J K Field

Publications of J K Field

• The clinical determinants of malignant transformation in oral epithelial dysplasia.

  Authors: M W Ho, J M Risk, J A Woolgar, E A Field, J K Field, J Steele, B P Rajalwat, A Triantafyllou, S N Rogers, D Lowe, R J Shaw

  Oral oncology. 05/2012;

  BACKGROUND: While the size and clinical appearance are known risk factors for malignant transformation of potentially malignant oral the importance of site, grade of dysplasia and exposure toBACKGROUND: While the size and clinical appearance are known risk factors for malignant transformation of potentially malignant oral the importance of site, grade of dysplasia and exposure to environmental carcinogens remains controversial. We aim to report the clinical determinants of malignant progression in a series of patients with histopathologically graded oral epithelial dysplasia (OED). METHODS: We recruited patients with a histopathological diagnosis of OED to a longitudinal observational study in a tertiary oral dysplasia clinic. Clinical, histopathological and risk factor data were recorded at baseline. One of three clinical endpoints were determined: malignant transformation, progression of dysplasia grade, remission/stable dysplasia grade. RESULTS: Ninety-one patients meeting the criteria gave consent for inclusion to the cohort, with outcomes reported after a median follow up of 48months. An estimated 22% (SE 6%) of patients underwent malignant transformation within 5years, with significant predictors being: non-smoking status (χ(2)=15.1, p=0.001), site (χ(2)=15.3, p=0.002), non-homogeneous appearance (χ(2)=8.2, p=0.004), size of lesion >200mm(2) (χ(2)=4.7, p=0.03) and, of borderline significance, high grade (χ(2)=5.8, p=0.06). Gender, age, number of lesions and alcohol history did not predict for malignant transformation. CONCLUSIONS: Although a number of these clinical determinants have previously been associated with higher malignant transformation in OED, the high-risk nature of lesions in non-smokers is of particular note and requires a greater emphasis and recognition amongst clinicians dealing with OED. It suggests that those non-smokers with OED, have an inherited or acquired predisposition and should be treated more aggressively; these should form the focus for further investigation.

• Prognostic value of TP53, KRAS and EGFR mutations in Non-Small Cell Lung Cancer: EUELC cohort.

  Authors: C Scoccianti, A Vesin, G Martel, M Olivier, E Brambilla, J-F Timsit, L Tavecchio, C Brambilla, J K Field, P Hainaut

  The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 01/2012;

  Non-Small Cell Lung cancer samples from the European Early Lung Cancer biobank were analysed to assess the prognostic significance of mutations in TP53, KRAS and EGFR genes.The series included 11Non-Small Cell Lung cancer samples from the European Early Lung Cancer biobank were analysed to assess the prognostic significance of mutations in TP53, KRAS and EGFR genes.The series included 11 never smokers, 86 former smokers, 152 current smokers and 1 patient without smoking status informed. There were 110 Squamous Cell Carcinomas (SCC), 133 ADenoCarcinoma (ADC) and 7 Large Cell Carcinoma or mixed histologies. Expression of p53 protein was analysed by immunohistochemistry. DNA was extracted from frozen tumour tissues.TP53 mutations were detected in 48.8% of cases and were more frequent among SCC than ADC (p<0.0001). TP53 mutation status was not associated with prognosis. G to T transversions, known to be associated with smoking, were marginally more common among patients who developed a second-primary lung cancer or recurrence/metastasis (Progressive Disease). EGFR mutations were almost exclusively found in never smoking females (p=0.0067). KRAS mutations were detected in 18.5% of cases, mainly ADC (p<0.0001), and showed a tendency for association with Progressive Disease status.These results suggest that mutations are good markers of different aetiologies and histopathological forms of lung cancers but have little prognostic value, with the exception of KRAS mutation which may have a prognostic value in ADC.

• Smoking history and lung carcinoma: KRAS mutation is an early hit in lung adenocarcinoma development.

