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The analysis of whole-genome sequencing studies is challenging due to the large number of rare variants in noncoding regions and the lack of natural units for testing. We propose a statistical method to detect and localize rare and common risk variants in whole-genome sequencing studies based on a recently developed knockoff framework. It can (1) prioritize causal variants over associations due to linkage disequilibrium thereby improving interpretability; (2) help distinguish the signal due to rare variants from shadow effects of significant common variants nearby; (3) integrate multiple knockoffs for improved power, stability and reproducibility; and (4) flexibly incorporate state-of-the-art and future association tests to achieve the benefits proposed here. In applications to whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (ADSP) and COPDGene samples from NHLBI Trans-Omics for Precision Medicine (TOPMed) Program we show that our method compared with conventional association tests can lead to substantially more discoveries.

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Introduction: Patients with vitiligo present with different repigmentation patterns in the early recovery stage. Objective: To analyze the relationships between early repigmentation patterns in vitiliginous patches, their clinical charcateristics, and therapeutic choices. Materials and Methods: Patients with vitiligo seen in the Department of Dermatology, The First Affiliated Hospital of Nanjing Medical University from 2010 to 2015, were included, and their clinical records, especially photographs and medical treatments, were reviewed. Results: 116 patients were included in this study, and 326 lesions with different degrees of depigmentation, locations, stages, distributions, therapies, and repigmentation patterns were included and analyzed. Perifollicular repigmentation occurred more frequently in lesions with complete depigmentation (P ¼ 0.005), in non-sun exposed areas (P < 0.001), a stable stage (P ¼ 0.008), and lesions treated with narrow band ultraviolet B (NB-UVB) (P < 0.001, despite lesion distributions). Marginal repigmentation is more frequent in lesions with complete depigmentation (P ¼ 0.016), lesions treated without NB-UVB (P ¼ 0.002), and facial lesions treated with topical vitamin D analogs (TVDAs) monotherapy (P ¼ 0.022). Diffuse repigmentation is the predominant pattern in lesions with incomplete depigmentation (P < 0.001), in sunexposed areas (P < 0.001), progressive stage (P ¼ 0.044), and truncal lesions treated with TVDAs (P < 0.001). Conclusions: The different repigmentation patterns of vitiligo lesions depend on the different source and status of melanocytes and their abilities to produce melanin on the choice of therapy. ABSTRACTS | Skin of Color

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Acral melanoma (AM) occurs on the palms, soles and subungual sites and occurs in a much higher proportion in darker-skinned individuals compared to cutaneous melanoma. AM is the most common subtype of melanoma in patients of African and Asian descent. AM is associated with activation mutations in the KIT gene and/or inactivating mutations in NF1 (neuro-fibromin1). These tumors respond poorly to currently available targeted therapies and immune checkpoint inhibition, underscoring the urgent need for treatment alternatives that improve overall survival of patients with metastatic disease. The protein kinase CK2 (casein kinase II) is upregulated in several types of cancer, including melanoma, and especially in AM. CK2 overexpression contributes to maintenance of the malignant phenotype and is associated with resistance to targeted therapies. Here, we investigated the potential of CK2 inhibition to overcome resistance to MEK inhibitors (MEKi) in preclinical models of AM. We found that in vitro treatment of NF1-null human melanoma cells with a small-molecule CK2 inhibitor (CX4945, silmitasertib) resulted in inhibition of cell proliferation. This was accompanied by downregulation of PI3K and ERK-MAPK signaling, as demonstrated by dephosphorylation of AKT (S129 and S473) and ERK (p44/42 MAPK; Thr202/Tyr204). CX4945 also showed a synergistic anti-proliferative effect with the MEKi trametinib in MTS viability assays, and an increase in apoptosis. Further, in colony formation assays, CX4945 significantly reduced the appearance of trametinib resistant colonies. To translate these findings, we treated NF1-null human melanoma cells grown as xenografts in nude mice with CX4945, and noted a significant reduction in tumor growth that resulted in stable disease. Together, our results suggest that the combination of CK2 inhibitors with MEK inhibitors, and potentially other tyrosine kinase inhibitors, may improve therapeutic outcomes in difficult to treat malignant melanomas of acral origin.

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