Faculty Bibliography

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.

PURPOSE/OBJECTIVE:While multimodal chemotherapy has improved outcomes for patients with osteosarcoma (OS), the prognosis for patients who present with metastatic and/or recurrent disease remains poor. In this study, we sought to define how often clinical genomic sequencing of OS samples could identify potentially actionable alterations. EXPERIMENTAL DESIGN/METHODS:We analyzed genomic data from 71 OS samples from 66 pediatric and adult patients sequenced using MSK-IMPACT, a hybridization capture-based large panel NGS assay. Potentially actionable genetic events were categorized according to the OncoKB precision oncology knowledge base, of which Levels 1-3 were considered clinically actionable. RESULTS:We found at least one potentially actionable alteration in 14/66 patients (21%), including amplification of CDK4 (n=9, 14%: Level 2B) and/or MDM2 (n=9, 14%: Level 3B), and somatic truncating mutations/deletions in BRCA2 (n=3, 5%: Level 2B) and PTCH1 (n=1, Level 3B). Additionally, we observed mutually exclusive patterns of alterations suggesting distinct biological subsets defined by gains at 4q12 and 6p12-21. Specifically, potentially targetable gene amplifications at 4q12 involving KIT, KDR and PDGFRA were identified in 13 of 66 patients (20%), which showed strong PDGFRA expression by immunohistochemistry. In another largely non-overlapping subset of 14 patients (24%) with gains at 6p12-21, VEGFA amplification was identified. CONCLUSIONS:We found potentially clinically actionable alterations in approximately 21% of OS patients. Additionally, at least 40% of patients have tumors harboring PDGFRA or VEGFA amplification, representing candidate subsets for clinical evaluation of additional therapeutic options. We propose a new genomically-based algorithm for directing OS patients to clinical trial options.

Glioblastoma (GBM), representing WHO grade IV astrocytoma, is a relatively common primary brain tumor in adults with an exceptionally dismal prognosis. With an incidence rate of over 10 000 cases in the United States annually, the median survival rate ranges from 10-15 months in IDH1/2-wildtype tumors and 24-31 months in IDH1/2-mutant tumors, with further variation depending on factors such as age, MGMT methylation status, and treatment regimen. We present a cohort of 4 patients, aged 37-60 at initial diagnosis, with IDH1-mutant GBMs that were associated with unusually long survival intervals after the initial diagnosis, currently ranging from 90 to 154 months (all still alive). We applied genome-wide profiling with a methylation array (Illumina EPIC Array 850k) and a next-generation sequencing panel to screen for genetic and epigenetic alterations in these tumors. All 4 tumors demonstrated methylation patterns and genomic alterations consistent with GBM. Three out of four cases showed focal amplification of the CCND2 gene or gain of the region on 12p that included CCND2, suggesting that this may be a favorable prognostic factor in GBM. As this study has a limited sample size, further evaluation of patients with similar favorable outcome is warranted to validate these findings.

Cutaneous metastases are not particularly common compared to metastases to other system organs, but they are an important entity to diagnose correctly given their prognostic implications. Clinically cutaneous metastases can mimic more common dermatologic disorders (e.g. cysts, adnexal tumors, lipomas, cellulitis, vascular tumors, etc.) that may result in diagnosis delay if not considered. An understanding of the clinical spectrum as well as advances in histopathologic assessment of skin metastases is vital to establish the correct diagnosis. Herein we review the clinical, histopathologic, and prognostic salient findings of three different types of cutaneous metastases: carcinomas, melanomas, and sarcomas. We also highlight important immunohistochemical studies and molecular platforms that assist in determining the primary site of origin and/or the line of differentiation.

BACKGROUND:The role of the mammalian target of rapamycin (mTOR) in hair follicle tumorigenesis is unclear. mTOR controls cell growth and can be activated through ribosomal S6 kinase. Herein, we sought to evaluate the expression of phospho-S6 in six different benign and malignant follicular tumor types. METHODS:test (p<0.05). RESULTS:All malignant neoplasms in our series [8/8 (100%) cases of tricholemmal carcinoma, 1/1 (100%) trichoblastic carcinoma and 1/1 (100%) malignant proliferating tricholemmal tumor] demonstrated a strong and diffuse pattern of staining with phospho-S6 involving 70-90% of tumor cells. By contrast, a minority of benign tumors were positive for phospho-S6 and most stained in a patchy pattern including 12/17 (71%) fibrofolliculomas, 9/20 (45%) trichoepitheliomas and 1/10 (10%) tricholemmomas, involving 30-50%, 5-20%, and 40-50% of tumor cells, respectively. Most pilomatricomas [17/19 (89%)] exhibited a stronger, but distinctive staining pattern, staining mostly the basaloid cells with a multifocal distribution, involving 70-90% of tumor cell. CONCLUSIONS:Phospho-S6 is differentially expressed among benign and malignant hair follicle tumors (p = 0.0044). While malignant tumors show diffuse expression, only a small subset of benign neoplasms were positive, primarily in a patchy distribution.

Microglandular adenosis (MGA) is a rare breast lesion reported to be associated with invasive carcinoma in up to 20-30% of cases, and has been proposed as a non-obligate precursor to basal-like breast cancers. We identified a case of matrix-producing metaplastic carcinoma with morphologic and immunohistochemical evidence of progression from MGA to atypical MGA (AMGA), carcinoma in situ (CIS) and invasive carcinoma. We performed whole exome sequencing of each component (MGA, AMGA, CIS and cancer) to characterize the mutational landscape of these foci. There was significant copy number overlap between all foci, including a segmental amplification of the CCND1 locus (partial chromosome 11 trisomy) and MYC (8q24.12-13). Using a bioinformatics approach, we were able to identify three putative mutational clusters and recurrent, stop-gain non-synonymous mutations in both ZNF862 and TP53 that were shared across all foci. Finally, we identified a novel deleterious splice-acceptor site mutation of chr5:5186164G>T (chromosome 5p15) encoding the gene, ADAMTS16, in the invasive component.