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We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCCs/PGLs), a rare tumor type. Multi-platform integration revealed that PCCs/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, and NF1). We also discovered fusion genes in PCCs/PGLs, involving MAML3, BRAF, NGFR, and NF1. Integrated analysis classified PCCs/PGLs into four molecularly defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCCs/PGLs included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.

The presence of lymphocytic infiltration (LI) has been correlated with nodal metastasis and tumor recurrence in HER2+ breast cancer (BC). The ability to automatically detect and quantify extent of LI on histopathology imagery could potentially result in the development of an image based prognostic tool for human epidermal growth factor receptor-2 (HER2+) BC patients. Lymphocyte segmentation in hematoxylin and eosin (H&E) stained BC histopathology images is complicated by the similarity in appearance between lymphocyte nuclei and other structures (e.g., cancer nuclei) in the image. Additional challenges include biological variability, histological artifacts, and high prevalence of overlapping objects. Although active contours are widely employed in image segmentation, they are limited in their ability to segment overlapping objects and are sensitive to initialization. In this paper, we present a new segmentation scheme, expectation-maximization (EM) driven geodesic active contour with overlap resolution (EMaGACOR), which we apply to automatically detecting and segmenting lymphocytes on HER2+ BC histopathology images. EMaGACOR utilizes the expectation-maximization algorithm for automatically initializing a geodesic active contour (GAC) and includes a novel scheme based on heuristic splitting of contours via identification of high concavity points for resolving overlapping structures. EMaGACOR was evaluated on a total of 100 HER2+ breast biopsy histology images and was found to have a detection sensitivity of over 86% and a positive predictive value of over 64%. By comparison, the EMaGAC model (without overlap resolution) and GAC model yielded corresponding detection sensitivities of 42% and 19%, respectively. Furthermore, EMaGACOR was able to correctly resolve over 90% of overlaps between intersecting lymphocytes. Hausdorff distance (HD) and mean absolute distance (MAD) for EMaGACOR were found to be 2.1 and 0.9 pixels, respectively, and significantly better compared to the corresponding performance of the EMaGAC and GAC models. EMaGACOR is an efficient, robust, reproducible, and accurate segmentation technique that could potentially be applied to other biomedical image analysis problems. [ABSTRACT FROM AUTHOR]

The identification of phenotypic changes in breast cancer (BC) histopathology on account of corresponding molecular changes is of significant clinical importance in predicting disease outcome. One such example is the presence of lymphocytic infiltration (LI) in histopathology, which has been correlated with nodal metastasis and distant recurrence in HER2+ BC patients. In this paper, we present a computer-aided diagnosis (CADx) scheme to automatically detect and grade the extent of LI in digitized HER2+ BC histopathology. Lymphocytes are first automatically detected by a combination of region growing and Markov random field algorithms. Using the centers of individual detected lymphocytes as vertices, three graphs (Voronoi diagram, Delaunay triangulation, and minimum spanning tree) are constructed and a total of 50 image-derived features describing the arrangement of the lymphocytes are extracted from each sample. A nonlinear dimensionality reduction scheme, graph embedding (GE), is then used to project the high-dimensional feature vector into a reduced 3-D embedding space. A support vector machine classifier is used to discriminate samples with high and low LI in the reduced dimensional embedding space. A total of 41 HER2+ hematoxylin-and-eosin-stained images obtained from 12 patients were considered in this study. For more than 100 three-fold cross-validation trials, the architectural feature set successfully distinguished samples of high and low LI levels with a classification accuracy greater than 90%. The popular unsupervised Varma-Zisserman texton-based classification scheme was used for comparison and yielded a classification accuracy of only 60%. Additionally, the projection of the 50 image derived features for all 41 tissue samples into a reduced dimensional space via GE allowed for the visualization of a smooth manifold that revealed a continuum between low, intermediate, and high levels of LI. Since it is known that extent of LI in BC biopsy specimens is a prognostic indicator, our CADx scheme will potentially help clinicians determine disease outcome and allow them to make better therapy recommendations for patients with HER2+ BC. [ABSTRACT FROM AUTHOR]

