoma, Anaplastic Thyroid Carcino-ma, Non-Hodgkin Lymphoma and Poorly Differenti-ated (Insular) Carcinoma each constituted of 11 cases (6.47%), 10 cases (5.88%), 4 cases (2.35%) and 2 ca-ses (1.17%) respectively. 2 cases (1.17%) of Carcino-ma Larynx showed local extension into the thyroid and there was a single case of Mixed Medullary / Papillary Carcinoma. 15 cases (8.82%) of these thyroid cancers were seen in children and adolescents. Papillary Carcinoma was also the commonest thyroid cancer in children comprising of 13 cases. One case of Papillary Carci-noma was detected incidentally in an excised Thyro-glossal duct cyst. Medullary Carcinoma (associated with MEN II syndrome) and Follicular Carcinoma constituted one case each of these childhood cancers. Conclusions: Papillary Carcinoma was the commo-nest morphological type of thyroid cancer in both sexes and all age groups. All major histological types of thyroid cancers were more common in females. Key Words: Papillary Carcinoma (PC), Follicular Carcinoma (FC), Medullary Thyroid Carcinoma (MTC), Anaplastic Thyroid Carcinoma (ATC), Thyro-glossal Duct Cyst Carcinoma (TDCC).

Thyroid cancer incidence patterns in the United States by histologic type, 1992-2006.

The increasing incidence of thyroid cancer in the United States is well documented. In this study, we assessed the incidence patterns by histologic type according to demographic and tumor characteristics to further our understanding of these cancers. We used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program for cases diagnosed during 1992-2006 to investigate patterns for the four major histologic types of thyroid cancer by gender, race/ethnicity, and age as well as registry, tumor stage, and size. Among women, papillary thyroid cancer rates were highest among Asians (10.96 per 100,000 woman-years) and lowest among blacks (4.90 per 100,000 woman-years); follicular cancer rates did not vary substantially by race/ethnicity (p-values >0.05), medullary cancer rates were highest among Hispanics (0.21 per 100,000 woman-years) and whites (0.22 per 100,000 woman-years), and anaplastic rates were highest among Hispanics (0.17 per 100,000 woman-years). Among men, both papillary and follicular thyroid cancer rates were highest among whites (3.58 and 0.58 per 100,000 man-years, respectively), medullary cancer rates were highest among Hispanics (0.18 per 100,000 man-years), and anaplastic rates were highest among Asians (0.11 per 100,000 man-years). Racial/ethnic-specific rates did not vary notably across registries. In contrast to age-specific rates of papillary thyroid cancer that peaked in midlife (age 50), especially pronounced among women, rates for follicular, medullary, and anaplastic types continued to rise across virtually the entire age range, especially for anaplastic carcinomas. Female-to-male incidence rate ratios among whites decreased with age most steeply for the follicular type and least steeply for the medullary type; it was <1 until the very oldest ages for the anaplastic type. We conclude that the similar age-specific patterns and lack of geographical variation across the SEER racial/ethnic groups indicate that detection effects cannot completely explain the observed thyroid cancer incidence patterns as variation in the amount or quality of healthcare provided has been shown to vary by SEER racial/ethnic groups, gender, and age. We find that the variations in age-specific patterns by gender and across histologic types are intriguing and recommend that future etiologic investigation focus on exogenous and endogenous exposures that are experienced similarly by racial/ethnic groups, more strongly among women, and distinctively by age.

Advances in neuroendocrine lung tumors

Pulmonary neuroendocrine (NE) tumors include a spectrum of tumors from the low-grade typical carcinoid (TC) and intermediate-grade atypical carcinoid (AC) to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and small-cell carcinoma (SCLC). Nodular NE proliferations ≥ 0.5 cm are classified as carcinoid tumors and smaller ones are called tumorlets. When NE cell hyperplasia and tumorlets are extensive they represent the rare preinvasive lesion for carcinoids known as diffuse idiopathic pulmonary NE cell hyperplasia. Carcinoid tumors have significant clinical, epidemiologic and genetic differences from the high-grade SCLC and LCNEC. Multiple endocrine neoplasia type I can be found in TC and AC patients but not those with LCNEC and SCLC. Also both LCNEC and SCLC can demonstrate histologic heterogeneity with other major histologic types of lung carcinoma such as adenocarcinoma or squamous cell carcinoma, but is not characteristic of TC or AC. Genetic changes are very high in SCLC and LCNEC, but usually low for TC, intermediate for AC. The diagnosis of SCLC, TC and AC can be made by light microscopy without the need for special tests in most cases, but for LCNEC it is required to demonstrate NE differentiation by immunohistochemistry or electron microscopy.

