In recent years, the extent of our vulnerability to misinterpretation due to poorly characterized reagents has become an issue of great concern. Antibody reagents have been identified as a major source of error, contributing to the “reproducibility crisis.” In the current report, we define an additional dimension of the crisis; in particular, we define variation of the targets being analyzed. We report that natural variation in the immunoglobulin “constant” region alters the reactivity with commonly used subtype-specific anti-IgG reagents, resulting in cross-reactivity of polyclonal regents with inappropriate targets and blind spots of monoclonal reagents for desired targets. This raises the practical concern that numerous studies characterizing IgG subtypes in human disease may contain errors due to such previously unappreciated defects. These studies also focus attention on the broader concern that genetic variation may affect the performance of any laboratory or research test that uses antibodies for detection.
Heather L. Howie, Meghan Delaney, Xiaohong Wang, Lay See Er, Linda Kapp, Jenna N. Lebedev, James C. Zimring
Airway epithelial cells are prone to the damage caused by lung cancer risk factors, such as cigarette smoking. Little is known about surrogate biomarkers in the bronchial airway epithelium that can be used to assess the effect of potential chemoprevention drugs on lung adenocarcinoma formation/progression. Pioglitazone has been suggested as a chemoprevention drug for lung cancer. To study the mechanisms underlying the role of pioglitazone in lung cancer prevention, we performed transcriptome sequencing (RNA-Seq) and found that Kras signaling was repressed by pioglitazone treatment in the airway epithelial cells of mice with lung adenocarcinoma (FDR q = 9.8E-04). It was also found that glucose metabolic pathways were elevated in the airway epithelium of mice with lung adenocarcinomas and inhibited by pioglitazone treatment (FDR q = 0.01). Downregulation of glucose metabolism genes was also observed in lung tumors of mice treated with pioglitazone. The high-risk expression signature of elevated glucose metabolism was associated with poor survival outcome in multiple lung adenocarcinoma patient populations (P values ranging from 1.0E-9 to 5.5E-5). Our results suggest that the role of pioglitazone in preventing lung adenocarcinoma may depend on inhibiting Kras signaling and glucose metabolism, which may serve as biomarkers of agent action in the airway epithelium.
Donghai Xiong, Jing Pan, Qi Zhang, Eva Szabo, Mark Steven Miller, Ronald A. Lubet, Yian Wang, Ming You
Chromophobe renal cell carcinoma (chRCC) typically shows ~7 chromosome losses (1, 2, 6, 10, 13, 17, and 21) and ~31 exonic somatic mutations, yet carries ~5%–10% metastatic incidence. Since extensive chromosomal losses can generate proteotoxic stress and compromise cellular proliferation, it is intriguing how chRCC, a tumor with extensive chromosome losses and a low number of somatic mutations, can develop lethal metastases. Genomic features distinguishing metastatic from nonmetastatic chRCC are unknown. An integrated approach, including whole-genome sequencing (WGS), targeted ultradeep cancer gene sequencing, and chromosome analyses (FACETS, OncoScan, and FISH), was performed on 79 chRCC patients including 38 metastatic (M-chRCC) cases. We demonstrate that TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD, duplication of ≥ 3 chromosomes) (25%) were enriched in M-chRCC. Reconstruction of the subclonal composition of paired primary-metastatic chRCC tumors supports the role of TP53, PTEN, and ICD in metastatic evolution. Finally, the presence of these 3 genomic features in primary tumors of both The Cancer Genome Atlas kidney chromophobe (KICH) (n = 64) and M-chRCC (n = 35) cohorts was associated with worse survival. In summary, our study provides genomic insights into the metastatic progression of chRCC and identifies TP53 mutations, PTEN mutations, and ICD as high-risk features.
