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Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs. A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. Moreover, sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC. We also integrated sQTLs into NSCLC GWAS datasets (13,327 affected individuals and 13,328 control individuals) by using splice-transcriptome-wide association study (spTWAS) and identified alternative splicing events in 19 genes that were significantly associated with NSCLC risk. By using functional annotation and experiments, we confirmed an sQTL variant, rs35861926, that reduced the risk of lung adenocarcinoma (rs35861926-T, OR = 0.88, 95% confidence interval [CI]: 0.82–0.93, p = 1.87 × 10−5) by promoting FARP1 exon 20 skipping to downregulate the expression level of the long transcript FARP1 -011. Transcript FARP1 -011 promoted the migration and proliferation of lung adenocarcinoma cells. Overall, our study provided informative lung sQTL resources and insights into the molecular mechanisms linking sQTL variants to NSCLC risk. [Display omitted] This study provided a comprehensive catalog of splicing quantitative trait loci (sQTLs) in lung tissues. Integrative sQTL analysis revealed risk loci for non-small-cell lung cancer. Further experiments confirmed that rs35861926 could reduce lung adenocarcinoma risk by promoting FARP1 exon 20 skipping to downregulate the expression level of transcript FARP1 -011. [ABSTRACT FROM AUTHOR]

Idiopathic achalasia (IA) is a severe motility disorder characterized by neuronal degeneration in the myenteric plexus, but the etiology remains largely unknown. We performed whole-exome sequencing (WES) in 100 IA-affected individuals and 313 non-IA control subjects and validated the results in 230 IA-affected individuals and 1,760 non-IA control subjects. Common missense variants rs1705003 (CUTA , GenBank: NC_000006.11:g.33385953A>G) and rs1126511 (HLA-DPB1 , GenBank: NC_000006.11:g.33048466G>T) at 6p21.32 were reproducibly associated with increased risk of IA (rs1126511: OR = 1.83, p = 2.34 × 10−9; rs1705003: OR = 2.37, p = 3.21 × 10−7), meeting exome-wide significance. Both variants can affect the expression of their target genes at the transcript level. An array-based association analysis in 280 affected individuals and 1,121 control subjects determined the same signal at 6p21.32. Further conditional analyses supported that the two missense variants identified in WES-based association study were potential causal variants of IA. For rare variants, the top genes identified by gene-based analysis were significantly enriched in nerve and muscle phenotypic genes in the mouse. Moreover, the functional rare variants in these genes tended to cooccur in IA-affected individuals. In an independent cohort, we successfully validated three rare variants (CREB5 , GenBank: NC_000007.13:g.28848865G>T; ESYT3 , GenBank: NC_000003.11:g.138183253C>T; and LPIN1 , GenBank: NC_000002.11:g.11925128A>G) which heightens the risk of developing IA. Our study identified and validated two common variants and three rare variants associated with IA in immunologic and neurological genes, providing new insight into the etiology of IA. [ABSTRACT FROM AUTHOR]

Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy. [Display omitted] • Fumarate directly targets and succinates PTEN at C211 • C211 succination abrogates the interaction of PTEN with the cellular membrane • PTEN C211 succination is positively correlated with PI3K/AKT activation in PRCC2 • Inhibiting PTEN C211 succination or AKT sensitizes PRCC2 to sunitinib treatment Ge et al. report that fumarate, an oncometabolite, succinates PTEN at C211, which abrogates the binding of PTEN with the cellular membrane. C211 succination of PTEN thereby activates PI3K/AKT signaling and promotes tumor growth of PRCC2. Inhibiting PTEN C211 succination or AKT activation enhances sensitivity of PRCC2 to sunitinib treatment. [ABSTRACT FROM AUTHOR]

Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high K M of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM , TFB1M , and TFB2M , resulting in reduced mitochondrial biogenesis. Expression of PGC-1α K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis. • Hypoxia suppresses mitochondrial biogenesis of tumor cells • PGC-1α's activity is inhibited by K224 monomethylation under hypoxic conditions • KDM3A senses oxygen availability for its activity and demethylates PGC-1α • PGC-1α monomethylation reduces hypoxia-induced ROS and apoptosis for tumor growth Qian et al. demonstrated that KDM3A functions as an oxygen sensor and demethylates K224-monomethylated PGC-1α under normoxic conditions. Hypoxia inhibits KDM3A activity and increases PGC-1α K224 monomethylation, resulting in the inhibition of PGC-1α and PGC-1α-dependent mitochondrial biogenesis, a decrease of ROS levels and apoptosis, and the promotion of brain tumor development. [ABSTRACT FROM AUTHOR]