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1. Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features

Author: Hitoshi Dejima, Xin Hu, Runzhe Chen, Jiexin Zhang, Junya Fujimoto, Edwin R. Parra, Cara Haymaker, Shawna M. Hubert, Dzifa Duose, Luisa M. Solis, Dan Su, Junya Fukuoka, Kazuhiro Tabata, Hoa H. N. Pham, Nicholas Mcgranahan, Baili Zhang, Jie Ye, Lisha Ying, Latasha Little, Curtis Gumbs, Chi-Wan Chow, Marcos Roberto Estecio, Myrna C. B. Godoy, Mara B. Antonoff, Boris Sepesi, Harvey I. Pass, Carmen Behrens, Jianhua Zhang, Ara A. Vaporciyan, John V. Heymach, Paul Scheet, J. Jack Lee, Jia Wu, P. Andrew Futreal, Alexandre Reuben, Humam Kadara, Ignacio I. Wistuba, and Jianjun Zhang
Subjects: Science
Abstract: The evolution of immune landscape in lung adenocarcinoma (ADC) is largely unknown. Here the authors use a cohort of resected invasive lung ADC and its precursors and show a gradual increase of immunosuppression and decrease of anti-tumor response associated with specific genomic and epigenetic features.
Published: 2021
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2. Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

Author: Xin Hu, Marcos R. Estecio, Runzhe Chen, Alexandre Reuben, Linghua Wang, Junya Fujimoto, Jian Carrot-Zhang, Nicholas McGranahan, Lisha Ying, Junya Fukuoka, Chi-Wan Chow, Hoa H. N. Pham, Myrna C. B. Godoy, Brett W. Carter, Carmen Behrens, Jianhua Zhang, Mara B. Antonoff, Boris Sepesi, Yue Lu, Harvey I. Pass, Humam Kadara, Paul Scheet, Ara A. Vaporciyan, John V. Heymach, Ignacio I. Wistuba, J. Jack Lee, P. Andrew Futreal, Dan Su, Jean-Pierre J. Issa, and Jianjun Zhang
Subjects: Science
Abstract: It is known that invasive lung adenocarcinomas evolve from pre-cancerous dysplastic lesions. In this study, the authors show that evolution of pre-cancerous lesions is accompanied by DNA methylation alterations, and that global hypomethylation correlates with immune infiltration, mutational burden and copy number alterations.
Published: 2021
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3. Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

Author: Won-Chul Lee, Alexandre Reuben, Xin Hu, Nicholas McGranahan, Runzhe Chen, Ali Jalali, Marcelo V. Negrao, Shawna M. Hubert, Chad Tang, Chia-Chin Wu, Anthony San Lucas, Whijae Roh, Kenichi Suda, Jihye Kim, Aik-Choon Tan, David H. Peng, Wei Lu, Ximing Tang, Chi-Wan Chow, Junya Fujimoto, Carmen Behrens, Neda Kalhor, Kazutaka Fukumura, Marcus Coyle, Rebecca Thornton, Curtis Gumbs, Jun Li, Chang-Jiun Wu, Latasha Little, Emily Roarty, Xingzhi Song, J. Jack Lee, Erik P. Sulman, Ganesh Rao, Stephen Swisher, Lixia Diao, Jing Wang, John V. Heymach, Jason T. Huse, Paul Scheet, Ignacio I. Wistuba, Don L. Gibbons, P. Andrew Futreal, Jianhua Zhang, Daniel Gomez, and Jianjun Zhang
Subjects: Lung cancer, Metastasis, Multiomics, Immune profiling, Genomics, DNA methylation, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract: Abstract Background Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. Results We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. Conclusions Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.
Published: 2020
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4. Comprehensive T cell repertoire characterization of non-small cell lung cancer

