While it has been recognized that human papillomavirus–associated (HPV-associated) oropharyngeal cancer (OPC) portends an improved prognosis, distinct patterns of disease recurrence have emerged. Molecular characterization of this subset of HPV patients remains unexplored. We evaluated 52 metastatic HPV+ OPC patients from our institution and paired massively parallel sequencing data with clinical parameters and survival outcomes in 81% of patients. Genomic data were then compared with 2 molecularly defined, curable HPV+ cohorts. Metastatic HPV+ OPC patients with pulmonary-only metastases demonstrated worse outcomes. Nonexclusive somatic alterations in KMT2D and PIK3CA were most frequent, with PRKDC alterations occurring at higher frequency when compared with all sequenced HPV+ OPC patients. PI3K pathway alterations were associated with improved outcomes among metastatic HPV+ OPC patients. We demonstrate subtle differences in the mutational landscape between curable and metastatic HPV+ OPC populations, with a trend towards more frequent DNA repair protein alterations in the latter. We demonstrate improved outcomes when PI3K pathway alterations are present in these patients. We provide molecular insights for this important HPV+ subgroup that have significant therapeutic implications.
Glenn J. Hanna, Alec Kacew, Nicole G. Chau, Priyanka Shivdasani, Jochen H. Lorch, Ravindra Uppaluri, Robert I. Haddad, Laura E. MacConaill
BACKGROUND. The extent of weight loss among patients undergoing bariatric surgery is highly variable. Herein, we tested the contribution of genetic background to such interindividual variability after biliopancreatic diversion with duodenal switch. METHODS. Percentage of excess body weight loss (%EBWL) was monitored in 865 patients over a period of 48 months after bariatric surgery, and two polygenic risk scores were constructed with 186 and 11 (PRS186 and PRS11) single nucleotide polymorphisms previously associated with body mass index (BMI). RESULTS. The accuracy of the %EBWL logistic prediction model — including initial BMI, age, sex, and surgery modality, and assessed as the area under the receiver operating characteristics (ROC) curve adjusted for optimism (AUCadj = 0.867) — significantly increased after the inclusion of PRS186 (ΔAUCadj = 0.021; 95% CI of the difference [95% CIdiff] = 0.005–0.038) but not PRS11 (ΔAUCadj= 0.008; 95% CIdiff= –0.003–0.019). The overall fit of the longitudinal linear mixed model for %EBWL showed a significant increase after addition of PRS186 (–2 log-likelihood = 12.3; P = 0.002) and PRS11 (–2 log-likelihood = 9.9; P = 0.007). A significant interaction with postsurgery time was found for PRS186 (β = –0.003; P = 0.008) and PRS11 (β = –0.008; P = 0.03). The inclusion of PRS186 and PRS11 in the model improved the cost-effectiveness of bariatric surgery by reducing the percentage of false negatives from 20.4% to 10.9% and 10.2%, respectively. CONCLUSION. These results revealed that genetic background has a significant impact on weight loss after biliopancreatic diversion with duodenal switch. Likewise, the improvement in weight loss prediction after addition of polygenic risk scores is cost-effective, suggesting that genetic testing could potentially be used in the presurgical assessment of patients with severe obesity. FUNDING. Heart and Stroke Foundation of Canada (G-17-0016627) and Canada Research Chair in Genomics Applied to Nutrition and Metabolic Health (no. 950-231-580).
Juan de Toro-Martín, Frédéric Guénard, André Tchernof, Louis Pérusse, Simon Marceau, Marie-Claude Vohl
Offspring of women with gestational diabetes mellitus (GDM) are at increased risk of developing metabolic disease, potentially mediated by epigenetic mechanisms. We recruited 608 GDM and 626 control offspring from the Danish National Birth Cohort, aged between 9 and 16 years. DNA methylation profiles were measured in peripheral blood of 93 GDM offspring and 95 controls using the Illumina HumanMethylation450 BeadChip. Pyrosequencing was performed for validation/replication of putative GDM-associated, differentially methylated CpGs in additional 905 offspring (462 GDM, 444 control offspring). We identified 76 differentially methylated CpGs in GDM offspring compared with controls in the discovery cohort (FDR, P < 0.05). Adjusting for offspring BMI did not affect the association between methylation levels and GDM status for any of the 76 CpGs. Most of these epigenetic changes were due to confounding by maternal prepregnancy BMI; however, 13 methylation changes were independently associated with maternal GDM. Three prepregnancy BMI–associated CpGs (cg00992687 and cg09452568 of ESM1 and cg14328641 of MS4A3) were validated in the replication cohort, while cg09109411 (PDE6A) was found to be associated with GDM status. The identified methylation changes may reflect developmental programming of organ disease mechanisms and/or may serve as disease biomarkers.