  Authors: F B Thunnissen, C Prinsen, B Hol, M Van der Drift, A Vesin, C Brambilla, L Montuenga, J K Field

  Lung cancer (Amsterdam, Netherlands). 08/2011; 75(2):156-60.

  In a European multicenter prospective study patients with lung cancer were interviewed for smoking history and biological samples centrally collected. The aim of this study was to compare KRASIn a European multicenter prospective study patients with lung cancer were interviewed for smoking history and biological samples centrally collected. The aim of this study was to compare KRAS mutation analysis with smoking status at the time of diagnosis. A nested case-study was performed on 233 non-small cell lung carcinomas. Cases were selected on the basis of progressive disease or disease-free post surgery based on specific criteria. KRAS mutation analysis was performed with the point-EXACCT method. KRAS mutations were found in 39 adenocarcinomas and 1 squamous cell carcinoma in the 233 NSCLC. The median quitting smoking time (QST) for patients with and without KRAS mutations was 9 years, interquartile range [IQR 16-38] and 3 years, IQR [13-50], respectively (p=0.039). No difference was found for age at initiation of smoking, duration of smoking, average tobacco consumption, and smoking status at the time of diagnosis. The QST was longer for patients with KRAS mutations, supporting the notion that the presence of a KRAS mutation is a dominant early effect, supporting its role as a driver oncogen.

• Comparison of discriminatory power and accuracy of three lung cancer risk models.

  Authors: A M D'Amelio, A Cassidy, K Asomaning, O Y Raji, S W Duffy, J K Field, M R Spitz, D Christiani, C J Etzel

  British journal of cancer. 07/2010; 103(3):423-9.

  Three lung cancer (LC) models have recently been constructed to predict an individual's absolute risk of LC within a defined period. Given their potential application in prevention strategies, aThree lung cancer (LC) models have recently been constructed to predict an individual's absolute risk of LC within a defined period. Given their potential application in prevention strategies, a comparison of their accuracy in an independent population is important. We used data for 3197 patients with LC and 1703 cancer-free controls recruited to an ongoing case-control study at the Harvard School of Public Health and Massachusetts General Hospital. We estimated the 5-year LC risk for each risk model and compared the discriminatory power, accuracy, and clinical utility of these models. Overall, the Liverpool Lung Project (LLP) and Spitz models had comparable discriminatory power (0.69), whereas the Bach model had significantly lower power (0.66; P=0.02). Positive predictive values were highest with the Spitz models, whereas negative predictive values were highest with the LLP model. The Spitz and Bach models had lower sensitivity but better specificity than did the LLP model. We observed modest differences in discriminatory power among the three LC risk models, but discriminatory powers were moderate at best, highlighting the difficulty in developing effective risk models.

• EUELC project: a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration.

  Authors: J K Field, T Liloglou, A Niaz, J Bryan, J R Gosney, T Giles, C Brambilla, E Brambilla, A Vesin, J F Timsit [......] H D Becker, J S Elborn, N D Magee, L M Montuenga, M J Pajares, M D Lozano, K J O'Byrne, D J Harrison, J Niklinski, A Cassidy

  The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology. 12/2009; 34(6):1477-1486.

  The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue thisThe European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular-pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARbeta genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes.

• Cytoglobin is upregulated by tumour hypoxia and silenced by promoter hypermethylation in head and neck cancer.

  Authors: R J Shaw, M. M Omar, S. Rokadiya, F. A. Kogera, D Lowe, G. L. Hall, J A Woolgar, J. Homer, T Liloglou, J K Field, J M Risk

  British journal of cancer. 08/2009; 101(1):139-44.