Cigarette smoking and lung cancer – Risk estimates for the major histological types from a pooled analysis of European case-control studies

Cigarette smoking and lung cancer – Risk estimates for the major histological types from a pooled analysis of European case-control studies

Immunohistochemical evidence for the over-expression of Glutathione peroxidase 3 in clear cell type ovarian adenocarcinoma

Glutathione peroxidase 3 (GPX3) is a member of glutathione peroxidase family, exerting one of the most important cellular defense mechanisms against stress signals, including oxidative damage. In this study, the expression of GPX3 mRNA and protein was analyzed for ovarian cancer tissues to test its applicability as a biomarker that can distinguish the four major histologic types of epithelial ovarian cancer. A public microarray dataset containing 99 ovarian cancer and 4 normal ovary samples was downloaded, and GPX3 mRNA expression was analyzed. The expression of GPX3 protein was measured by immunohistochemical staining in 40 epithelial ovarian cancer tissues, 10 for each of the serous, endometrioid, mucinous, and clear cell type. Histoscores were made from the immunohistostaining, and analysis of variance (ANOVA) was performed to quantitate the differences in protein level. Analysis of genomic dataset confirms a GPX3 overexpression in clear cell type ovarian adenocarcinoma compared with normal ovary and 3 other subtypes of epithelial ovarian cancer at mRNA level. GPX3 also shows the highest average antibody staining intensities in clear cell type ovarian adenocarcinomas over the other 3 types in immunostaining on tissue arrays. This is the first validation of GPX3 as a clear cell type-specific biomarker in ovarian cancer patients' tissues by immunostaining. GPX3 may serve as an important molecular marker for the diagnosis and molecular understanding of clear cell carcinoma of the ovary.

Pattern and outcome of childhood teratoma: a 10-year review.

Background: Teratomas are neoplasms which originate from pluripotent stem cells. They are composed of a wide variety of tissues foreign to the organ or anatomic site in which they arose. This study sought to determine the clinical manifestations and outcome of treatment of childhood teratomas. Method: A retrospective analysis of the case files of children treated for teratoma at the University of Benin Teaching Hospital Benin City, Nigeria between January 1999 and December 2008 was done. Results: Fifty-three children aged between 5 days and 16 years, comprising 15 males and 38 females with male:female ratio of 2:5 were treated for teratoma; gonadal 27(50.9%) and extragonadal 26 (49.1%). Ovarian, 23 (43.4%) and sacrococcygeal, 17 (32.1%) sites were frequently involved. Other sites included testicular, 4 (7.5%), retroperitoneal, 4 (7.5%) and renal, 2 (3.8%), while posteriormediastinal, cervical and breast involvement were 1 (1.9%) each. Despite late presentation, no frankly malignant primary teratoma was diagnosed. Benign cystic teratomas with malignant elementscomprising yolk sac tumour and immature neuroepithelial elements (mixed germ cells tumour) were the major histological types. Complete tumour resection that included total coccygectomy, oophorectomyand orchidectomy, plus combination chemotherapy using vincristine, actinomycin, and cyclophosphamide was curative in 25 (47.2%) children. Eighteen (34%) cases of recurrence were all malignant. They presented very late with rapid disease progression that resulted in 10 (18.8%) deaths during the five years of follow-up. Conclusion: Although all primary teratoma were benign, recurrent malignant tumours with rapid progression to carcinomatosis, multiple organs failure and deaths were common in childhood teratoma. We advocate close follow-up of all children with teratoma to detect and commence early treatment.

