Biomedical subjects

Christopher M Heaphy

Publications and source records attributed to Christopher M Heaphy.

6 recordsLinked to original sources

PubMed2006

Telomeres: prognostic markers for solid tumors.

Solid tumors continue to affect millions of people worldwide. Increasingly sophisticated diagnostic tools contribute to the high incidence rates for some tumor types, and treatment options continue to expand. However, the progression of solid tumors represents a challenge for the appropriate treatment of individual patients because of the relative inaccuracy of current prognostic markers, including the widely used Tumor-Nodes-Metastasis (TNM) staging system, to predict the course of disease. As a result, both over- and undertreatment are clinical realities in the management of patients diagnosed with solid tumors. Therefore, population-based screening programs that increase the overall cancer incidence rates are controversial, as they may do little to improve the patient's quality of life. Consequently, there is a strong need to develop novel and independent markers of prognosis. In this context, we review the use of telomeres as prognostic markers for solid tumors, including cancers from lung, breast, prostate, colon, brain and head and neck. Telomeric sequences, the repetitive DNA at the end of human chromosomes, are mediators of genomic stability and can undergo length alterations during tumor initiation and progression. In a number of studies reviewed here, these alterations, measured as telomere attrition and elongation, have been shown either to be associated with clinical markers of disease progression or to be independent markers of cancer prognosis. We conclude from these studies that careful assessment of telomere length or its proxies, such as telomere DNA content, will be part of novel risk assessment and prognostic modalities for patients with solid tumors.

Animals↗

PubMed2006

Telomere DNA content and allelic imbalance demonstrate field cancerization in histologically normal tissue adjacent to breast tumors.

Cancer arises from an accumulation of mutations that promote the selection of cells with progressively malignant phenotypes. Previous studies have shown that genomic instability, a hallmark of cancer cells, is a driving force in this process. In the present study, two markers of genomic instability, telomere DNA content and allelic imbalance, were examined in two independent cohorts of mammary carcinomas. Altered telomeres and unbalanced allelic loci were present in both tumors and surrounding histologically normal tissues at distances at least 1 cm from the visible tumor margins. Although the extent of these genetic changes decreases as a function of the distance from the visible tumor margin, unbalanced loci are conserved between the surrounding tissues and the tumors, implying cellular clonal evolution. Our results are in agreement with the concepts of "field cancerization" and "cancer field effect," concepts that were previously introduced to describe areas within tissues consisting of histologically normal, yet genetically aberrant, cells that represent fertile grounds for tumorigenesis. The finding that genomic instability occurs in fields of histologically normal tissues surrounding the tumor is of clinical importance, as it has implications for the definition of appropriate tumor margins and the assessment of recurrence risk factors in the context of breast-sparing surgery.

Adolescent↗

PubMed2006

Telomere content correlates with stage and prognosis in breast cancer.

PURPOSE: To evaluate the hypothesis that telomere DNA content (TC) in breast tumor tissue correlates with TNM staging and prognosis. EXPERIMENTAL DESIGN: Slot blot assay was used to quantitate TC in 70 disease-free normal tissues from multiple organ sites, and two independent sets of breast tumors containing a total of 140 samples. Non-parametric Rank-Sums tests, logistic regression and Cox proportional hazards models were used to evaluate the relationships between TC and tumor size, nodal involvement, TNM stage, 5-year survival and disease-free interval. RESULTS: TC in 95% of normal tissues was 75-143% of that in the placental DNA standard, whereas only 50% of tumors had TC values in this range. TC was associated with tumor size (p=0.02), nodal involvement (p<0.0001), TNM stage (p=0.004), 5-year overall survival (p=0.0001) and 5-year disease-free survival (p=0.0004). A multivariable Cox model was developed using age at diagnosis, TNM stage and TC as independent predictors of breast cancer-free survival. Relative to the high TC group (>123% of standard), low TC (<101% of standard) conferred an adjusted relative hazard of 4.43 (95% CI 1.4-13.6, p=0.009). Receiver operating characteristic curves using thresholds defined by the TC distribution in normal tissues predicted 5-year breast cancer-free survival with 50% sensitivity and 95% specificity, and predicted death due to breast cancer with 75% sensitivity and 70% specificity. CONCLUSIONS: TC in breast cancer tissue is an independent predictor of clinical outcome and survival interval, and may discriminate by stage.

Adolescent↗

PubMed2006

Protease nexin-1 expression is altered in human breast cancer.