  BACKGROUND: Cytoglobin (Cygb) was first described in 2002 as an intracellular globin of unknown function. We have previously shown the downregulation of cytoglobin as a key event in a familial cancerBACKGROUND: Cytoglobin (Cygb) was first described in 2002 as an intracellular globin of unknown function. We have previously shown the downregulation of cytoglobin as a key event in a familial cancer syndrome of the upper aerodigestive tract. METHODS: Cytoglobin expression and promoter methylation were investigated in sporadic head and neck squamous cell carcinoma (HNSCC) using a cross-section of clinical samples. Additionally, the putative mechanisms of Cygb expression in cancer were explored by subjecting HNSCC cell lines to hypoxic culture conditions and 5-aza-2-deoxycitidine treatment. RESULTS: In clinically derived HNSCC samples, CYGB mRNA expression showed a striking correlation with tumour hypoxia (measured by HIF1A mRNA expression P=0.013) and consistent associations with histopathological measures of tumour aggression. CYGB expression also showed a marked negative correlation with promoter methylation (P=0.018). In the HNSCC cell lines cultured under hypoxic conditions, a trend of increasing expression of both CYGB and HIF1A with progressive hypoxia was observed. Treatment with 5-aza-2-deoxycitidine dramatically increased CYGB expression in those cell lines with greater baseline promoter methylation. CONCLUSION: We conclude that the CYGB gene is regulated by both promoter methylation and tumour hypoxia in HNSCC and that increased expression of this gene correlates with clincopathological measures of a tumour's biological aggression.

• Epigenetic silencing of the endothelin-B receptor gene in non-small cell lung cancer

  Authors: L.J. Knight, J. Burrage, S.R. Bujac, C. Haggerty, A. Graham, N.J. Gibson, G. Ellison, J.W. Growcott, A.N. Brooks, A.M. Hughes, G. Xinarianos, G. Nikolaidis, J.K. Field, T. Liloglou

  Int.J.Oncol. 02/2009; 34(2).

  Endothelin-1 is overexpressed in several tumor types. Activation of the endothelin-A (ETA) receptor may promote cell growth, angiogenesis and invasion, and inhibits the apoptotic process, whileEndothelin-1 is overexpressed in several tumor types. Activation of the endothelin-A (ETA) receptor may promote cell growth, angiogenesis and invasion, and inhibits the apoptotic process, while activation of the endothelin-B (ETB) receptor may induce cell death by apoptosis and inhibit tumor progression. Hypermethylation and subsequent silencing of the ETB receptor gene promoter has been reported in some cancer types. As the endothelin pathway is subject to research for pharmacological cancer treatment, we investigated the extent of epigenetic deregulation of the ETB receptor gene in non-small cell lung cancer (NSCLC). We scanned 64 NSCLC paired tumor/normal surgical specimens for the ETB receptor promoter for methylation by developing four pyrosequencing assays that covered 24 CpGs. The ETB receptor promoter was significantly hypermethylated in 31 (48%) of tumor samples, presenting considerably higher methylation in 22/24 CpG sites compared with the normal counterpart tissues. ETB receptor mRNA levels were reduced in all lung tumors compared with normal adjacent lung tissue, indicating the potentially important involvement of this gene in lung cancer development. Furthermore, tumor samples with ETB receptor gene methylation tended to have lower receptor mRNA levels compared with unmethylated tumor specimens, suggesting a primary epigenetic role in ETB receptor silencing. Our results point to a significant involvement of ETB receptor epigenetic deregulation in the pathogenesis of lung cancer making the gene a promising candidate biomarker for response to regimens modulating the endothelin axis

• Lung cancer screening: the way forward.

  Authors: J K Field, S W Duffy

  British journal of cancer. 09/2008; 99(4):557-62.

  To take lung cancer screening into national programmes, we first have to answer the question whether low-dose computed tomography (LDCT) screening and treatment of early lesions will decrease lungTo take lung cancer screening into national programmes, we first have to answer the question whether low-dose computed tomography (LDCT) screening and treatment of early lesions will decrease lung cancer mortality compared with a control group, to accurately estimate the balance of benefits and harms, and to determine the cost-effectiveness of the intervention.

• The LLP risk model: an individual risk prediction model for lung cancer.

  Authors: A Cassidy, J P Myles, M van Tongeren, R D Page, T Liloglou, S W Duffy, J K Field

  British journal of cancer. 02/2008; 98(2):270-6.

