Carolyn S. Lee

Control of somatic tissue differentiation by the long non-coding RNA TINCR

Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized; however, potential roles for lncRNAs in somatic tissue differentiation remain poorly understood. Here we show that a 3.7-kilobase lncRNA, terminal differentiation-induced ncRNA (TINCR), controls human epidermal differentiation by a post-transcriptional mechanism. TINCR is required for high messenger RNA abundance of key differentiation genes, many of which are mutated in human skin diseases, including FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14 and ELOVL3. TINCR-deficient epidermis lacked terminal differentiation ultrastructure, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs. TINCR–mRNA interaction occurs through a 25-nucleotide ‘TINCR box’ motif that is strongly enriched in interacting mRNAs and required for TINCR binding. A high-throughput screen to analyse TINCR binding capacity to approximately 9,400 human recombinant proteins revealed direct binding of TINCR RNA to the staufen1 (STAU1) protein. STAU1-deficient tissue recapitulated the impaired differentiation seen with TINCR depletion. Loss of UPF1 and UPF2, both of which are required for STAU1-mediated RNA decay, however, did not have differentiation effects. Instead, the TINCR–STAU1 complex seems to mediate stabilization of differentiation mRNAs, such as KRT80. These data identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression.

Suppression of progenitor differentiation requires the long noncoding RNA ANCR

Long noncoding RNAs (lncRNAs) regulate diverse processes, yet a potential role for lncRNAs in maintaining the undifferentiated state in somatic tissue progenitor cells remains uncharacterized. We used transcriptome sequencing and tiling arrays to compare lncRNA expression in epidermal progenitor populations versus differentiating cells. We identified ANCR (anti-differentiation ncRNA) as an 855-base-pair lncRNA down-regulated during differentiation. Depleting ANCR in progenitor-containing populations, without any other stimuli, led to rapid differentiation gene induction. In epidermis, ANCR loss abolished the normal exclusion of differentiation from the progenitor-containing compartment. The ANCR lncRNA is thus required to enforce the undifferentiated cell state within epidermis.

Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2

Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma

Here we report the discovery of recurrent mutations concentrated at an ultraviolet signature hotspot in KNSTRN, which encodes a kinetochore protein, in 19% of cutaneous squamous cell carcinomas (SCCs). Cancer-associated KNSTRN mutations, most notably those encoding p.Ser24Phe, disrupt chromatid cohesion in normal cells, occur in SCC precursors, correlate with increased aneuploidy in primary tumors and enhance tumorigenesis in vivo. These findings suggest a role for KNSTRN mutagenesis in SCC development.

Rapid identification of non-human sequences in high-throughput sequencing datasets

UNLABELLED Rapid identification of non-human sequences (RINS) is an intersection-based pathogen detection workflow that utilizes a user-provided custom reference genome set for identification of non-human sequences in deep sequencing datasets. In <2 h, RINS correctly identified the known virus in the dataset SRR73726 and is compatible with any computer capable of running the prerequisite alignment and assembly programs. RINS accurately identifies sequencing reads from intact or mutated non-human genomes in a dataset and robustly generates contigs with these non-human sequences (Supplementary Material). AVAILABILITY RINS is available for free download at http://khavarilab.stanford.edu/resources.html.

Expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor gamma during malignant melanoma progression

Background:  Cancer chemoprevention using nonsteroidal anti‐inflammatory drugs is frequently attributed to cyclooxygenase‐2 (COX‐2) inhibition, although recent studies suggest that peroxisome proliferator‐activated receptor gamma (PPARγ) may also be involved. While surgical excision remains the treatment mainstay for localized malignant melanoma, certain high‐risk patients may benefit from adjunctive chemotherapy. In this study, we compared COX‐2 and PPARγ immunohistological staining in benign nevi, primary melanomas and metastatic melanomas to help predict the effectiveness of compounds targeting these markers.

Adoption of Western Culture by Californian Asian Americans: Attitudes and Practices Promoting Sun Exposure

OBJECTIVE To investigate whether the adoption of Western culture is associated with attitudes and practices promoting sun exposure among Asian Americans. DESIGN Survey conducted from November 28, 2007, to January 28, 2008. SETTING Primarily northern California community groups via online survey. PARTICIPANTS Adult volunteers who self-identified as Asian American. MAIN OUTCOME MEASURES Results based on 546 questionnaires returned. RESULTS The overall response rate was 74.4%. Multivariate regression analysis controlling for age and skin type showed that westernization (as determined by generation in the United States, location raised, or self-rated acculturation) was associated with attitudes and behaviors promoting sun exposure (including the belief that having a tan is attractive, negative attitudes toward use of sunscreen and sun protective clothing, and increased weekend sun exposure, lying out to get a tan, and tanning bed use) at a level of P < .05. CONCLUSIONS Our data suggest that adoption of Western culture may be associated with attitudes and behaviors promoting sun exposure among Asian Americans. This group should be targeted by dermatologists for increased education regarding sun protection, solar damage, and skin cancer prevention and detection.

Node-positive cutaneous squamous cell carcinoma of the head and neck: Survival, high-risk features, and adjuvant chemoradiotherapy outcomes: Regionally metastatic cutaneous HNSCC

Data lacks to guide treatment of regionally metastatic cutaneous head and neck squamous cell carcinoma (HNSCC).

Mutations in the Kinetochore Gene KNSTRN in Basal Cell Carcinoma

Institute Innovation Award. Theresa H.M. Keegan, Susan M. Swetter, Li Tao, John B. Sunwoo and Christina A. Clarke Department of Research, Cancer Prevention Institute of California, Fremont, California, USA; Division of Epidemiology, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California, USA; Department of Dermatology, Pigmented Lesion and Melanoma Program, Stanford University Medical Center and Cancer Institute, and Dermatology Service, VA Palo Alto Health Care System, Palo Alto, California, USA and Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine and Cancer Institute, Palo Alto, California, USA E-mail:tkeegan@ucdavis.edu

Skin Cancer Prevention and Treatment in Solid Organ Transplant Patients: A Survey of the International Transplant Skin Cancer Collaborative.

visit. His funeral was on an arctic evening, and it took me 90 minutes to drive the 20 miles in blinding snow from Burlington to St Albans. I laid a poster compilation of his dermatology friends along with the many from his family and walleye friends. His daughter came over and I paid my respects—my respects to this deeply wonderful man. When I left the funeral home, the snow had stopped and I nosed my truck onto the freeway home. As I passed over the Lamoille River, I imagined Dan’s walleye spawning in the spring. I miss my friend.