Metastasis via the lymphatics is a major risk factor in squamous cell carcinoma of the oral cavity (OSCC). We sought to determine whether the presence of metastasis in the regional lymph node could be predicted by a gene expression signature of the primary tumor. A total of 18 OSCCs were characterized for gene expression by hybridizing RNA to Affymetrix U133A gene chips. Genes with differential expression were identified using a permutation technique and verified by quantitative RT-PCR and immunohistochemistry. A predictive rule was built using a support vector machine, and the accuracy of the rule was evaluated using crossvalidation on the original data set and prediction of an independent set of four patients. Metastatic primary tumors could be differentiated from nonmetastatic primary tumors by a signature gene set of 116 genes. This signature gene set correctly predicted the four independent patients as well as associating five lymph node metastases from the original patient set with the metastatic primary tumor group. We concluded that lymph node metastasis could be predicted by gene expression profiles of primary oral cavity squamous cell carcinomas. The presence of a gene expression signature for lymph node metastasis indicates that clinical testing to assess risk for lymph node metastasis should be possible.Oncogene (2005) 24, 1244-1251. doi:10.1038/sj.onc.1208285 Published online 22 November 2004 [ABSTRACT FROM AUTHOR]

A 71-year-old manwitha history of a pituitary prolactinoma and metastatic pancreatic carcinoma presented with epi-staxis, visual changes, bilateral ophthalmoplegia, involuntary closure of the left eye, andptosis of the right eye. The patient was found to have a soft-tissue mass in the posterior nasal cavity with extension through the floor of the sella turcica, the sphenoid sinuses, cavernous sinuses, and suprasellar region. The patient was subsequently taken to the operating room. Intraoperative frozen section of the sinonasal mass demonstrated carcinoma. The final pathology of the mass revealedsinonasal undifferentiated carcinoma (SNUC)--the patient's secondskull base lesion and thirdprimary neoplasm. SNUC is a rare neoplasm of the sinonasal cavities that rapidly progresses from symptom onset to mortality in the presence of aggressive multidimensional therapies. Given its poor prognosis andpossibly devastatingtreatments, an open discussion of treatment options between physicians and the patient is of the utmost importance. Although SNUC is rare, it is important that practicing otolaryngologists, neurosur-geons, and skull base surgeons be familiar with this disease process--especially when caring for patients with a history of a benign skull base neoplasm and concern for possible recurrence, as was the case in this report. [ABSTRACT FROM AUTHOR]

Functional PDGFα receptors are selectively expressed on highly lung-metastasizing clones of the 3LL Lewis lung carcinoma, but not on low-mestastatic clones. The highly metastatic clones are also growth induced in vitro by PDGF and lung conditioned medium. To investigate whether modification of PDGFα receptor expression or function can affect metastatic capability, we transfected cells of a low-metastatic 3LL clone with a full length PDGFα receptor gene and cells of a highly-metastatic clone with a truncated kinase domain PDGFα receptor gene. Introduction of the full length PDGFα receptor conferred upon low-metastatic cells the ability to grow in vitro in the presence of PDGF-AA and to colonize the lung in experimental and spontaneous metastases assays. Conversely, introduction of a truncated version of the PDGFα receptor into highly metastatic cells reduced their metastatic load to control levels. Accordingly, their responses to PDGF-AA, including growth stimulation and receptor autophosphorylation, were reduced. These results demonstrate that PDGFα receptor expression and function can control the capacity of tumor cells to generate metastases in the lung. The response of this receptor to lung-derived PDGF-like factors may define a paracrine mode of metastatic cell growth in the target organ. [ABSTRACT FROM AUTHOR]

Nearly all breast cancer deaths result from metastatic disease. Despite this, the genomic events that drive metastatic recurrence are poorly understood. We performed whole-exome and shallow whole-genome sequencing to identify genes and pathways preferentially mutated or copy-number altered in metastases compared with the paired primary tumors from which they arose. Seven genes were preferentially mutated in metastases - MYLK, PEAK1, SLC2A4RG, EVC2, XIRP2, PALB2, and ESR1 - 5 of which are not significantly mutated in any type of human primary cancer. Four regions were preferentially copy-number altered: loss of STK11 and CDKN2A/B, as well as gain of PTK6 and the membrane-bound progesterone receptor, PAQR8. PAQR8 gain was mutually exclusive with mutations in the nuclear estrogen and progesterone receptors, suggesting a role in treatment resistance. Several pathways were preferentially mutated or altered in metastases, including mTOR, CDK/RB, cAMP/PKA, WNT, HKMT, and focal adhesion. Immunohistochemical analyses revealed that metastases preferentially inactivate pRB, upregulate the mTORC1 and WNT signaling pathways, and exhibit nuclear localization of activated PKA. Our findings identify multiple therapeutic targets in metastatic recurrence that are not significantly mutated in primary cancers, implicate membrane progesterone signaling and nuclear PKA in metastatic recurrence, and provide genomic bases for the efficacy of mTORC1, CDK4/6, and PARP inhibitors in metastatic breast cancer. [ABSTRACT FROM AUTHOR]

