Genomic analysis of mycosis fungoides and Sezary syndrome identifies recurrent alterations in TNFR2
2015; 47 (9): 1056-?
Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2.
2015; 47 (9): 1056-1060
Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma
2014; 46 (10): 1060-1062
Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma.
2014; 46 (10): 1060-1062
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.
View details for DOI 10.1038/ng.3370
View details for PubMedID 26258847
Control of somatic tissue differentiation by the long non-coding RNA TINCR.
2013; 493 (7431): 231-235
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.
View details for DOI 10.1038/ng.3091
View details for PubMedID 25194279
Control of somatic tissue differentiation by the long non-coding RNA TINCR
2013; 493 (7431): 231-U245
Transcriptome sequencing in Sezary syndrome identifies Sezary cell and mycosis fungoides-associated lncRNAs and novel transcripts
2012; 120 (16): 3288-3297
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.
View details for DOI 10.1038/nature11661
View details for PubMedID 23201690
Rapid identification of non-human sequences in high-throughput sequencing datasets
2012; 28 (8): 1174-1175
Sézary syndrome (SS) is an aggressive cutaneous T-cell lymphoma (CTCL) of unknown etiology in which malignant cells circulate in the peripheral blood. To identify viral elements, gene fusions, and gene expression patterns associated with this lymphoma, flow cytometry was used to obtain matched pure populations of malignant Sézary cells (SCs) versus nonmalignant CD4(+) T cells from 3 patients for whole transcriptome, paired-end sequencing with an average depth of 112 million reads per sample. Pathway analysis of differentially expressed genes identified mis-regulation of PI3K/Akt, TGF?, and NF-?B pathways as well as T-cell receptor signaling. Bioinformatic analysis did not detect either nonhuman transcripts to support a viral etiology of SS or recurrently expressed gene fusions, but it did identify 21 SC-associated annotated long noncoding RNAs (lncRNAs). Transcriptome assembly by multiple algorithms identified 13 differentially expressed unannotated transcripts termed Sézary cell-associated transcripts (SeCATs) that include 12 predicted lncRNAs and a novel transcript with coding potential. High-throughput sequencing targeting the 3' end of polyadenylated transcripts in archived tumors from 24 additional patients with tumor-stage CTCL confirmed the differential expression of SC-associated lncRNAs and SeCATs in CTCL. Our findings characterize the SS transcriptome and support recent reports that implicate lncRNA dysregulation in human malignancies.
View details for DOI 10.1182/blood-2012-04-423061
View details for Web of Science ID 000311619200020
View details for PubMedID 22936659
Suppression of progenitor differentiation requires the long noncoding RNA ANCR
GENES & DEVELOPMENT
2012; 26 (4): 338-343
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).RINS is available for free download at http://khavarilab.stanford.edu/resources.html.
View details for DOI 10.1093/bioinformatics/bts100
View details for Web of Science ID 000302806900022
View details for PubMedID 22377895
Adoption of Western Culture by Californian Asian Americans Attitudes and Practices Promoting Sun Exposure
ARCHIVES OF DERMATOLOGY
2009; 145 (5): 552-556
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.
View details for DOI 10.1101/gad.182121.111
View details for Web of Science ID 000300626800004
View details for PubMedID 22302877
Expression of cyclooxygenase-2 and peroxisome proliferator-activated receptor gamma during malignant melanoma progression
JOURNAL OF CUTANEOUS PATHOLOGY
2008; 35 (11): 989-994
To investigate whether the adoption of Western culture is associated with attitudes and practices promoting sun exposure among Asian Americans.Survey conducted from November 28, 2007, to January 28, 2008.Primarily northern California community groups via online survey.Adult volunteers who self-identified as Asian American.Results based on 546 questionnaires returned.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.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.
View details for Web of Science ID 000266207400006
View details for PubMedID 19451499
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 (PPARgamma) 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 PPARgamma immunohistological staining in benign nevi, primary melanomas and metastatic melanomas to help predict the effectiveness of compounds targeting these markers.COX-2 and PPARgamma immunohistological staining was performed and reviewed in 99 melanocytic lesions, including 38 benign nevi, 32 primary melanomas and 29 metastatic melanomas.There was a significant increase in both COX-2 and PPARgamma immunostaining in melanomas compared with benign nevi. Metastatic melanomas were more likely to have a higher number of PPARgamma-immunopositive cells. They were also more likely to express COX-2 than primary melanomas. Neither COX-2 nor PPARgamma expression was associated with a specific pathologic subtype.COX-2 and PPARgamma may help modulate the progression of melanocytic precursor lesions to disseminated malignant melanoma. As such, they may serve as candidate substrates for targeted cancer therapies and may be particularly useful as adjuncts to surgery.
View details for DOI 10.1111/j.1600-0560.2007.00939.x
View details for Web of Science ID 000259955200002
View details for PubMedID 18537861