Line Hjort, David Martino, Louise Groth Grunnet, Haroon Naeem, Jovana Maksimovic, Anders Henrik Olsson, Cuilin Zhang, Charlotte Ling, Sjurdur Frodi Olsen, Richard Saffery, Allan Arthur Vaag
Ion channel-controlled cell volume regulation is of fundamental significance to the physiological function of sperm. In addition to volume regulation, LRRC8A-dependent volume-regulated anion channel (VRAC) activity is involved in cell cycle progression, insulin signaling, and cisplatin resistance. Nevertheless, the contribution of LRRC8A and its dependent VRAC activity in the germ cell lineage remain unknown. By utilizing a spontaneous Lrrc8a mouse mutation (c.1325delTG, p.F443*) and genetically engineered mouse models, we demonstrate that LRRC8A-dependent VRAC activity is essential for male germ cell development and fertility. Lrrc8a-null male germ cells undergo progressive degeneration independent of the apoptotic pathway during postnatal testicular development. Lrrc8a-deficient mouse sperm exhibit multiple morphological abnormalities of the flagella (MMAF), a feature commonly observed in the sperm of infertile human patients. Importantly, we identified a human patient with a rare LRRC8A hypomorphic mutation (c.1634G>A, p.Arg545His) possibly linked to Sertoli cell–only syndrome (SCOS), a male sterility disorder characterized by the loss of germ cells. Thus, LRRC8A is a critical factor required for germ cell development and volume regulation in the mouse, and it might serve as a novel diagnostic and therapeutic target for SCOS patients.
Jianqiang Bao, Carlos J. Perez, Jeesun Kim, Huan Zhang, Caitlin J. Murphy, Tewfik Hamidi, Jean Jaubert, Craig D. Platt, Janet Chou, Meichun Deng, Meng-Hua Zhou, Yuying Huang, Héctor Gaitán-Peñas, Jean-Louis Guénet, Kevin Lin, Yue Lu, Taiping Chen, Mark T. Bedford, Sharon Y.R. Dent, John H. Richburg, Raúl Estévez, Hui-Lin Pan, Raif S. Geha, Qinghua Shi, Fernando Benavides
BACKGROUND. There is currently no clinical distinction between different TP53 mutations, despite increasing evidence that not all mutations have equally deleterious effects on the activity of the encoded tumor suppressor protein p53. The objective of this study was to determine whether these biological differences have clinical significance. METHODS. This retrospective cohort analysis included 2,074 patients with sporadic TP53 mutations (403 unique mutations) and 1,049 germline TP53 mutation carriers (188 unique mutations). Survival was projected by stratifying patients according to their p53 mutant–specific residual transcriptional activity scores. RESULTS. Pan-cancer survival analyses revealed a strong association between increased mutant p53 residual activity and improved survival in males with glioma and gastric adenocarcinoma (P = 0.002 and P = 0.02) that was not present in the female cohorts (P = 0.16 and P = 0.50). Male glioma and gastric cancer patients with TP53 mutations resulting in >5% transcriptional activity had 3.1-fold (95% CI, 2.4–3.8; P = 0.002; multivariate analysis hazard ratio [HR]) and 4.6-fold (95% CI, 3.7–5.6; P = 0.001; multivariate analysis HR) lower risk of death as compared with patients harboring inactive (0% activity) p53 mutants. The correlation between mutant p53 residual activity with survival was recapitulated in the dataset of germline TP53 mutation carriers (HR = 3.0, 95% CI, 2.7–3.4, P < 0.001 [females]; HR = 2.2, 95% CI, 1.8–2.6, P < 0.001 [males]), where brain and gastric tumors were more common among males (P < 0.001 and P = 0.001, respectively). CONCLUSION. The retention of mutant p53 transcriptional activity prognosticates superior survival for men with glioma and gastric adenocarcinoma harboring sporadic TP53 mutations. Among germline TP53 mutation carriers, increased residual transcriptional activity is correlated with prolonged lifetime cancer survival and delayed tumor onset, and males are more prone to develop brain and gastric tumors. FUNDING. Canadian Institutes of Health Research (no. 148556).