  Using a model-based approach, we estimated the probability that an individual, with a specified combination of risk factors, would develop lung cancer within a 5-year period.Data from 579 lung cancerUsing a model-based approach, we estimated the probability that an individual, with a specified combination of risk factors, would develop lung cancer within a 5-year period.Data from 579 lung cancer cases and 1157 age- and sex-matched population-based controls were available for this analysis. Significant risk factors were fitted into multivariate conditional logistic regression models. The final multivariate model was combined with age-standardised lung cancer incidence data to calculate absolute risk estimates.Combinations of lifestyle risk factors were modelled to create risk profiles. For example, a 77-year-old male non-smoker, with a family history of lung cancer (early onset) and occupational exposure to asbestos has an absolute risk of 3.17% (95% CI, 1.67-5.95). Choosing a 2.5% cutoff to trigger increased surveillance, gave a sensitivity of 0.62 and specificity of 0.70, while a 6.0% cutoff gave a sensitivity of 0.34 and specificity of 0.90. A 10-fold cross validation produced an AUC statistic of 0.70, indicating good discrimination.If independent validation studies confirm these results, the LLP risk models' application as the first stage in an early detection strategy is a logical evolution in patient care.

• Family history and risk of lung cancer: age-at-diagnosis in cases and first-degree relatives.

  Authors: A Cassidy, J P Myles, S W Duffy, T Liloglou, J K Field

  British journal of cancer. 12/2006; 95(9):1288-90.

  To investigate the little known risk of lung cancer at an early age when a first-degree relative has had such a diagnosis, 579 incident cases and 1157 population controls were studied in LiverpoolTo investigate the little known risk of lung cancer at an early age when a first-degree relative has had such a diagnosis, 579 incident cases and 1157 population controls were studied in Liverpool between 1998 and 2004 using standardised questionnaires covering demography and lifestyle. A history of lung cancer in first-degree relatives was associated with a significantly increased risk in the proband where in both individuals the cancers were diagnosed before the age of 60 years (odds ratio (OR)=4.89; 95% confidence interval (CI): 1.47-16.25). A significantly elevated risk of lung cancer was also observed in association with a relative affected before the age of 60 years, regardless of age-at-onset of the disease (OR=2.08; 95% CI: 1.20-3.59). This finding is strongly consistent with a genetic component in early-onset lung cancer risk.

• P096 Cytoglobin: A Candidate Tumor Suppressor Gene Epigenetically Silenced in Head and Neck Cancer.

  Authors: R J Shaw, T Liloglou, J K Field, J M Risk

  Archives of otolaryngology--head & neck surgery. 08/2006; 132(8):884.

• S076 Epigenetics of Head and Neck Cancer: The Role of Pyrosequencing.

  Authors: R J Shaw, T Liloglou, S Rogers, J Brown, D Lowe, J K Field, J M Risk

  Archives of otolaryngology--head & neck surgery. 08/2006; 132(8):856.

• P182 Clinical Application of Epigenetic Biomarkers in Head and Neck Cancer.

  Authors: R J Shaw, G Hall, T Liloglou, S Rogers, J Brown, J K Field, J M Risk

  Archives of otolaryngology--head & neck surgery. 08/2006; 132(8):900-901.

• The Liverpool Statement 2005: priorities for the European Union/United States spiral computed tomography collaborative group.

  Authors: J K Field, R A Smith, S W Duffy, C D Berg, R van Klaveren, C I Henschke, D Carbone, P E Postmus, E Paci, F R Hirsch, J L Mulshine

  Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 07/2006; 1(5):497-8.

