Biomedical subjects

Joseph A Califano

Publications and source records attributed to Joseph A Califano.

14 recordsLinked to original sources

PubMed2003

Methylation of the thyroid-stimulating hormone receptor gene in epithelial thyroid tumors: a marker of malignancy and a cause of gene silencing.

Thyroid-stimulating hormone receptor (TSHR) expression is frequently silenced in epithelial thyroid cancers associated with decreased or absent TSH-promoted iodine uptake. To study the underlying molecular mechanism of decreased TSHR expression, we examined the methylation status of the TSHR gene promoter by sequencing bisulfite-treated DNA from thyroid tumors. After identification of methylated sites by sequencing bisulfite-treated DNA, we used methylation-specific polymerase chain reaction and found frequent CpG methylation in papillary thyroid cancer (23 of 39 patients; 59%) and follicular thyroid cancers (7 of 15 patients; 47%). In contrast, we saw no methylation in normal thyroid tissues and benign adenomas (0 of 8 patients; 0%). In human thyroid tumor cell lines, we observed that TSHR was normally expressed at the protein and mRNA level in cells where the TSHR gene was unmethylated, whereas it was silenced in cell lines where the TSHR promoter was hypermethylated. Treatment of the latter cells with a demethylating agent partially restored TSHR expression. We thus demonstrate aberrant methylation of human TSHR as a likely molecular pathway responsible for the silencing of this gene in thyroid cancers. We propose that methylation of TSHR may provide a novel diagnostic marker of malignancy and a basis for potential use of demethylating agents in conjunction with TSH-promoted radioiodine therapy for epithelial thyroid cancers.

Adenoma↗

PubMed2003

Alcohol consumption and expenditures for underage drinking and adult excessive drinking.

CONTEXT: Although estimates of the amount and proportion of alcohol consumed by underage and adult drinkers have been reported, more accurate estimates are possible and the economic impact has not been explored. OBJECTIVES: To provide accurate estimates of underage and adult excessive drinking and to describe consumer expenditures linked to underage and adult excessive drinking. DESIGN AND SETTING: Information was obtained from national data sets, including 1999 versions of the National Household Survey of Drug Abuse, the Youth Risk Behavior Survey (YRBS), the Behavior Risk Factor Surveillance System (BRFSS), 2000 US Census, and national data on consumption and consumer expenditures for alcohol, published by Adams Business Research. PARTICIPANTS: A total of 217 192 persons aged 12 years or older across 3 data sources. MAIN OUTCOME MEASURES: Amount as a proportion of total alcohol consumed and proportion of consumer expenditures on alcohol among underage (12-20 years) and adult excessive (> or =21 years) drinkers. RESULTS: The proportion of 12- to 20-year-olds who drink was estimated to be 50.0% using data from the YRBS; the proportion of adults aged 21 or older who drink was estimated to be 52.8% using data from the BRFSS. The estimated total number of drinks consumed per month was 4.21 billion; underage drinkers consumed 19.7% of this total. The amount of adult drinking that was excessive (>2 drinks per day) was 30.4%. Consumer expenditure on alcohol in the United States in 1999 was $116.2 billion; of that, $22.5 billion was attributed to underage drinking and $34.4 billion was attributed to adult excessive drinking. CONCLUSION: These data suggest that underage drinkers and adult excessive drinkers are responsible for 50.1% of alcohol consumption and 48.9% of consumer expenditure.

Adolescent↗

PubMed2003

Mitochondrial DNA alterations in thyroid cancer.

BACKGROUND: Alterations in mitochondrial DNA have been identified in a number of solid tumor types, including gastric, head and neck, breast, colorectal, lung, and bladder carcinomas. Recently, a homopolymeric C stretch (D310) located within the noncoding D-loop of the mitochondrial genome was identified and described as a mutational hotspot. The objective of the present study was to examine a series of thyroid cancers for genetic alterations in this region. METHODS: Seventy-two (72) thyroid cancers were examined for alterations in D310 using PCR-based methods. The primary tumors tested included 35 papillary carcinomas, 18 medullary carcinomas, 9 anaplastic carcinomas, 9 follicular carcinomas, and 1 insular carcinoma. RESULTS: Alterations in D310 were observed in 2/35 papillary carcinomas (5.7%), 1/18 medullary carcinomas (5.6%), 1/9 anaplastic carcinomas (11.1%), and 1/9 follicular carcinomas (11.1%). Overall, the rate of alterations was 5/72 (6.9%). CONCLUSIONS: Mutations in the D310 region of the D-loop of mitochondrial DNA are found in thyroid tumors of varying histologic types and grades. This mutation rate is lower than the reported rate of alteration in tumors of epithelial origin, and shows no relationship to histologic grade.

Adenocarcinoma↗

PubMed2002

Progression of microsatellite instability from premalignant lesions to tumors of the head and neck.

