Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; p(combined) = 3.9 x 10(-20) and 1.6 x 10(-19), respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; p(combined) = 8.97 x 10(-17)) and HLA-F (rs3129055 and rs9258122; p(combined) = 7.36 x 10(-11) and 3.33 x 10(-10), respectively). Notably, the association of rs29232 remained significant (residual p < 5 x 10(-4)) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABA(B) receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.

This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

Radioresistance of EBV-associated nasopharyngeal carcinoma (NPC) is associated with poor prognosis for patients with this form of cancer. Here, we found that NPC patients had increased serum levels of leukemia inhibitory factor (LIF) and that higher LIF levels correlated with local tumor recurrence. Furthermore, in vitro studies with NPC cells and in vivo xenograft mouse studies demonstrated that LIF critically contributes to NPC tumor growth and radioresistance. Using these model systems, we found that LIF treatment activated the mTORC1/p70S6K signaling pathway, enhanced tumor growth, inhibited DNA damage responses, and enhanced radioresistance. Treatment with either soluble LIF receptor (sLIFR), a LIF antagonist, or the mTOR inhibitor rapamycin reversed LIF-mediated effects, resulting in growth arrest and increased sensitivity to γ irradiation. Immunohistochemical (IHC) analyses of human NPC biopsies revealed that LIF and LIFR were overexpressed in tumor cells and that LIF expression correlated with the presence of the activated p-p70S6K. Finally, we found that the EBV-encoded protein latent membrane protein 1 (LMP1) enhances LIF production. Together, our findings indicate that LIF promotes NPC tumorigenesis and suggest that serum LIF levels may predict local recurrence and radiosensitivity in NPC patients.

The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

Understanding how plants respond to drought can benefit drought resistance (DR) breeding. Using a non-destructive phenotyping facility, 51 image-based traits (i-traits) for 507 rice accessions were extracted. These i-traits can be used to monitor drought responses and evaluate DR. High heritability and large variation of these traits was observed under drought stress in the natural population. A genome-wide association study (GWAS) of i-traits and traditional DR traits identified 470 association loci, some containing known DR-related genes. Of these 470 loci, 443 loci (94%) were identified using i-traits, 437 loci (93%) co-localized with previously reported DR-related quantitative trait loci, and 313 loci (66.6%) were reproducibly identified by GWAS in different years. Association networks, established based on GWAS results, revealed hub i-traits and hub loci. This demonstrates the feasibility and necessity of dissecting the complex DR trait into heritable and simple i-traits. As proof of principle, we illustrated the power of this integrated approach to identify previously unreported DR-related genes. OsPP15 was associated with a hub i-trait, and its role in DR was confirmed by genetic transformation experiments. Furthermore, i-traits can be used for DR linkage analyses, and 69 i-trait locus associations were identified by both GWAS and linkage analysis of a recombinant inbred line population. Finally, we confirmed the relevance of i-traits to DR in the field. Our study provides a promising novel approach for the genetic dissection and discovery of causal genes for DR.

No abstract

Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan. By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13. APOBEC3A expression is significantly higher in tumors carrying APOBEC3B-deletion allele(s). High-level APOBEC3A expression is associated with better overall survival, especially among patients carrying APOBEC3B-deletion alleles, as examined in a second cohort (n = 188; p = 0.004). The frequency of APOBEC3B-deletion alleles is ~50% in 143 genotyped oral squamous cell carcinoma -Taiwan samples (27A3B −/−:89A3B +/−:27A3B +/+), compared to the 5.8% found in 314 OSCC-TCGA samples. We thus report a frequent APOBEC mutational profile, which relates to a APOBEC3B-deletion germline polymorphism in Taiwanese oral squamous cell carcinoma that impacts expression of APOBEC3A, and is shown to be of clinical prognostic relevance. Our finding might be recapitulated by genomic studies in other cancer types.

Plant responses to abiotic stresses are coordinated by arrays of growth and developmental programs. Phytohormones such as abscisic acid (ABA) and indole-3-acetic acid (IAA) play critical roles in developmental progresses and environmental responses through complex signalling networks. However, crosstalk between the two hormones at the biosynthesis level remains largely unknown. Here, we report that carotenoid-deficient mutants (phs1, phs2, phs3-1, phs4, and PDS-RNAi transgenic rice) were impaired in the biosynthesis of ABA and IAA. Under drought conditions, phs3-1 and PDS-RNAi transgenic rice showed larger stomata aperture and earlier wilting compared to the wild type at both seedling and panicle developmental stage. Interestingly, these carotenoid-deficient lines showed increased cold resistance, which was likely due to the combined effects of reduced IAA content, alleviated oxidative damage and decreased membrane penetrability. Furthermore, we found that IAA content was significantly declined in rice treated with fluridone (a carotenoid and ABA biosynthesis inhibitor), and expression of auxin synthesis and metabolism-related genes were altered in the fluridone-treated rice similar to that in the carotenoid-deficient mutants. In addition, exogenous IAA, but not ABA, could restore the dwarf phenotype of phs3-1 and PDS-RNAi transgenic rice. These results support a crosstalk between ABA and IAA at the biosynthesis level, and this crosstalk is involved in development and differentially affects drought and cold tolerance in rice.