Close mapping of the focal non-epidermolytic palmoplantar keratoderma (PPK) locus associated with oesophageal cancer (TOC)

Focal non-epidermolytic palmoplantar keratoderma (PPK or palmoplantar ectodermal dysplasia type III) is associated with oesophageal cancer in three families: two large pedigrees located in Liverpool, UK and in the midwestern American states and one smaller family from Germany. In these families, the PPK is inherited as autosomal dominant and has a late onset, usually manifesting between 7 and 8 years of age. The disease is characterised by thickening of the pressure areas of the soles, but is not restricted to the feet and also presents with oral leukokeratosis and follicular hyperkeratosis. The disease locus [previously termed the "tylosis oesophageal cancer gene' (TOC) locus] has been mapped to 17q23-qter by linkage analysis. This region is located telomeric to the keratin 16 gene, in which mutations have been identified in focal PPK families who show no increased cancer risk. We describe the close mapping of this locus to the interval between AFMb054zf9 and D17S1603 using haplotype analysis of additional Genethon markers in the region and show that although the American family is unlikely to be related to either of the other two, the UK and German pedigrees may share a common descent. This work provides a basis for positional cloning and candidate gene analysis in order to identify a gene that may be involved in familial oesophageal cancer.      

First- and second-trimester evaluation of risk for Down syndrome

OBJECTIVE: To investigate the differences in costs and outcomes of Down syndrome screening using data from the First and Second Trimester Evaluation of Risk (FASTER) Trial. METHODS: Seven possible screening options for Down syndrome were compared: 1) Triple Screen-maternal serum alpha fetoprotein, estriol, and hCG; 2) Quad-maternal serum alpha fetoprotein, estriol, hCG, and Inhibin A; 3) Combined First-nuchal translucency, pregnancy-associated plasma protein A (PAPP-A), free beta-hCG; 4) Integrated-nuchal translucency, PAPP-A, plus Quad; 5) Serum Integrated-PAPP-A, plus Quad; 6) Stepwise Sequential-Combined First plus Quad with results given after each test; and 7) Contingent Sequential-Combined First and only those with risk between 1:30 and 1:1,500 have Quad screen. The detection rates for each option were used given a 5% false-positive rate except for Contingent Sequential with a 4.3% false-positive rate. Outcomes included societal costs of each screening regimen (screening tests, amniocentesis, management of complications, and cost of care of Down syndrome live births), Down syndrome fetuses identified and born, the associated quality-adjusted life years, and the incremental cost-utility ratio. RESULTS: Based on the screening results derived from the 38,033 women evaluated in the FASTER trial, the Contingent Sequential screen dominated (lower costs with better outcomes) all other screens. For example, the Contingent Sequential cost 32.3 million dollars whereas the other screens ranged from 32.8 to 37.5 million dollars. The Sequential strategy led to the identification of the most Down syndrome fetuses of all of the screens, but at a higher cost per Down syndrome case diagnosed ($719,675 compared with $690,427) as compared with the Contingent Sequential. Because of the lower overall false-positive rate leading to fewer procedure-related miscarriages, the Contingent Sequential resulted in the highest quality-adjusted life years as well. The Contingent Sequential remained the most cost-effective option throughout sensitivity analysis of inputs, including amniocentesis rate after positive screen, rate of therapeutic abortion after Down syndrome diagnosis, and rate of procedure-related miscarriages. CONCLUSION: Analysis of this actual data from the FASTER Trial demonstrates that the Contingent Sequential test is the most cost-effective. This information can help shape future policy regarding Down syndrome screening.     

Influence of retirement on leisure-time physical activity: the atherosclerosis risk in communities study

Cross-sectional data suggest that leisure-time physical activity may increase during retirement. Prospective population-based studies are necessary to characterize leisure activity patterns through retirement among the same persons to verify this observation. Therefore, the purpose of this study was to describe the influence of retirement on leisure activity using data from Atherosclerosis Risk in Communities Study cohort participants aged 45-64 years at baseline. Physical activity was measured by the Baecke questionnaire in 1,825 African-American and 5,957 White participants who were working at the initial visit (1986-1989) and either retired or working 6 years later (1993-1995). Participants who retired during follow-up were more likely to increase their sport participation and television watching than those who continued to work over the 6-year period. Among those reporting sport or exercise at baseline, those retiring over follow-up were more likely to maintain their sport and exercise participation than those who continued to work across race-gender groups. Among those not reporting sport or exercise at baseline, those who retired were more likely to adopt activity than those who continued to work except for African-American women. In this study, retirement was associated with gains in sport and exercise participation as well as television watching.     