Nicholas W. Fischer, Aaron Prodeus, Jean Gariépy
Site-1 protease (S1P), encoded by MBTPS1, is a serine protease in the Golgi. S1P regulates lipogenesis, endoplasmic reticulum (ER) function, and lysosome biogenesis in mice and in cultured cells. However, how S1P differentially regulates these diverse functions in humans has been unclear. In addition, no human disease with S1P deficiency has been identified. Here, we report a pediatric patient with an amorphic and a severely hypomorphic mutation in MBTPS1. The unique combination of these mutations results in a frequency of functional MBTPS1 transcripts of approximately 1%, a finding that is associated with skeletal dysplasia and elevated blood lysosomal enzymes. We found that the residually expressed S1P is sufficient for lipid homeostasis but not for ER and lysosomal functions, especially in chondrocytes. The defective S1P function specifically impairs activation of the ER stress transducer BBF2H7, leading to ER retention of collagen in chondrocytes. S1P deficiency also causes abnormal secretion of lysosomal enzymes due to partial impairment of mannose-6-phosphate–dependent delivery to lysosomes. Collectively, these abnormalities lead to apoptosis of chondrocytes and lysosomal enzyme–mediated degradation of the bone matrix. Correction of an MBTPS1 variant or reduction of ER stress mitigated collagen-trafficking defects. These results define a new congenital human skeletal disorder and, more importantly, reveal that S1P is particularly required for skeletal development in humans. Our findings may also lead to new therapies for other genetic skeletal diseases, as ER dysfunction is common in these disorders.
Yuji Kondo, Jianxin Fu, Hua Wang, Christopher Hoover, J. Michael McDaniel, Richard Steet, Debabrata Patra, Jianhua Song, Laura Pollard, Sara Cathey, Tadayuki Yago, Graham Wiley, Susan Macwana, Joel Guthridge, Samuel McGee, Shibo Li, Courtney Griffin, Koichi Furukawa, Judith A. James, Changgeng Ruan, Rodger P. McEver, Klaas J. Wierenga, Patrick M. Gaffney, Lijun Xia
Treatment of individuals with cystic fibrosis (CF) has been transformed by small molecule therapies that target select pathogenic variants in the CF transmembrane conductance regulator (CFTR). To expand treatment eligibility, we stably expressed 43 rare missense CFTR variants associated with moderate CF from a single site in the genome of human CF bronchial epithelial (CFBE41o–) cells. The magnitude of drug response was highly correlated with residual CFTR function for the potentiator ivacaftor, the corrector lumacaftor, and ivacaftor-lumacaftor combination therapy. Response of a second set of 16 variants expressed stably in Fischer rat thyroid (FRT) cells showed nearly identical correlations. Subsets of variants were identified that demonstrated statistically significantly higher responses to specific treatments. Furthermore, nearly all variants studied in CFBE cells (40 of 43) and FRT cells (13 of 16) demonstrated greater response to ivacaftor-lumacaftor combination therapy than either modulator alone. Together, these variants represent 87% of individuals in the CFTR2 database with at least 1 missense variant. Thus, our results indicate that most individuals with CF carrying missense variants are (a) likely to respond modestly to currently available modulator therapy, while a small fraction will have pronounced responses, and (b) likely to derive the greatest benefit from combination therapy.
