Comprehensive DNA methylation study identifies novel progression-related and prognostic markers for cutaneous melanoma.

BACKGROUND: Cutaneous melanoma is the deadliest skin cancer, with an increasing incidence and mortality rate. Currently, staging of patients with primary melanoma is performed using histological biomarkers such as tumor thickness and ulceration. As disruption of the epigenomic landscape is recognized as a widespread feature inherent in tumor development and progression, we aimed to identify novel biomarkers providing additional clinical information over current factors using unbiased genome-wide DNA methylation analyses. METHODS: We performed a comprehensive DNA methylation analysis during all progression stages of melanoma using Infinium HumanMethylation450 BeadChips on a discovery cohort of benign nevi (n = 14) and malignant melanoma from both primary (n = 33) and metastatic (n = 28) sites, integrating the DNA methylome with gene expression data. We validated the discovered biomarkers in three independent validation cohorts by pyrosequencing and immunohistochemistry. RESULTS: We identified and validated biomarkers for, and pathways involved in, melanoma development (e.g., HOXA9 DNA methylation) and tumor progression (e.g., TBC1D16 DNA methylation). In addition, we determined a prognostic signature with potential clinical applicability and validated PON3 DNA methylation and OVOL1 protein expression as biomarkers with prognostic information independent of tumor thickness and ulceration. CONCLUSIONS: Our data underscores the importance of epigenomic regulation in triggering metastatic dissemination through the inactivation of central cancer-related pathways. Inactivation of cell-adhesion and differentiation unleashes dissemination, and subsequent activation of inflammatory and immune system programs impairs anti-tumoral defense pathways. Moreover, we identify several markers of tumor development and progression previously unrelated to melanoma, and determined a prognostic signature with potential clinical utility.

MRI-directed cognitive fusion-guided biopsy of the anterior prostate tumors.

PURPOSE: We aimed to evaluate the efficacy of magnetic resonance imaging (MRI)-directed cognitive fusion transrectal ultrasonography (TRUS)-guided anterior prostate biopsy for diagnosis of anterior prostate tumors and to illustrate this technique. METHODS: A total of 39 patients with previous negative TRUS biopsy, but high clinical suspicion of occult prostate cancer, prospectively underwent prostate MRI including diffusion-weighted imaging (DWI). Patients with a suspicious anterior lesion on MRI underwent targeted anterior gland TRUS-guided biopsy with cognitive fusion technique using sagittal probe orientation. PIRADS version 1 scores (T2, DWI, and overall), lesion size, prostate-specific antigen (PSA), PSA density, and prostate gland volume were compared between positive and negative biopsy groups and between clinically significant cancer and remaining cases. Logistic regression analysis of imaging parameters and prostate cancer diagnosis was performed. RESULTS: Anterior gland prostate adenocarcinoma was diagnosed in 18 patients (46.2%) on targeted anterior gland TRUS-guided biopsy. Clinically significant prostate cancer was diagnosed in 13 patients (33.3%). MRI lesion size, T2, DWI, and overall PIRADS scores were significantly higher in patients with positive targeted biopsies and those with clinically significant cancer (P < 0.05). Biopsies were positive in 90%, 33%, and 29% of patients with overall PIRADS scores of 5, 4, and 3 respectively. Overall PIRADS score was an independent predictor of all prostate cancer diagnosis and of clinically significant prostate cancer diagnosis. CONCLUSION: Targeted anterior gland TRUS-guided biopsy with MRI-directed cognitive fusion enables accurate sampling and may improve tumor detection yield of anterior prostate cancer.

Tumor profiling using protein biomarker panels in malignant melanoma: application of tissue microarrays and beyond.

Despite advances in our knowledge of the disease, malignant melanoma remains an unpredictable entity. The revolution in molecular biological techniques, such as DNA sequencing and gene-expression profiling, has uncovered many potential protein targets and biomarkers relevant to melanoma progression. Successful clinical application would be aided significantly by downstream proteomic validation of those candidate markers using a combination of immunohistochemistry and tissue microarrays. Yet, research in this context seems to lag behind the output of genomic data relating to melanoma. In this article, we look at the strengths and pitfalls of tissue microarrays in malignant melanoma. We will show how tissue microarrays have become a vital step in the transition from molecular techniques to useful clinical assays and interventions and look at likely future developments for advances in this field.

P-Rex1 is required for efficient melanoblast migration and melanoma metastasis.

Metastases are the major cause of death from melanoma, a skin cancer that has the fastest rising incidence of any malignancy in the Western world. Molecular pathways that drive melanoblast migration in development are believed to underpin the movement and ultimately the metastasis of melanoma. Here we show that mice lacking P-Rex1, a Rac-specific Rho GTPase guanine nucleotide exchange factor, have a melanoblast migration defect during development evidenced by a white belly. Moreover, these P-Rex1(-/-) mice are resistant to metastasis when crossed to a murine model of melanoma. Mechanistically, this is associated with P-Rex1 driving invasion in a Rac-dependent manner. P-Rex1 is elevated in the majority of human melanoma cell lines and tumour tissue. We conclude that P-Rex1 has an important role in melanoblast migration and cancer progression to metastasis in mice and humans.

Analysis of patients with false negative mammography and symptomatic breast carcinoma.

AIM: False-negative mammograms may result in a delay in breast carcinoma diagnosis and have important implications for patient care. In this study, the characteristics of symptomatic patients with false-negative mammograms were analysed. METHODS: Patients with symptomatic breast carcinoma were identified over a 10-year period (1994-2004). One hundred and twenty-four patients had false-negative preoperative mammograms and 1241 patients had abnormal preoperative mammograms. Clinical presentation, diagnostic methods and pathology were analysed. False-negative mammograms were reviewed by a specialist breast radiologist. RESULTS: Following retrospective review, 42% of false-negative mammograms were re-categorised as suspicious. The most commonly misinterpreted lesion was architectural distortion/asymmetrical density. Adjuvant ultrasound, where performed (n = 27), raised the level of suspicion in 93% of cases. Patients with false-negative mammograms were more likely to be younger (P < 0.0001), present with nipple discharge (P = 0.002) and have smaller tumours (P < 0.0001). Their tumours were more frequently located outside the upper outer quadrant (P = 0.002). False-negative mammography led to a delay in diagnosis of >2 months in 12 patients. CONCLUSION: Symptomatic patients with false-negative mammograms often demonstrate definite abnormalities on imaging, the most common of which is architectural distortion/asymmetrical density. Those at particular risk were younger patients, those with nipple discharge, and patients with lesions located outside the upper outer quadrant.