Drug use among two American Indian populations: prevalence of lifetime use and DSM-IV substance use disorders

American Indians (AIs) have often reported higher rates of drug use than have other racial/ethnic groups. However, the majority of these studies have focused on drug use among high school adolescents, with little attention to pathological use such as drug abuse or dependence. This study is among the first to report lifetime drug use and disorder (abuse/dependence) information from community samples of two culture groups of AI people-one in the Southwest (SW), one in the Northern Plains (NP)-ranging in age from 15 to 57 years old. Analyses were conducted within four groups: SW men, SW women, NP men, and NP women. Across the four groups, lifetime use rates for marijuana (36.9-57.5%), cocaine (4.3-21.5%), and inhalants (3.6-17.0%) were the highest drug use rates; heroin (0.5-2.1%), the lowest. Lifetime drug disorder rates were highest for marijuana (4.5-14.1%), cocaine (1.1-2.3%), and stimulants (0.7-1.7%). Lifetime polydrug use disorder rates from 1.2 to 4.5%. Women generally had lower prevalence rates than did men in their culture group. The SW women generally had the lowest rates of use and disorder. Lifetime use and disorder rates among the youngest group were often not different from rates of the older groups. Overall, 40-60% had never used any drugs; 85-95% had not developed any drug disorder. Despite widespread concern and rhetoric about drug problems among AIs, many who had used various drugs either were using them without serious consequences or had quit use altogether.     

Methylation of viral and host genes and severity of cervical lesions associated with human papillomavirus type 16

Methylation of human papillomavirus (HPV) and host genes may predict cervical cancer risk. We examined the methylation status of selected sites in HPV16 and human genes in DNA extracted from exfoliated cervical cell samples of 244 women harboring HPV16‐positive cancer or cervical intraepithelial neoplasia (CIN) or negative for intraepithelial lesions or malignancy (NILM). We quantified the methylation of CpG sites in the HPV16 L1 gene (CpG 6367 and 6389) and in the human genes EPB41L3 (CpG 438, 427, 425) and LMX1 (CpG 260, 262, 266, 274) following bisulfite treatment and pyrosequencing. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic utility of methylation level for the different sites and for a joint predictor score. Methylation in all sites significantly increased with lesion severity (p < 0.0001). Area under the curve (AUC) was highest among the CIN2/3 vs. cancer ranging from 0.786 to 0.853 among the different sites. Site‐specific methylation levels strongly discriminated CIN2/3 from NILM/CIN1 and cancer from CIN2/3 (range of odds ratios [OR]: 3.69–12.76, range of lower 95% confidence bounds: 1.03–4.01). When methylation levels were mutually adjusted for each other EPB41L3 was the only independent predictor of CIN2/3 vs. NILM/CIN1 contrasts (OR = 9.94, 95%CI: 2.46–40.27). High methylation levels of viral and host genes are common among precancerous and cancer lesions and can serve as independent risk biomarkers. Methylation of host genes LMX1 and EPB41L3 and of the viral HPV16 L1 sites has the potential to distinguish among precancerous lesions and to distinguish the latter from invasive disease.     

SERPINE1 and SMA expression at the invasive front predict extracapsular spread and survival in oral squamous cell carcinoma

Background:

Extracapsular spread (ECS) in cervical lymph nodes is the single-most prognostic clinical variable in oral squamous cell carcinoma (OSCC), but diagnosis is possible only after histopathological examination. A promising biomarker in the primary tumour, alpha smooth muscle actin (SMA) has been shown to be highly prognostic, however, validated biomarkers to predict ECS prior to primary treatment are not yet available.

