Faculty Bibliography

Tenosynovial giant cell tumor (TGCT) is a benign neoplasm characterized by recurrent fusions involving the colony-stimulating factor 1 (CSF1) gene and translocation partners including collagen type VI alpha 3 chain (COL6A3) or S100 calcium-binding protein A10 (S100A10). Herein, we report three atypical TGCT cases with very unusual morphology comprising areas with increased cellular atypia, mitotic activity, and worrisome features that harbor unique non-CSF1 gene fusions. Anchored multiplex PCR (AMP) for next-generation sequencing utilizing a customized panel targeting 86 cancer-related genes was performed, and it identified novel non-CSF1-driven gene fusions: NIPBL-ERG, FN1-ROS1, and YAP1-MAML2. Screening of three control TGCTs with conventional morphology found translocations involving CSF1, with partner genes COL6A3, FN1, and newly identified KCNMA1. All novel fusions were further validated by reverse transcriptase-PCR (RT-PCR) and Sanger sequencing. Late and multiple local recurrences occurred in the atypical TGCTs, while no recurrences were reported in the conventional TGCTs. Our findings reveal that atypical TGCTs harbor gene fusions not implicating CSF1 and suggest that non-CSF1 fusions potentially confer greater propensity to recurrences and local aggressiveness while indicating the presence of alternate pathogenic mechanisms that warrant further investigation.

Acral melanoma (AM) is a rare, aggressive type of cutaneous melanoma (CM) with a distinct genetic profile. We aimed to identify a methylome signature distinguishing primary acral lentiginous melanoma (PALM) from primary non-lentiginous AM (NALM), metastatic ALM (MALM), primary non-acral CM (PCM), and acral nevus (AN). A total of 22 PALM, nine NALM, 10 MALM, nine PCM, and three AN were subjected to genome-wide methylation analysis using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. A prominent finding was that the methylation profiles of PALM and NALM were distinct. Four of the genes most differentially methylated between PALM and NALM or MALM were HHEX, DIPK2A, NELFB, and TEF. However, when primary AMs (PALM + NALM) were compared with MALM, IFITM1 and SIK3 were the most differentially methylated, highlighting their pivotal role in the metastatic potential of AMs. Patients with NALM had significantly worse disease-specific survival (DSS) than patients with PALM. Aberrant methylation was significantly associated with aggressive clinicopathologic parameters and worse DSS. Our study emphasizes the importance of distinguishing the two epigenetically distinct subtypes of AM. We also identified novel epigenetic prognostic biomarkers that may serve to risk-stratify patients with AM and may be leveraged for the development of targeted therapies.

ROS1 is a transmembrane receptor tyrosine kinase proto-oncogene that has been shown to have rearrangements with several genes in glioblastoma and other neoplasms, including intrachromosomal fusion with GOPC due to microdeletions at 6q22.1. ROS1 fusion events are important findings in these tumors, as they are potentially targetable alterations with newer tyrosine kinase inhibitors; however, whether these tumors represent a distinct entity remains unknown. In this report, we identify 3 cases of unusual pediatric glioma with GOPC-ROS1 fusion. We reviewed the clinical history, radiologic and histologic features, performed methylation analysis, whole genome copy number profiling, and next generation sequencing analysis for the detection of oncogenic mutation and fusion events to fully characterize the genetic and epigenetic alterations present in these tumors. Two of 3 tumors showed pilocytic features with focal expression of synaptophysin staining and variable high-grade histologic features; the third tumor aligned best with glioblastoma and showed no evidence of neuronal differentiation. Copy number profiling revealed chromosome 6q22 microdeletions corresponding to the GOPC-ROS1 fusion in all 3 cases and methylation profiling showed that the tumors did not cluster together as a single entity or within known methylation classes by t-Distributed Stochastic Neighbor Embedding.

In the recent decade, cutting edge molecular and proteomic analysis platforms revolutionized biomarkers discovery in cancers. Melanoma is the prototype with over 51,100 biomarkers discovered and investigated thus far. These biomarkers include tissue based tumor cell and tumor microenvironment biomarkers and circulating biomarkers including tumor DNA (cf-DNA), mir-RNA, proteins and metabolites. These biomarkers provide invaluable information for diagnosis, prognosis and play an important role in prediction of treatment response. In this review, we summarize the most recent discoveries in each of these biomarker categories. We will discuss the challenges in their implementation and standardization and conclude with some perspectives in melanoma biomarker research.

Angiogenesis, the formation of new blood vessels from existing blood vessels, is a complex and highly regulated process that plays a role in a wide variety of physiological and pathological processes. In malignancy, angiogenesis is essential for neoplastic cells to acquire the nutrients and oxygen critical for their continued proliferation. Angiogenesis requires a sequence of well-coordinated events mediated by a number of tightly regulated interactions between pro-angiogenic factors and their corresponding receptors expressed on various vascular components (e.g., endothelial cells and pericytes) and stromal components forming the extracellular matrix. In this review, we discuss the functional roles of key growth factors and cytokines known to promote angiogenesis in cutaneous melanoma and key factors implicated in the extracellular matrix remodeling that acts synergistically with angiogenesis to promote tumor progression in melanoma, incorporating some of the most up-to-date basic science knowledge from recently published in vivo and in vitro experimental studies.