BACKGROUND: Urokinase-type Plasminogen Activator (uPA), a serine protease, plays a pivotal role in human breast cancer metastasis by mediating the degradation of extracellular matrix proteins and promoting cell motility. In more advanced breast cancers, uPA activity is significantly up regulated and serves as a prognostic indicator of poor patient outcome. Classically, regulation of uPA activity, especially in breast cancers, is thought to be mediated by Type 1 Plasminogen Activator Inhibitor (PAI-1). However, we have recently found that a lesser known natural inhibitor of uPA, Protease Nexin 1 (PN-1), is expressed in normal human mammary tissue. Based on this observation, we investigated if PN-1 is also expressed in human breast cancers where it may contribute to the regulation of uPA and participate in the development of a metastatic phenotype. RESULTS: Using quantitative real-time PCR analysis, we measured PN-1 mRNA expression in tissues obtained from 26 human breast tumor biopsies and compared these values with those obtained from 10 normal breast tissue samples. Since both PAI-1 and uPA expression levels are known to be elevated in metastatic breast cancer, we also measured their levels in our 26 tumor samples for direct comparison with PN-1 expression. We found that PN-1 expression was elevated over that found in normal mammary tissue; an increase of 1.5- to 3.5-fold in 21 of 26 human breast tumors examined. As anticipated, both PAI-1 and uPA mRNA levels were significantly higher in the majority of breast tumors; 19 of 26 tumors for PAI-1 and 22 of 26 tumors for uPA. A quantile box plot of these data demonstrates that the elevated PN-1 expression in breast tumor tissues directly correlates with the increased expression levels found for PAI-1 and uPA. CONCLUSION: The fact that PN-1 expression is elevated in human breast cancer, and that its increased expression is directly correlated with increases measured for PAI-1 and uPA, suggests that PN-1 may contribute to the regulation of uPA-mediate tumor cell motility and metastatic spread.

Journal Article↗

PubMed2005

Association between cancer-free survival and telomere DNA content in prostate tumors.

PURPOSE: We evaluated the hypothesis that telomere DNA content (TC) in prostate tumor tissue is associated with time to prostate cancer recurrence. MATERIALS AND METHODS: The cohort was comprised of 77 men who underwent prostatectomy between 1982 and 1995. Slot blot assay was used to measure TC in DNA extracted from paraffin embedded tumor and nearby, histologically normal prostate (NHN) tissues. Multivariate Cox proportional hazards analysis was done to relate TC, patient age at diagnosis, Gleason sum and pelvic node involvement to time of prostate cancer recurrence. Regression analysis was done to relate TC in paired tumor and NHN tissues. Nonparametric Kruskal-Wallis analysis was done to relate TC in tumor and NHN tissues with 72-month disease-free survival. RESULTS: TC was a predictor of time to prostate cancer recurrence when controlling for age at diagnosis, Gleason sum and pelvic node involvement (RH = 5.02, 95% CI 1.40 to 17.96, p = 0.0132). TC in tumor tissue was associated with TC in NHN tissue (R = 0.601, p <0.0001). Median TC in tumor and NHN tissues from men in whom cancer recurred within 6 years was approximately half that in men who remained disease-free (p = 0.012 and 0.024, respectively). CONCLUSIONS: Decreased TC in prostate tissues obtained by radical prostatectomy predicts prostate cancer recurrence independent of age at diagnosis, Gleason sum and pelvic node involvement. TC in tumor tissue is also associated with TC in NHN prostate tissue. Thus, mechanisms known to generate genomic instability are operative in fields of cells beyond the tumor margins prior to histological changes.

Aged↗

PubMed2002

Chemiluminescent measurement of telomere DNA content in biopsies.

Telomeres are nucleoprotein complexes that protect the ends of chromosomes from fusion and degradation. They are typically shorter in tumor cells than in paired normal cells, and shorter telomeres are associated with poor outcome in cancer. We previously described a slot blot-based methodfor measuring telomere DNA content, a proxy for telomere length. Although this method represented an improvement over existing methods, its 30-ng limit of sensitivity was insufficient for use with biopsy or other scant tissues. Here we describe a chemiluminescent slot blot assay for telomere DNA content that has the sensitivity required for use with biopsy materials. The results obtained with DNA derived from human placental, HeLa, human peripheral blood lymphocytes, sham-needle core prostate biopsies, and archival prostatectomy tissues demonstrated that telomere DNA content can be reliably and reproducibly measured in 5 ng, and sometimes as little as 2 ng, genomic DNA. Sham-needle core prostate biopsy and prostatectomy specimens processed in parallel produced comparable results. The contribution of truncated telomeres in admixtures containing as much as 75% normal placental DNA could be established. We also demonstrated that the treatment of tissue with formalin before DNA purification does not decrease the efficacy of the assay.

Biopsy↗