Bridging Cancer Biology with the Clinic: Relative Expression of a <i>GRHL2</i>-Mediated Gene-Set Pair Predicts Breast Cancer Metastasis

Identification and characterization of crucial gene target(s) that will allow focused therapeutics development remains a challenge. We have interrogated the putative therapeutic targets associated with the transcription factor Grainy head-like 2 (GRHL2), a critical epithelial regulatory factor. We demonstrate the possibility to define the molecular functions of critical genes in terms of their personalized expression profiles, allowing appropriate functional conclusions to be derived. A novel methodology, relative expression analysis with gene-set pairs (RXA-GSP), is designed to explore the potential clinical utility of cancer-biology discovery. Observing that Grhl2-overexpression leads to increased metastatic potential in vitro, we established a model assuming Grhl2-induced or -inhibited genes confer poor or favorable prognosis respectively for cancer metastasis. Training on public gene expression profiles of 995 breast cancer patients, this method prioritized one gene-set pair (GRHL2, CDH2, FN1, CITED2, MKI67 versus CTNNB1 and CTNNA3) from all 2717 possible gene-set pairs (GSPs). The identified GSP significantly dichotomized 295 independent patients for metastasis-free survival (log-rank tested p = 0.002; severe empirical p = 0.035). It also showed evidence of clinical prognostication in another independent 388 patients collected from three studies (log-rank tested p = 3.3e–6). This GSP is independent of most traditional prognostic indicators, and is only significantly associated with the histological grade of breast cancer (p = 0.0017), a GRHL2-associated clinical character (p = 6.8e–6, Spearman correlation), suggesting that this GSP is reflective of GRHL2-mediated events. Furthermore, a literature review indicates the therapeutic potential of the identified genes. This research demonstrates a novel strategy to integrate both biological experiments and clinical gene expression profiles for extracting and elucidating the genomic impact of a novel factor, GRHL2, and its associated gene-sets on the breast cancer prognosis. Importantly, the RXA-GSP method helps to individualize breast cancer treatment. It also has the potential to contribute considerably to basic biological investigation, clinical tools, and potential therapeutic targets.</p

Hyperkeratotic variant of porokeratosis in a patient with Hepatitis C virus infection and a concomitant immunosuppressed state

Porokeratoses are acquired and hereditary disorders of keratinization that share a distinctive lesion characterized by raised keratotic borders corresponding histologically to an angled column of parakeratotic cells, called a cornoid lamella. Although a precise mechanistic explanation is lacking, ultraviolet radiation and immunosuppressed states are considered causally-associated with most cases of acquired porokeratosis. Hepatitis C virus (HCV) infection has been proposed as a link between the immunosuppressed states and development of acquired porokeratosis. Among the various recognized clinical entities that constitute this group, rare cases of hyperkeratotic variants have been described that may pose a diagnostic challenge. Herein we describe a remarkable case of the hyperkeratotic variant of porokeratosis that occurred in a patient with known HIV and HCV infections and a coexisting therapy-related immunosuppressed state. We also provide a review of the relevant literature

Posterior Mediastinal Adenomatoid Tumor: A Case Report and Review of the Literature

Adenomatoid tumor is an uncommon benign neoplasm of mesothelial differentiation that distinctively arises in and around the genital organs. In rare instances, it has been described in extragenital locations. There have been only two reports documenting its occurrence in the anterior mediastinum, and no reports documenting its occurrence in the posterior mediastinum. We report the first case of posterior mediastinal adenomatoid tumor. A 37-year-old Caucasian woman presented with symptoms of bronchitis. Imaging studies identified a 2.0 cm posterior mediastinal mass abutting the T9 vertebral body, clinically and radiologically most consistent with schwannoma. Histologic sections revealed a lesion composed of epithelioid cells arranged in cords and luminal profiles embedded in a fibrotic to loose stroma and surrounded by a fibrous pseudocapsule. Lesional cells showed vacuolated eosinophilic cytoplasm and peripherally displaced nuclei with prominent nucleoli. There was focal cytologic atypia but no mitotic figures or necrosis was identified. The lesional cells expressed cytokeratin, calretinin, and nuclear WT1 but were negative for PAX8, TTF1, p53, chromogranin, CD31, and CD34, and Ki67 showed <2% proliferation rate, diagnostic of adenomatoid tumor. Three years after resection, the patient is in good health without tumor recurrence. Thus, our encounter effectively expands the differential diagnosis of posterior mediastinal neoplastic entities

