Person:

Nazarian, Rosalynn

A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes.

A 14-month-old boy presented with a slow-growing, asymptomatic back plaque, which was biopsied and found to have S100 positivity, sparse CD34 staining, and no significant mitotic activity, nuclear pleomorphism, or necrosis; genetic workup found LMNA-NTRK1 gene fusion, overall consistent with lipofibromatosis-like neural tumor (LPF-NT). LPF-NT is rare, with 14 cases previously reported, and our patient is the first report of this diagnosis in infancy. This case report and literature review includes comparison of similar diagnoses including lipofibromatosis, low-grade malignant peripheral nerve sheath tumor, infantile fibrosarcoma, and dermatofibrosarcoma protuberans and serves to aid detection of LPF-NT presenting in pediatric patients by highlighting similarities and differences that should prompt consideration. LPF-NT shows locally aggressive behavior only and should not be confused with conditions that have potential for distant spread. However, case reports of metastasizing LMNA-NTRK1 tumors draw into question whether growths with this gene fusion exist on a spectrum of disease severity. Our patient was treated with wide local excision and has developed no complications or evidence of recurrence with 6 months of follow-up time.

Background/Aims The development of programmed cell death-1 (PD-1) inhibitors has greatly improved patient outcomes in the treatment of a variety of advanced malignancies. These novel immunotherapies are not without adverse effects, the most common of which are dermatologic. Methods: We report our experience with an atypical erythema multiforme-like eruption in a patient with primary central nervous system diffuse large B-cell lymphoma treated with nivolumab. Results: The patient presented with oral mucositis and scattered erythematous papules which progressed to targetoid purpuric plaques with hyperkeratotic centers. Histopathology demonstrated interface dermatitis with dyskeratotic keratinocytes and pigment incontinence. The patient experienced improvement of the eruption with discontinuation of nivolumab and on systemic and topical glucocorticoids. Conclusion: As PD-1 inhibitors become more widely used in the treatment of advanced malignancies, the early recognition and treatment of rare dermatologic toxicities remain of great importance.

On average, the Peruvian population is among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvians, and identify a novel, population-specific, missense variant in FBN1 (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency=4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). This is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin-1, a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals homozygous for G1297 compared to individuals homozygous for E1297. Moreover, we show that E1297G locus is under positive selection in non-African populations, and the E1297 variant shows subtle evidence of positive selection within the Peruvian population specifically. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, suggesting that short stature might be the result of adaptation to factors associated with the coastal environment in Peru.