  The Liverpool Statement 2005 was developed at the Fourth International Lung Cancer Molecular Biomarkers Workshop in Liverpool (October 27-29, 2005) and focused on the priorities for the EuropeanThe Liverpool Statement 2005 was developed at the Fourth International Lung Cancer Molecular Biomarkers Workshop in Liverpool (October 27-29, 2005) and focused on the priorities for the European Union/United States (EU-US) Spiral Computed Tomography (CT) Collaborative Group. The application of spiral CT technology for early lung cancer screening has gained enormous momentum in the past 5 years. The EU-US Spiral CT Collaboration was initiated in 2001 in Liverpool, and subsequent meetings throughout Europe have resulted in the development of collaborative protocols and minimal data sets that provide a mechanism for the different trial groups to work together, with the ultimate aim to pool results. Considerable progress has been made with major national screening trials in the U.S. and Europe, which include IELCAP, NLST, and NELSON. The major objective of this international collaboration is the planned cross-analysis of the individual studies after they are reported. The EU-US researchers have agreed to a number of long-term objectives and to explore strategic areas for harmonization of complementary investigations.

• Promoter methylation of P16, RARbeta, E-cadherin, cyclin A1 and cytoglobin in oral cancer: quantitative evaluation using pyrosequencing.

  Authors: R J Shaw, T Liloglou, S N Rogers, J S Brown, E D Vaughan, D Lowe, J K Field, J M Risk

  British journal of cancer. 03/2006; 94(4):561-8.

  Methylation profiling of cancer tissues has identified this mechanism as an important component of carcinogenesis. Epigenetic silencing of tumour suppressor genes through promoter methylation hasMethylation profiling of cancer tissues has identified this mechanism as an important component of carcinogenesis. Epigenetic silencing of tumour suppressor genes through promoter methylation has been investigated by a variety of means, the most recent of which is pyrosequencing. We have investigated quantitative methylation status in oral squamous cell carcinoma patients. Fresh tumour tissue and normal control tissue from resection margin was obtained from 79 consecutive patients undergoing resection of oral squamous cell carcinoma. DNA was extracted and bisulphite treated. PCR primers were designed to amplify 75-200 bp regions of the CpG rich gene promoters of p16, RARbeta, E-cadherin, cytoglobin and cyclinA1. Methylation status of 4-5 CpG sites per gene was determined by pyrosequencing. Significant CpG methylation of gene promoters within tumour specimens was found in 28% for p16, 73% for RARbeta, 42% for E-cadherin, 65% for cytoglobin and 53% for cyclinA1. Promoter methylation was significantly elevated in tumours compared to normal tissue for p16 (P = 0.048), cytoglobin (P = 0.002) and cyclin A1 (P = 0.001) but not in RARbeta (P = 0.088) or E-cadherin (P = 0.347). Concordant methylation was demonstrated in this tumour series (P = 0.03). Significant differences in degree of methylation of individual CpG sites were noted for all genes except RARbeta and these differences were in a characteristic pattern that was reproduced between tumour samples. Cyclin A1 promoter methylation showed an inverse trend with histological grade. Promoter methylation analysis using pyrosequencing reveals valuable quantitative data from several CpG sites. In contrast to qualitative data generated from methylation specific PCR, our data demonstrated p16 promoter methylation in a highly tumour specific pattern. Significant tumour specific methylation of cyclin A1 promoter was also seen. Cytoglobin is a novel candidate tumour suppressor gene highly methylated in upper aero-digestive tract squamous cancer.

• The Liverpool Lung Project research protocol.

  Authors: J K Field, D L Smith, S Duffy, A Cassidy

  International journal of oncology. 01/2006; 27(6):1633-45.