Bridging Cancer Biology with the Clinic: Relative Expression of a <em>GRHL2</em>-Mediated Gene-Set Pair Predicts Breast Cancer Metastasis

<div><p>Identification and characterization of crucial gene target(s) that will allow focused therapeutics development remains a challenge. We have interrogated the putative therapeutic targets associated with the transcription factor Grainy head-like 2 (<i>GRHL2</i>), a critical epithelial regulatory factor. We demonstrate the possibility to define the molecular functions of critical genes in terms of their personalized expression profiles, allowing appropriate functional conclusions to be derived. A novel methodology, relative expression analysis with gene-set pairs (RXA-GSP), is designed to explore the potential clinical utility of cancer-biology discovery. Observing that <i>Grhl2</i>-overexpression leads to increased metastatic potential <i>in vitro</i>, we established a model assuming <i>Grhl2</i>-induced or -inhibited genes confer poor or favorable prognosis respectively for cancer metastasis. Training on public gene expression profiles of 995 breast cancer patients, this method prioritized one gene-set pair (<i>GRHL2, CDH2, FN1, CITED2, MKI67 versus CTNNB1</i> and <i>CTNNA3</i>) from all 2717 possible gene-set pairs (GSPs). The identified GSP significantly dichotomized 295 independent patients for metastasis-free survival (log-rank tested p = 0.002; severe empirical p = 0.035). It also showed evidence of clinical prognostication in another independent 388 patients collected from three studies (log-rank tested p = 3.3e–6). This GSP is independent of most traditional prognostic indicators, and is only significantly associated with the histological grade of breast cancer (p = 0.0017), a <i>GRHL2</i>-associated clinical character (p = 6.8e–6, Spearman correlation), suggesting that this GSP is reflective of <i>GRHL2</i>-mediated events. Furthermore, a literature review indicates the therapeutic potential of the identified genes. This research demonstrates a novel strategy to integrate both biological experiments and clinical gene expression profiles for extracting and elucidating the genomic impact of a novel factor, <i>GRHL2</i>, and its associated gene-sets on the breast cancer prognosis. Importantly, the RXA-GSP method helps to individualize breast cancer treatment. It also has the potential to contribute considerably to basic biological investigation, clinical tools, and potential therapeutic targets.</p> </div

High level expression of <i>GRHL2</i> contributes to increased metastatic potential.

<p><b>A</b>) Temporal comparison of wound repair in MCF7 and MDCK cells in which <i>Grhl2</i> expression is baseline (Control) or enforced (<i>Grhl2</i>+). <b>B</b>) Boyden chamber migration and invasion assays on control and <i>Grhl2</i> overexpressed (<i>Grhl2</i>+) stable clones for MDCK cells. Fraction of seeded cells that migrated to the bottom chamber at 48 hours is dramatically higher in <i>Grhl2</i>+ clones than in the controls. Data represent mean±SD from triplicates. <b>C</b>) Continuous expression measurement of <i>GRHL2</i> is significantly correlated with the histological tumor grade and the measurement of tumor size in mm (p = 6.8e–6 and 0.041, respectively, Spearman measurement). <b>D</b>) <i>GRHL2</i> expression is significantly higher in patients with grade III breast tumors when compared with grade I or II tumors (two-sided t-test with unequal-variance). <b>E</b>) <i>GRHL2</i> expression reaches significance in patients with large tumors at diagnosis (>2 cm) when compared to smaller tumors (two-sided t-test with unequal-variance).</p

A gene-set pair shows significant prognosis for breast cancer distant metastasis-free survival (DMFS).

<p>The positive individualized prognostic index, i.e. relatively higher expression of the poor-prognosis gene-set (<i>GRHL2, CDH2, FN1, CITED2, MKI67</i>) compared to the good-prognosis gene-set (<i>CTNNB1, CTNNA3</i>), significantly predicts unfavorable DMFS in the training datasets (<b>Panels A</b> 1–3). Importantly, the identified GSP shows significant prognosis in two independent validation datasets (<b>Panel B</b>), theoretically (<b>Panels B</b> 1–2) and empirically (<b>Panels B</b> 3).</p