Jozefina Casuscelli, Nils Weinhold, Gunes Gundem, Lu Wang, Emily C. Zabor, Esther Drill, Patricia I. Wang, Gouri J. Nanjangud, Almedina Redzematovic, Amrita M. Nargund, Brandon J. Manley, Maria E. Arcila, Nicholas M. Donin, John C. Cheville, R. Houston Thompson, Allan J. Pantuck, Paul Russo, Emily H. Cheng, William Lee, Satish K. Tickoo, Irina Ostrovnaya, Chad J. Creighton, Elli Papaemmanuil, Venkatraman E. Seshan, A. Ari Hakimi, James J. Hsieh
Izumi Ohigashi, Yuki Ohte, Kazuya Setoh, Hiroshi Nakase, Akiko Maekawa, Hiroshi Kiyonari, Yoko Hamazaki, Miho Sekai, Tetsuo Sudo, Yasuharu Tabara, Hiromi Sawai, Yosuke Omae, Rika Yuliwulandari, Yasuhito Tanaka, Masashi Mizokami, Hiroshi Inoue, Masanori Kasahara, Nagahiro Minato, Katsushi Tokunaga, Keiji Tanaka, Fumihiko Matsuda, Shigeo Murata, Yousuke Takahama
Perforin-2 is a highly conserved pore-forming protein encoded by macrophage expressed gene 1 (
Ryan M. McCormack, Eva P. Szymanski, Amy P. Hsu, Elena Perez, Kenneth N. Olivier, Eva Fisher, E. Brook Goodhew, Eckhard R. Podack, Steven M. Holland
Ta-Chiang Liu, Takeo Naito, Zhenqiu Liu, Kelli L. VanDussen, Talin Haritunians, Dalin Li, Katsuya Endo, Yosuke Kawai, Masao Nagasaki, Yoshitaka Kinouchi, Dermot P.B. McGovern, Tooru Shimosegawa, Yoichi Kakuta, Thaddeus S. Stappenbeck
Parathyroid carcinoma (PC) is an extremely rare malignancy lacking effective therapeutic intervention. We generated and analyzed whole-exome sequencing data from 17 patients to identify somatic and germline genetic alterations. A panel of selected genes was sequenced in a 7-tumor expansion cohort. We show that 47% (8 of 17) of the tumors harbor somatic mutations in the
Chetanya Pandya, Andrew V. Uzilov, Justin Bellizzi, Chun Yee Lau, Aye S. Moe, Maya Strahl, Wissam Hamou, Leah C. Newman, Marc Y. Fink, Yevgeniy Antipin, Willie Yu, Mark Stevenson, Branca M. Cavaco, Bin T. Teh, Rajesh V. Thakker, Hans Morreau, Eric E. Schadt, Robert Sebra, Shuyu D. Li, Andrew Arnold, Rong Chen
Noonan syndrome (NS; MIM 163950) is an autosomal dominant disorder and a member of a family of developmental disorders termed “RASopathies,” which are caused mainly by gain-of-function mutations in genes encoding RAS/MAPK signaling pathway proteins. Whole exome sequencing (WES) and trio-based genomic triangulation of a 15-year-old female with a clinical diagnosis of NS and concomitant cardiac hypertrophy and her unaffected parents identified a de novo variant in
Erin M. Higgins, J. Martijn Bos, Heather Mason-Suares, David J. Tester, Jaeger P. Ackerman, Calum A. MacRae, Katia Sol-Church, Karen W. Gripp, Raul Urrutia, Michael J. Ackerman
The epigenome provides a substrate through which environmental exposures can exert their effects on gene expression and disease risk, but the relative importance of epigenetic variation on human disease onset and progression is poorly characterized. Asthma is a heterogeneous disease of the airways, for which both onset and clinical course result from interactions between host genotype and environmental exposures, yet little is known about the molecular mechanisms for these interactions. We assessed genome-wide DNA methylation using the Infinium Human Methylation 450K Bead Chip and characterized the transcriptome by RNA sequencing in primary airway epithelial cells from 74 asthmatic and 41 nonasthmatic adults. Asthma status was based on doctor’s diagnosis and current medication use. Genotyping was performed using various Illumina platforms. Our study revealed a regulatory locus on chromosome 17q12-21 associated with asthma risk and epigenetic signatures of specific asthma endotypes and molecular networks. Overall, these data support a central role for DNA methylation in lung cells, which promotes distinct molecular pathways of asthma pathogenesis and modulates the effects of genetic variation on disease risk and clinical heterogeneity.
Jessie Nicodemus-Johnson, Rachel A. Myers, Noburu J. Sakabe, Debora R. Sobreira, Douglas K. Hogarth, Edward T. Naureckas, Anne I. Sperling, Julian Solway, Steven R. White, Marcelo A. Nobrega, Dan L. Nicolae, Yoav Gilad, Carole Ober
Lynette M. Sholl, Khanh Do, Priyanka Shivdasani, Ethan Cerami, Adrian M. Dubuc, Frank C. Kuo, Elizabeth P. Garcia, Yonghui Jia, Phani Davineni, Ryan P. Abo, Trevor J. Pugh, Paul van Hummelen, Aaron R. Thorner, Matthew Ducar, Alice H. Berger, Mizuki Nishino, Katherine A. Janeway, Alanna Church, Marian Harris, Lauren L. Ritterhouse, Joshua D. Campbell, Vanesa Rojas-Rudilla, Azra H. Ligon, Shakti Ramkissoon, James M. Cleary, Ursula Matulonis, Geoffrey R. Oxnard, Richard Chao, Vanessa Tassell, James Christensen, William C. Hahn, Philip W. Kantoff, David J. Kwiatkowski, Bruce E. Johnson, Matthew Meyerson, Levi A. Garraway, Geoffrey I. Shapiro, Barrett J. Rollins, Neal I. Lindeman, Laura E. MacConaill
No posts were found with this tag.