  The Liverpool Lung Project (LLP) is being conducted within a defined geographic area of Merseyside, based on contiguous districts with a high incidence of lung cancer. As well as increasing theThe Liverpool Lung Project (LLP) is being conducted within a defined geographic area of Merseyside, based on contiguous districts with a high incidence of lung cancer. As well as increasing the scientific understanding of the interactions between the different risk factors for lung cancer, the LLP aims to develop a model which predicts lung cancer risk from an extensive record of epidemiological risk factors, molecular/genetic risk factors and from changes in molecular biomarkers, which maybe used in early detection programmes. The LLP has two components: Firstly, a case-control study of 800 newly diagnosed cases of lung cancer matched 2:1 for age (+/-2 years) and gender will facilitate the development of the molecular genetic and epidemiological model to assess an individual's risk of developing lung cancer. Secondly, a prospective cohort study will recruit 7,500 individuals to identify markers of pre-clinical carcinogenesis in a high-risk population and validate and strengthen the molecular genetic and epidemiological risk assessment model. Structured questionnaires collect detailed information on lifestyle factors (active and passive smoking, medical history, family cancer history, occupation, residence and diet) over the whole life course. Collection of biological specimens includes blood, sputum, bronchial lavage, oral scrapes and tumour. Cohort study subjects will be followed up over a 10-year period. In addition, serial biological samples (blood and induced sputum) will be collected from a high-risk subgroup of the cohort. The LLP protocol provides detailed information on the study design and analysis strategy, together with the informed consent documentation and the LLP lifestyle questionnaire. Conclusions from the LLP programme will be based around epidemiological and genotyping risk assessment models enabling us to identify high-risk populations, and will ultimately contribute to, and facilitate the development of effective prevention, early detection and chemoprevention strategies.

• Methylation discriminators in NSCLC identified by a microarray based approach.

  Authors: J K Field, T Liloglou, S Warrak, M Burger, E Becker, K Berlin, I Nimmrich, S Maier

  International journal of oncology. 08/2005; 27(1):105-11.

  Aberrant DNA methylation is a frequent phenomenon in non-small cell lung cancers. We have used a microarray approach to assess the methylation status of 245 CpG positions in 59 candidate genes in 26Aberrant DNA methylation is a frequent phenomenon in non-small cell lung cancers. We have used a microarray approach to assess the methylation status of 245 CpG positions in 59 candidate genes in 26 squamous cell carcinomas, and 22 adenocarcinomas as well as 26 normal adjacent lung tissue samples from smokers to identify genes that show a distinct methylation status difference between the two different tumour type tissues and normal adjacent tissue. Tumour tissue samples were grouped together and compared to the normal tissue sample group. A multivariate test was performed, taking into account all CpG positions that were analyzed for a particular gene, to calculate p-values for each gene based on the observed methylation difference between the two groups, p-values obtained were corrected for multiple testing. The highest degree of differential DNA methylation in squamous cell carcinoma compared to normal was observed in ARHI, MGMT, GP1bbeta, RARbeta and TMEFF2 genes, while TMEFF2, MGMT and CDKNIC genes differentiated between adenocarcinomas and normal tissue. It is of note that some of the genes for which differential methylation status was observed, have not been previously described in lung cancer. Our results provide compelling evidence that different histological types of lung cancer may be distinguished from normal tissue based on methylation profiles of specific genes.

• S100A2 is strongly expressed in airway basal cells, preneoplastic bronchial lesions and primary non-small cell lung carcinomas.

  Authors: S L Smith, M Gugger, P Hoban, D Ratschiller, S G Watson, J K Field, D C Betticher, J Heighway

  British journal of cancer. 10/2004; 91(8):1515-24.

  S100A2 gene products were shown to be frequently and dramatically over-represented in non-small cell lung cancer (NSCLC) lesions over normal tissue by microarray analysis. We have now analysed anS100A2 gene products were shown to be frequently and dramatically over-represented in non-small cell lung cancer (NSCLC) lesions over normal tissue by microarray analysis. We have now analysed an independent series of NSCLC tumours and multiple matched normal bronchial epithelial sites by RT-PCR and immunohistochemistry to investigate: whether this expression pattern can be confirmed and whether elevated expression is associated with tumour histology, clinical outcome or preneoplasia. In this second series, S100A2 was strongly expressed in 76% (35 out of 46) of tumours, more frequently in squamous cell than adenocarcinomas (P<0.002). This strong expression was not related to high-level gene amplification, but was associated in one of five informative cases with an allele-specific imbalance in transcript levels. Most tumours strongly expressed the DeltaNp63 transcript, the product of which is a putative regulator of S100A2 transcription and while all but one of the tumours positive for DeltaNp63 expressed S100A2, others negative for this regulator also expressed the gene. Contrary to the hypothesis that S100A2 is a tumour suppressor, no somatic mutations were identified in the coding sequence in 44 tumours. Furthermore, an examination of multiple tumour-free epithelial sites from 20 patients showed that strong expression was often associated with increasing levels of disorder in preinvasive bronchial lesions (P<0.0001).