Methods:

In 102 OSCC cases, conventional imaging was compared with pTNM staging. SERPINE1, identified from expression microarray of primary tumours as a potential biomarker for ECS, was validated through mRNA expression, and by immunohistochemistry (IHC) on a tissue microarray from the same cohort. Similarly, expression of SMA was also compared with its association with ECS and survival. Expression was analysed separately in the tumour centre and advancing front; and prognostic capability determined using Kaplan–Meier survival analysis.

Results:

Immunohistochemistry indicated that both SERPINE1 and SMA expression at the tumour-advancing front were significantly associated with ECS (P<0.001). ECS was associated with expression of either or both proteins in all cases. SMA+/SERPINE1+ expression in combination was highly significantly associated with poor survival (P<0.001). MRI showed poor sensitivity for detection of nodal metastasis (56%) and ECS (7%). Both separately, and in combination, SERPINE1 and SMA were superior to MRI for the detection of ECS (sensitivity: SERPINE1: 95% SMA: 82% combination: 81%).

Conclusion:

A combination of SMA and SERPINE1 IHC offer potential as prognostic biomarkers in OSCC. Our findings suggest that biomarkers at the invasive front are likely to be necessary in prediction of ECS or in therapeutic stratification.     

Frequent loss of heterozygosity on chromosome 17 at 17q11.2-q12 in Barrett's adenocarcinoma.

Allelic loss on chromosome 17 in 18 Barrett''s oesophageal tumours was analysed with 17 polymorphic microsatellite markers. Loss of heterozygosity (LOH) of one or more markers was seen in 72% (13 of 18) tumours on 17p and 56% (10 of 18) on 17q. The highest 17p losses were found at D17S799 (62%, five of eight) and D17S261 (55%, five of nine), while loss at the p53 locus was 31% (5 of 16). The highest loss on 17q was found at the TCF-2 (17q11.2-q12) locus with 66% (8 of 12) LOH. TCF-2 was the only marker lost in two of the tumour samples; furthermore, TCF-2 was lost in four other tumours which retained heterozygosity at the markers on either side of it, D17S261 and D17S740. Six markers were used to assess LOH at 17q11.2-q12, and five of eight of the tumour specimens which had LOH at TCF-2 had no other loss on 17q. No statistically significant correlations were found between loss on 17q or 17p and any clinicopathological parameters. We propose from these data that the 17q11.2-q12 region contains a novel predisposing gene in Barrett''s adenocarcinomas and may represent the site of a tumour-suppressor gene.     

Allelotype of squamous cell carcinoma of the head and neck: fractional allele loss correlates with survival.

Allelic imbalance or loss of heterozygosity (LOH) studies have been used extensively to identify regions on chromosomes that may contain putative tumour-suppressor genes. We have undertaken an extensive allelotype of 80 specimens of squamous cell carcinoma of the head and neck (SCCHN) using 145 polymorphic microsatellite markers on 39 chromosome arms. Allelic imbalances were found most frequently on chromosome arms 3p, 9p, 17p and 18q with over 45% LOH and imbalances on 1p, 1q, 2p, 5q, 6p, 6q, 8p, 8q, 9q, 11q, 13q, 17q and 19q were found in more than 20% of SCCHN. These LOH data were analysed against a range of clinicopathological parameters which included previously untreated and previously treated tumours; correlations were found between LOH on 9q and nodes at pathology (P = 0.02) and between histopathological grade and LOH on 12q (P = 0.02) and 13q (P = 0.01). In the group of previously untreated tumours, a correlation was found between site of tumour and LOH on 3p (P = 0.019), and 8p (P = 0.029), while TNM staging correlated with LOH on 3p (P = 0.019) and 17p (P = 0.016). Fractional allele loss (FAL) was calculated for 52 tumours with LOH data on nine or more chromosomal arms and found to have a median value of 0.22 (range 0.0-0.80). Correlations were found between FAL > median value and nodes at pathology (P = 0.01) and tumour grade (P = 0.06), demonstrating that advanced tumours with lymph node metastasis often had LOH at multiple sites. FAL > median value was found to correlate with a poor survival (P < 0.03) and, furthermore, FAL > median value correlated with poor survival in the previously untreated patients (P < 0.019). These results indicate that assessment of the accumulation of genetic damage, as provided by allelotype data, provides a useful molecular indicator of the tumour behaviour and clinical outcome.