A combination of functional polymorphisms in the CASP8, MMP1, IL10 and SEPS1 genes affects risk of non-small cell lung cancer

Exposure to tobacco smoke as well as environmental and occupational factors is the major cause of lung cancer. Non-small cell lung cancer (NSCLC) is the major histological type. Genes in pathways affecting inflammation, cellular stress and apoptosis are important, and the extent of inflammation in the lung could be affected by polymorphisms modifying these responses. In the present study we have investigated whether a combination of potential functional polymorphisms in genes related to inflammation may modulate risk of NSCLC. Eleven functional polymorphisms in nine genes were analyzed for association with risk of NSCLC in 882 subjects from the Norwegian population. The results showed that individuals carrying combination of three functional polymorphisms in the caspase-8, matrix metalloproteinase-1, seleno-protein S1, and interleukin-10 genes had two-fold increased risk of NSCLC (OR 2.06 (95% CI, 1.19–3.47) whereas individuals with four risk genotypes had 4.62-fold increased risk (OR 4.62, 95% CI, 1.69–12.63). These results highlight the need to investigate the combinatory effects of multiple SNPs in the carcinogenesis of the lung.

Abstract 1993: Higher activity of cell proliferation is associated with poor survival in lung adenocarcinoma

Abstract The number of patients with lung adenocarcinoma, a major histological type of lung cancer, has soared recently. Although some lung adenocarcinoma patients could be diagnosed at early stages and received surgical resection, nearly 50% of patients still died from recurrence. This phenomenon indicates that using only traditional prognostic factors, like TMN staging, is not sufficient for regimen decision. Here we proposed a bioinformatic method to evaluate the activity of cell cycle from expression profiles and proved that the activity of cell cycle can be applied as prognostic factor of lung adenocarcinoma, especially for early stages. A gene set named as cell cycle signature (CCS), which correlated with cell cycling, was used to measure the activity of tumor proliferation. The E2F1 target genes and E2F3 target genes were also applied to measure the E2F signaling pathway activity, which was regulated by the cell cycle. The prognostic ability of these gene sets was evaluated by applying Cox hazard proportional analysis to three microarray datasets of lung adenocarcinoma. Our result revealed that the association between high activities of cell cycle and poor survival outcomes existed in lung adenocarcinoma patients. The result of Cox hazard proportional analysis showed that the CCS and E2F1/E2F3 target genes are significant contributors to survival risk. The p-values of CCS, E2F1/E2F3 target genes were all showed significant (p&amp;lt;0.05), and these three gene sets still gave statistical significances after the survival analysis was applied on only early stage lung adenocarcinoma. The hazard ratios of CCS, E2F1 target genes and E2F3 target genes were 5.69, 3.32, and 3.96, respectively; all p-values were smaller than 0.002. We demonstrated that the three gene sets, which accountable for the activity of cell cycle, can be applied as prognostic factors for lung adenocarcinoma, including early stage patients. Our data inferred that tumor with higher activity of proliferation is malignant eventhough its size may still be small. This finding is valuable in predicting the survival of early stage lung adenocarcinoma patients and might be useful for making treatment decisions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1993.

A Pooled Analysis on the Associations between Involuntary Smoking and Lung Cancer Risk by Histological Types

Abstract Background: While the association between involuntary tobacco smoke exposure and lung cancer is well established, few studies with sufficient power have been conducted to evaluate the relationship between involuntary smoking (IS) and lung cancer by histological type, especially for the association between IS and small cell lung cancer among nonsmokers. Methods: We evaluated the associations between IS and lung cancer by histological type based on a pooled data of the International Lung Cancer Consortium (ILCCO). The individual-level epidemiological data from 17 participating studies were pooled, including 2,218 non-smoking lung cancer cases and 6,243 non-smoking controls. Logistic regression models were used to obtain adjusted odds ratios (OR) and 95% confidence intervals (CI), using SAS v9. Likelihood ratio tests were used to assess heterogeneity by study site. Results: Among never tobacco smokers, IS exposure was associated with lung cancer with an adjusted OR of 1.33 (95% CI 1.18, 1.50), compared to never exposure to IS, when adjusting for age, sex, ethnicity, and study site. Similar associations were observed in different histological types of lung cancer with adjusted ORs of 1.38 (95% CI 0.97, 1.98) for squamous cell carcinoma, 1.26 (95% CI 1.08, 1.46) for adenocarcinoma, 2.92 (95% CI 1.55, 5.48) for small cell lung cancer, and 1.30 (95% CI 1.14, 1.49) for non-small cell lung cancer. Similar associations with ever IS exposure were observed when the overall population including nonsmokers and smokers was included in the analysis. No apparent association was observed with IS exposure in childhood. Conclusion: This is the first study with a relatively large sample size investigating the relationship between IS exposure and small cell lung cancer among nonsmokers. Our results corroborated the association between IS and lung cancer regardless of histological types, including adenocarcinoma, and we observed the strongest association between IS and small cell lung cancer. Our study provides more precise estimates of the impact of IS on major histological types of lung cancer and suggests the importance of smoking intervention for lung cancer prevention, especially for small cell lung cancer type.