• METH-2 silencing and promoter hypermethylation in NSCLC.

  Authors: J R Dunn, D Panutsopulos, M W Shaw, J Heighway, R Dormer, E N Salmo, S G Watson, J K Field, T Liloglou

  British journal of cancer. 10/2004; 91(6):1149-54.

  The antiangiogenic factor METH-2 (ADAMTS-8) was identified in a previous dual-channel cDNA microarray analysis to be at least two-fold under-represented in 85% (28 out of 33) of primaryThe antiangiogenic factor METH-2 (ADAMTS-8) was identified in a previous dual-channel cDNA microarray analysis to be at least two-fold under-represented in 85% (28 out of 33) of primary non-small-cell lung carcinomas (NSCLCs). This observation has been validated in an independent series of NSCLCs and adjacent normal tissues by comparative multiplex RT-PCR, and METH-2 mRNA expression was dramatically reduced in all 23 tumour samples analysed. Immunohistochemical analysis of the same sample set demonstrated that METH-2 was strongly expressed in 14 out of 19 normal epithelial sites examined but only one out of 20 NSCLCs. DNA methylation analysis of the proximal promoter region of this gene revealed abnormal hypermethylation in 67% of the adenocarcinomas and 50% of squamous cell carcinomas, indicating that epigenetic mechanisms are involved in silencing this gene in NSCLC. No homozygous deletions of METH-2 were found in lung cancer cell lines. Allelic imbalance in METH-2 was assessed by an intronic single nucleotide polymorphism (SNP) assay and observed in 44% of informative primary samples. In conclusion, the downregulation of METH-2 expression in primary NSCLC, often associated with promoter hypermethylation, is a frequent event, which may be related to the development of the disease.

• An investigation of the tylosis with oesophageal cancer (TOC) locus in Iranian patients with oesophageal squamous cell carcinoma.

  Authors: M Shahabi, M R Noori-Daloii, J E Langan, L Rowbottom, E Jahanzad, E Khoshbin, M Taghikhani, J K Field, J M Risk

  International journal of oncology. 09/2004; 25(2):389-95.

  Oesophageal cancer is one of the ten leading causes of cancer mortality worldwide. Earlier loss of heterozygosity (or allelic imbalance) studies have implicated regions on chromosomes 3p, 5q, 9p,Oesophageal cancer is one of the ten leading causes of cancer mortality worldwide. Earlier loss of heterozygosity (or allelic imbalance) studies have implicated regions on chromosomes 3p, 5q, 9p, 13q, 17p, 17q, and 18q in the development of sporadic oesophageal cancer and recent data have linked the familial tylosis with oesophageal cancer (TOC) gene-containing region on chromosome 17q25 with this cancer. We have studied allelic imbalance (AI) at microsatellite markers both closely linked to and distant from the TOC gene locus in 60 sporadic squamous cell oesophageal cancers from Iran and have investigated the most likely candidate gene by mutation analysis in these tumours. Forty-four out of these 60 samples (73%) show allelic imbalance at one or more loci within or adjacent to the TOC minimal region, while the highest incidence of AI was observed at the D17S2244 and D17S2246 loci (almost 70% AI in informative cases), correlating with the TOC minimal region. Analysis of the coding regions of a candidate gene in these tumours failed to show an equivalently high incidence of mutation, although two mutations and one polymorphism were observed. These data support and extend previous observations that the TOC region of chromosome 17q25 may be involved in the aetiology of the sporadic form of oesophageal cancer from a number of different geographical populations and suggest that the causative gene may be epigenetically silenced rather than mutated.