The role of microsatellite alterations other than loss of heterozygosity (LOH) in the progression of benign epithelium to head-and-neck squamous cell cancer (HNSCC) has not been previously described. As the severity of the dysplasia increases at the microscopic level, there is an increase in the prevalence of LOH as defined by microsatellite analysis. Other alterations have been detected in the form of microsatellite instability (MSI), represented by insertions or deletions of base pairs. It is unknown, however, whether the prevalence of these alterations likewise increases during these early stages of tumor progression. Using 6 selected markers that demonstrate a high rate of MSI and allelic imbalance in invasive head-and-neck cancer, we examined 111 lesions ranging from hyperplasia without atypia to invasive mucosal HNSCC. Two of 34 (5.9%) of the hyperplasias without atypia, 2/12 (16.7%) of the mild dysplasias, 2/21 (9.5%) of the moderate dysplasias, 7/26 (26.9%) of the high-grade dysplasias/carcinomas in situ and 6/18 (33%) of the HNSCCs demonstrated microsatellite base pair length alterations. Our findings indicate that MSI becomes increasingly more common as early dysplastic lesions progress to fully malignant HNSCC and confirm this as a supplemental detection method in microsatellite analysis.

Base Pair Mismatch↗

PubMed2002

The molecular biology of laryngeal cancer.

Novel techniques have led to the discovery of many genes and gene products important in the development of HNSC and laryngeal cancer. Tumor suppressive genes and oncogenes have been identified, and many of their roles have been elucidated in a genetic progression model. As these molecular pathways become better understood, the information obtained will increasingly be used to guide patient therapy. Specifically, advances will probably be made in (1) molecular characterization of steps leading to laryngeal cancer; (2) molecular screening, staging, and surveillance; (3) molecularly based therapy, including gene transfer and small molecule therapy directed at specific molecular pathways involved in neoplasia; and (4) characterization of patients who are at high risk for laryngeal cancer. In the final analysis, however, smoking cessation for those at risk for head and neck cancer would have greater effect than all these efforts combined.

Carcinoma, Squamous Cell↗

PubMed2002

Real-time quantitative PCR demonstrates low prevalence of human papillomavirus type 16 in premalignant and malignant lesions of the oral cavity.

PURPOSE: Human papillomavirus (HPV) type-16 has been associated with invasive squamous cell carcinoma of the head and neck. This study examines the role of HPV-16 in the progression of oral head and neck cancer by determining the quantity of HPV-16 DNA in premalignant and malignant lesions, using real-time quantitative PCR, to more accurately determine the role of HPV-16 in oral head and neck squamous cell carcinogenesis. EXPERIMENTAL DESIGN: We examined 102 microdissected premalignant head and neck lesions (85 from the oral cavity), 34 invasive oral cavity squamous cell carcinomas, as well as 18 invasive tumors known to be HPV positive by traditional molecular technology for the presence of HPV-16 DNA using real-time quantitative PCR. RESULTS: HPV DNA was detected in 1 of 102 premalignant lesions (0.98%), 1 of 34 (2.9%) invasive oral cavity carcinomas, and 14 of 18 (78%) known HPV-positive tumors. CONCLUSIONS: HPV-16 infection and integration is seldom found in oral premalignant lesions and invasive carcinoma, and therefore rarely contributes to malignant progression in the oral cavity. Furthermore, quantitative PCR is a useful technique that reliably excludes contaminated samples and those with minimal HPV DNA content that is unlikely to be significant in carcinogenesis.

Adult↗

PubMed2002

Mitochondrial C-tract alteration in premalignant lesions of the head and neck: a marker for progression and clonal proliferation.

PURPOSE: Although mitochondrial DNA mutations have been described recently in many different tumor types, the nature and timing of such alterations remain unclear. In an effort to further examine the role of mitochondrial DNA mutations in carcinogenesis, we examined 137 premalignant lesions of the head and neck from 93 patients for DNA alterations in the poly-cytosine tract (C-tract) of the displacement loop, discovered recently to be a hot spot of mitochondrial DNA alteration. EXPERIMENTAL DESING: All premalignant lesions were tested using a length-based PCR assay, which amplified the C-tract region of mitochondrial DNA. Somatic microsatellites at six loci were also tested on a subset of patients with metachronous or synchronous lesions found to possess a mitochondrial C-tract alteration. RESULTS: Thirty-four of 93 (37%) patients harbored lesions that displayed a C-tract alteration. There was a clear increase in incidence from histologically benign hyperplasia (22%) to squamous carcinoma in situ (62%: P < 0.01). We also tested synchronous dysplastic lesions, metachronous dysplastic lesions, and normal epithelium adjacent to dysplastic epithelium with this assay. In most cases, the mitochondrial C-tract status identified a clonal relationship between these lesions. Genomic microsatellites also confirmed that a clonal relationship was present in many of these cases. CONCLUSIONS: Mitochondrial DNA alterations in the head and neck occur in the earliest premalignant lesions and demonstrate a rising incidence that parallels histological severity. These alterations are valuable as additional markers of histopathological progression.

Biomarkers, Tumor↗

PubMed1998