Risks of second primary cancer among patients with major histological types of lung cancers in both men and women.

Background:Patterns of second primary cancers (SPCs) following first primary lung cancers (FPLCs) may provide aetiological insights into FPLC.Methods:Cases of FPLCs in 13 cancer registries in Europe, Australia, Canada, and Singapore were followed up from the date of FPLC diagnosis to the date of SPC diagnosis, date of death, or end of follow-up. Standardised incidence ratios (SIRs) were calculated to estimate the magnitude of SPC development following squamous cell carcinoma (SCC), small cell lung carcinoma (SCLC), and adenocarcinoma (ADC).Results:Among SCC patients, male SIR=1.58 (95% confidence interval (CI)=1.50–1.66) and female SIR=2.31 (1.94–2.72) for smoking-related SPC. Among SCLC patients, the respective ratios were 1.39 (1.20–1.60) and 2.28 (1.73–2.95), and among ADC patients, they were 1.73 (1.57–1.90) and 2.24 (1.91–2.61). We also observed associations between first primary lung ADC and second primary breast cancer in women (SIR=1.25, 95% CI=1.05–1.48) and prostate cancer (1.56, 1.39–1.79) in men.Conclusion:The FPLC patients carried excess risks of smoking-related SPCs. An association between first primary lung ADC and second primary breast and ovarian cancer in women at younger age and prostate cancers in men may reflect an aetiological role of hormones in lung ADC.

Sarcomatoid mesothelioma: a clinical–pathologic correlation of 326 cases

Sarcomatoid mesothelioma is the least common, but most aggressive of the three major histological types of mesotheliomas. This study comprises 326 cases of sarcomatoid mesotheliomas among 2000 consecutive malignant mesothelioma cases received in consultation (16%). Patients included 312 men (96%) and 14 women (4%), with a median age of 70 years (range 41–94 years). Most tumors were pleural (319; 98%), and 7 were peritoneal (2%). Some desmoplastic features were identified in 110 cases (34%), and 70 (21%) were classified as desmoplastic. Rare subtypes included two cases with a lymphohistiocytoid pattern (<1%) and eight heterologous mesotheliomas (2%). Labeling for cytokeratins (CKs) was observed in 261/280 cases (93%), and for calretinin and vimentin in 31 and 91%, respectively. Pleural plaques were present in 79% of cases for which information was available, and asbestosis was diagnosed in 34/127 cases (27%). Median survival was 3.5 months. Fiber analysis was performed in 61 cases. The median asbestos body count was 1640/g wet lung tissue (by light microscopy). Amosite fibers were the most commonly identified fibers using energy-dispersive X-ray analysis and were significantly higher in the sarcomatoid cases, as were uncoated fibers using scanning electron microscopy. This study represents the largest series of sarcomatoid and desmoplastic malignant mesotheliomas to date and confirms the diagnostic usefulness of CK immunohistochemistry. The relationship with asbestos exposure—particularly amosite—and an association with pleural plaques and less often asbestosis is confirmed.