Sangwoo T. Han, Andras Rab, Matthew J. Pellicore, Emily F. Davis, Allison F. McCague, Taylor A. Evans, Anya T. Joynt, Zhongzhou Lu, Zhiwei Cai, Karen S. Raraigh, Jeong S. Hong, David N. Sheppard, Eric J. Sorscher, Garry R. Cutting
Mice are extremely important as the premier model organism in human biomedical and mammalian genetic research. The genomes of several tens of mouse inbred strains have been sequenced. They have been compared to the genome of C57BL/6J, considered by convention as the reference genome. Based on a comparison of this reference genome with 36 other sequenced mouse strains, we generated an overview of all protein-coding genes that are deviant in this reference genome, compared with consensus protein-coding mouse gene sequences. We provide PROVEAN scores, reflecting the likelihood that these C57BL/6J proteins have lost function. We thus identified numerous abnormal proteins, and biological pathways, specifically present in C57BL/6J, suggesting the important caveats of this reference mouse strain, and linking candidate genes to some of the best-known phenotypes of this strain.
Steven Timmermans, Claude Libert
Numerous studies of relatively few patients have linked T cell receptor (TCR) genes to psoriasis but have yielded dramatically conflicting results. To resolve these discrepancies, we have chosen to mine RNA-Seq datasets for patterns of TCR gene segment usage in psoriasis. A meta-analysis of 3 existing and 1 unpublished datasets revealed a statistically significant link between the relative expression of TRAJ23 and psoriasis and the psoriasis-associated cytokine IL-17A. TRGV5, a TCR-γ segment, was also associated with psoriasis but correlated instead with IL-36A, other IL-36 family members, and IL-17C (not IL-17A). In contrast, TRAJ39 was strongly associated with healthy skin. T cell diversity measurements and analysis of CDR3 sequences were also conducted, revealing no psoriasis-associated public CDR3 sequences. Finally, in comparison with the expression of TCR-αβ genes, the expression of TCR-γδ genes was relatively low but mildly elevated in psoriatic skin. These results have implications for the development of targeted therapies for psoriasis and other autoimmune diseases. Also, the techniques employed in this study have applications in other fields, such as cancer immunology and infectious disease.
Alexander A. Merleev, Alina I. Marusina, Chelsea Ma, James T. Elder, Lam C. Tsoi, Siba P. Raychauduri, Stephan Weidinger, Elizabeth A. Wang, Iannis E. Adamopoulos, Guillaume Luxardi, Johann E. Gudjonsson, Michiko Shimoda, Emanual Maverakis
Exon skipping uses chemically modified antisense oligonucleotides to modulate RNA splicing. Therapeutically, exon skipping can bypass mutations and restore reading frame disruption by generating internally truncated, functional proteins to rescue the loss of native gene expression. Limb-girdle muscular dystrophy type 2C is caused by autosomal recessive mutations in the SGCG gene, which encodes the dystrophin-associated protein γ-sarcoglycan. The most common SGCG mutations disrupt the transcript reading frame abrogating γ-sarcoglycan protein expression. In order to treat most SGCG gene mutations, it is necessary to skip 4 exons in order to restore the SGCG transcript reading frame, creating an internally truncated protein referred to as Mini-Gamma. Using direct reprogramming of human cells with MyoD, myogenic cells were tested with 2 antisense oligonucleotide chemistries, 2’-O-methyl phosphorothioate oligonucleotides and vivo–phosphorodiamidate morpholino oligomers, to induce exon skipping. Treatment with vivo–phosphorodiamidate morpholino oligomers demonstrated efficient skipping of the targeted exons and corrected the mutant reading frame, resulting in the expression of a functional Mini-Gamma protein. Antisense-induced exon skipping of SGCG occurred in normal cells and those with multiple distinct SGCG mutations, including the most common 521ΔT mutation. These findings demonstrate a multiexon-skipping strategy applicable to the majority of limb-girdle muscular dystrophy 2C patients.
Eugene J. Wyatt, Alexis R. Demonbreun, Ellis Y. Kim, Megan J. Puckelwartz, Andy H. Vo, Lisa M. Dellefave-Castillo, Quan Q. Gao, Mariz Vainzof, Rita C. M. Pavanello, Mayana Zatz, Elizabeth M. McNally
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