The integrated stress response (ISR) is a critical mediator of cancer cell survival, and targeting the I5R inhibits tumor progression. Here, we have shown that activating transcription factor 4 (ATF4), a master transcriptional effector of the ISR, protects transformed cells against anoikis - a specialized form of apoptosis - following matrix detachment and also contributes to tumor metastatic properties. Upon loss of attachment, ATF4 activated a coordinated program of cytoprotective autophagy and antioxidant responses, including induced expression of the major antioxidant enzyme heme oxygenase 1 (HO-1). HO-1 upregulation was the result of simultaneous activation of ATF4 and the transcription factor NRF2, which converged on the HOI promoter. Increased levels of HO-1 ameliorated oxidative stress and cell death. ATF4-defficient human fibrosarcoma cells were unable to colonize the lungs in a murine model, and reconstitution of ATF4 or HO-1 expression in ATF4-def icient cells blocked anoikis and rescued tumor lung colonization. HO-1 expression was higher in human primary and metastatic tumors compared with noncancerous tissue. Moreover, HO-1 expression correlated with reduced overall survival of patients with lung adenocarcinoma and glioblastoma. These results establish HO-1 as a mediator of ATF4-dependent anoikis resistance and tumor metastasis and suggest ATF4 and HO-1 as potential targets for therapeutic intervention in solid tumors. [ABSTRACT FROM AUTHOR]

Background: Oropharyngeal squamous cell carcinoma (OPSCC) has now surpassed cervical cancer as the most common site of HPV-related cancer in the United States. HPV-positive OPSCCs behave differently from HPV-negative tumors and often present with early lymph node involvement. The bacterial microbiome of HPV-associated OPSCC may contribute to carcinogenesis, and certain bacteria may influence the spread of cancer from the primary site to regional lymphatics.Objective: To determine the bacterial microbiome in patients with HPV-associated, early tonsil SCC and compare them to benign tonsil specimens.Method: The microbiome of primary tumor specimens and lymph nodes was compared to benign tonsillectomy specimens with pan-pathogen microarray (PathoChip).Results: A total of 114 patients were enrolled in the study. Patients with OPSCC had a microbiome that shifted towards more gram-negative. Numerous signatures of bacterial family and species were associated with the primary tumors and lymph nodes of cancer patients, including the urogenital pathogens Proteus mirabilis and Chlamydia trachomatis, Neisseria gonorrhoeae, Shigella dysenteriae, and Orientia tsutsugamushi.Conclusion: Our results suggest that detection of urogenital pathogens is associated with lymph node metastasis for patients with HPV-positive OPSCCs. Additional studies are necessary to determine the effects of the OPSCC microbiome on disease progression and clinical outcomes. [ABSTRACT FROM AUTHOR]

Context-Bone morphogenetic proteins (BMPs) are thought to be responsible for bone formation; they cause bone to form in soft tissues and are clinically used in helping fracture union or tumor reconstructions. Skeletal metastases from epithelial tumors may be either bone-forming (blastic) or non-bone-forming (lytic). Objective.-We studied the expression of BMPs in a variety of primary and secondary lesions of bone (both bone- forming and non-bone-forming) to determine if there was a consistent relationship between bone formation and BMP expression. Design.-We compared a bone-forming lesion (fibrous dysplasia) with a non-bone-forming lesion (desmoid tumor), using reverse transcription-polymerase chain reaction, Northern blot analysis, and immunohistochemistry to detect BMPs. We also studied a number of non-bone-forming secondary lesions (carcinomas that formed lytic metastases to the skeleton) and found BMP production in most of these tumors. Results.-We found that BMPs were expressed in both bone-forming and non-bone-forming benign musculoskeletal lesions. In the first part of the study, BMPs were found in both fibrous dysplasia and desmoid tumors. Bone morphogenetic proteins were also expressed by several tumors. In the next part of the study (paraffin-embedded tissue), BMPs were expressed by a variety of tumors, irrespective of the radiological nature (blastic or lytic) of their metastases. Conclusions-We conclude that BMP production alone cannot explain bone formation, and other factors either alone or in combination may be responsible for blastic metastases to the skeleton and for bone formation by primary bone lesions, such as fibrous dysplasia. [ABSTRACT FROM AUTHOR]