Targeting Ovarian Cancer-Initiating Cells

Evidence supports that a variety of cancers are sparked by the growth of cells that exhibit characteristics of stem cells. Such cancer-initiating cells are capable of populating a tumor with a heterogeneous group of daughter cells while still maintaining the ability to self-renew. Several groups have recently reported the identification of cancer-initiating cells in ovarian cancer, the most lethal gynecologic malignancy. Epithelial ovarian cancer comprises 90% of cancers of the ovary and consists of four major histologic types, each bearing some resemblance to tissues in the peritoneal cavity. Although epithelial ovarian cancer has traditionally been thought to originate from the single layer of cells surrounding each ovary, new findings suggest that many of these cancers derive from Müllerian epithelium. This raises questions about the origin of ovarian cancer-initiating cells, and if there may be more than one source. Despite the initial effectiveness of primary therapy against advanced stage ovarian cancer, most of these cases recur, months to years following diagnosis. The cause of disease recurrence is unknown, but may involve cancer-initiating cells that survive chemotherapy and enter a period of dormancy while residing in as-yet undefined niches within the body before being triggered to initiate renewed growth. Herein the nature of these cells is explored as well as novel approaches for therapeutic targeting.

Lung cancer incidence trends by histologic type in areas of California vs. other areas in the Surveillance, Epidemiology and End Results Program

Background: This study compared temporal trends in incidence rates for the major histological types of lung cancer in areas of California (CA), which started a comprehensive state tobacco control program in 1989, and other selected geographic areas for which data on long-term trends were available. Methods: Age-standardized incidence rates (ASIRs) within age 25–64 years, most likely to have been affected by tobacco control programs, were compared for lung-bronchus adenocarcinoma, squamous cell carcinoma, and small cell carcinoma in 1992–2005 for non-Hispanic whites in three areas of CA in the Surveillance, Epidemiology and End Results (SEER) Program vs. 10 non-CA SEER areas. For 1985–2005, data were available for all whites in the San Francisco-Oakland CA SEER area and eight non-CA SEER areas. Results: ASIRs were roughly similar in CA and non-CA areas in 1992, but declines from 1992 to 2005 were larger in CA than non-CA areas for each histological type. In San Francisco-Oakland CA, declines were not clearly evident from 1985 to 1988 (before the tobacco control program started) but from 1992 to 2005 declines were larger than in the non-CA areas. Conclusions: These findings provide further support for expansion of statewide tobacco control programs, in order to reduce incidence rates for all histologic types of lung cancer.

A Genome-wide Association Study of Lung Cancer Identifies a Region of Chromosome 5p15 Associated with Risk for Adenocarcinoma

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.

MicroRNA Expression in Squamous Cell Carcinoma and Adenocarcinoma of the Esophagus: Associations with Survival

The dismal outcome of esophageal cancer patients highlights the need for novel prognostic biomarkers, such as microRNAs (miRNA). Although recent studies have established the role of miRNAs in esophageal carcinoma, a comprehensive multicenter study investigating different histologic types, including squamous cell carcinoma (SCC) and adenocarcinoma with or without Barrett's, is still lacking. miRNA expression was measured in cancerous and adjacent noncancerous tissue pairs collected from 100 adenocarcinoma and 70 SCC patients enrolled at four clinical centers from the United States, Canada, and Japan. Microarray-based expression was measured in a subset of samples in two cohorts and was validated in all available samples. In adenocarcinoma patients, miR-21, miR-223, miR-192, and miR-194 expression was elevated, whereas miR-203 expression was reduced in cancerous compared with noncancerous tissue. In SCC patients, we found elevated miR-21 and reduced miR-375 expression levels in cancerous compared with noncancerous tissue. When comparing cancerous tissue expression between adenocarcinoma and SCC patients, miR-194 and miR-375 were elevated in adenocarcinoma patients. Significantly, elevated miR-21 expression in noncancerous tissue of SCC patients and reduced levels of miR-375 in cancerous tissue of adenocarcinoma patients with Barrett's were strongly associated with worse prognosis. Associations with prognosis were independent of tumor stage or nodal status, cohort type, and chemoradiation therapy. Our multicenter-based results highlight miRNAs involved in major histologic types of esophageal carcinoma and uncover significant associations with prognosis. Elucidating miRNAs relevant to esophageal carcinogenesis is potentially clinically useful for developing prognostic biomarkers and identifying novel drug targets and therapies.

Comprehensive Analysis of Conditioned Media from Ovarian Cancer Cell Lines Identifies Novel Candidate Markers of Epithelial Ovarian Cancer

Ovarian cancer remains a deadly threat to women as the disease is often diagnosed in the late stages when the chance of survival is low. There are no good biomarkers available for early detection and only a few markers have shown clinical utility for prognosis, response to therapy and disease recurrence. We mined conditioned media of four ovarian cancer cell lines (HTB75, TOV-112D, TOV-21G and RMUG-S) by two-dimensional liquid chromatography-mass spectrometry. Each cell line represented one of the major histological types of epithelial ovarian cancer. We identified 2039 proteins from which 228 were extracellular and 192 were plasma membrane proteins. Within the latter list, we identified several known markers of ovarian cancer including three that are well established, namely, CA-125, HE4, and KLK6. The list of 420 extracellular and membrane proteins was cross-referenced with the proteome of ascites fluid to generate a shorter list of 51 potential biomarker candidates. According to Ingenuity Pathway Analysis, two of the top 10 diseases associated with the list of 51 proteins were cancer and reproductive diseases. We selected nine proteins for preliminary validation using 20 serum samples from healthy women and 10 from women with ovarian cancer. Of the nine proteins, clusterin (increase) and IGFBP6 (decrease) showed significant differences between women with or without ovarian cancer. We conclude that in-depth proteomic analysis of cell culture supernatants of ovarian cancer cell lines can identify potential ovarian cancer biomarkers that are worth further clinical validation.

Cannabis, tobacco and domestic fumes intake are associated with nasopharyngeal carcinoma in North Africa

Background:The lifestyle risk factors for nasopharyngeal carcinoma (NPC) in North Africa are not known.Methods:From 2002 to 2005, we interviewed 636 patients and 615 controls from Algeria, Morocco and Tunisia, frequency-matched by centre, age, sex, and childhood household type (urban/rural). Conditional logistic regression was used to evaluate the association of lifestyles with NPC risk, controlling for socioeconomic status and dietary risk factors.Results:Cigarette smoking and snuff (tobacco powder with additives) intake were significantly associated with differentiated NPC but not with undifferentiated carcinoma (UCNT), which is the major histological type of NPC in these populations. As demonstrated by a stratified permutation test and by conditional logistic regression, marijuana smoking significantly elevated NPC risk independently of cigarette smoking, suggesting dissimilar carcinogenic mechanisms between cannabis and tobacco. Domestic cooking fumes intake by using kanoun (compact charcoal oven) during childhood increased NPC risk, whereas exposure during adulthood had less effect. Neither alcohol nor shisha (water pipe) was associated with risk.Conclusion:Tobacco, cannabis and domestic cooking fumes intake are risk factors for NPC in western North Africa.

Classification of follicular cell tumors of the thyroid gland: Analysis involving Japanese patients from one institute

Prognostic analyses of thyroid carcinomas of follicular cell origin were carried out on patients treated at Kuma Hospital, Kobe, Japan. A new histopathological classification based on the prognostic evidence is proposed in this study, and it is applicable to the patients treated curatively. Major histological types of papillary carcinoma, follicular carcinoma and poorly differentiated carcinoma were combined into one single entity of follicular cell adenocarcinoma because (i) they have the same cell origin (follicular cell); (ii) clear-cut separation of papillary and follicular carcinoma is not always possible, and 10 year cause-specific survival was essentially similar when the patients were treated curatively; and (iii) poorly differentiated carcinoma usually has a background of either papillary or follicular carcinoma. This adenocarcinoma together with undifferentiated carcinoma was stratified into four prognostic groups using pure morphological criteria of the degree of cellular differentiation and histological grade. They are termed well-differentiated adenocarcinoma, moderately differentiated adenocarcinoma, poorly differentiated carcinoma and undifferentiated carcinoma of the thyroid. The 10 year disease-free survival rates were 86.3-93.1%, 65.4-78.7%, and 43.0-53.8%, and 0%, respectively. The 10 year cause-specific survival rates were 97.2-100%, 91.5-97.4%, and 71.2-80.0%, and 0%, respectively.