Author: Alexandre Reuben, Jiexin Zhang, Shin-Heng Chiou, Rachel M. Gittelman, Jun Li, Won-Chul Lee, Junya Fujimoto, Carmen Behrens, Xiaoke Liu, Feng Wang, Kelly Quek, Chunlin Wang, Farrah Kheradmand, Runzhe Chen, Chi-Wan Chow, Heather Lin, Chantale Bernatchez, Ali Jalali, Xin Hu, Chang-Jiun Wu, Agda Karina Eterovic, Edwin Roger Parra, Erik Yusko, Ryan Emerson, Sharon Benzeno, Marissa Vignali, Xifeng Wu, Yuanqing Ye, Latasha D. Little, Curtis Gumbs, Xizeng Mao, Xingzhi Song, Samantha Tippen, Rebecca L. Thornton, Tina Cascone, Alexandra Snyder, Jennifer A. Wargo, Roy Herbst, Stephen Swisher, Humam Kadara, Cesar Moran, Neda Kalhor, Jianhua Zhang, Paul Scheet, Ara A. Vaporciyan, Boris Sepesi, Don L. Gibbons, Harlan Robins, Patrick Hwu, John V. Heymach, Padmanee Sharma, James P. Allison, Veera Baladandayuthapani, Jack J. Lee, Mark M. Davis, Ignacio I. Wistuba, P. Andrew Futreal, and Jianjun Zhang
Subjects: Science
Abstract: Relevant features of T cell repertoire in human cancer remain to be delineated. Here the authors show, by TCR sequencing in a large cohort of lung cancer patients, that while a majority of T cell clones are shared between tumor and adjacent lung tissue, less frequent tumor-unique T cell clones correlate with worse prognosis.
Published: 2020
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5. A whole-exome case-control association study to characterize the contribution of rare coding variation to pancreatic cancer risk

Author: Yao Yu, Kyle Chang, Jiun-Sheng Chen, Ryan J. Bohlender, Jerry Fowler, Di Zhang, Maosheng Huang, Ping Chang, Yanan Li, Justin Wong, Huamin Wang, Jian Gu, Xifeng Wu, Joellen Schildkraut, Lisa Cannon-Albright, Yuanqing Ye, Hua Zhao, Michelle A.T. Hildebrandt, Jennifer B. Permuth, Donghui Li, Paul Scheet, and Chad D. Huff
Subjects: Pancreatic Cancer, Case-Control Study, Association Analysis, ATM, SIK3, Genetics, QH426-470
Abstract: Summary: Pancreatic cancer is a deadly disease that accounts for approximately 5% of cancer deaths worldwide, with a dismal 5-year survival rate of 10%. Known genetic risk factors explain only a modest proportion of the heritable risk of pancreatic cancer. We conducted a whole-exome case-control sequencing study in 1,591 pancreatic cancer cases and 2,134 cancer-free controls of European ancestry. In our gene-based analysis, ATM ranked first, with a genome-wide significant p value of 1 × 10−8. The odds ratio for protein-truncating variants in ATM was 24, which is substantially higher than prior estimates, although ours includes a broad 95% confidence interval (4.0–1000). SIK3 was the second highest ranking gene (p = 3.84 × 10−6, false discovery rate or FDR = 0.032). We observed nominally significant association signals in several genes of a priori interest, including BRCA2 (p = 4.3 × 10−4), STK11 (p = 0.003), PALB2 (p = 0.019), and TP53 (p = 0.037), and reported risk estimates for known pathogenic variants and variants of uncertain significance (VUS) in these genes. The rare variants in established susceptibility genes explain approximately 24% of log familial relative risk, which is comparable to the contribution from established common susceptibility variants (17%). In conclusion, this study provides new insights into the genetic susceptibility of pancreatic cancer, refining rare variant risk estimates in known pancreatic cancer susceptibility genes and identifying SIK3 as a novel candidate susceptibility gene. This study highlights the prominent importance of ATM truncating variants and the underappreciated role of VUS in pancreatic cancer etiology.
Published: 2022
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6. The BE GONE trial study protocol: a randomized crossover dietary intervention of dry beans targeting the gut microbiome of overweight and obese patients with a history of colorectal polyps or cancer

Author: Xiaotao Zhang, Gladys Browman, Wesley Siu, Karen M. Basen-Engquist, Samir M. Hanash, Kristi L. Hoffman, Pablo C. Okhuysen, Paul Scheet, Joseph F. Petrosino, Scott Kopetz, and Carrie R. Daniel
Subjects: Colorectal cancer survivors, Precancerous colorectal polyps, Dry beans, Obesity, Diet, Gut microbiome, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Mouse and human studies support the promise of dry beans to improve metabolic health and to lower cancer risk. In overweight/obese patients with a history of colorectal polyps or cancer, the Beans to Enrich the Gut microbiome vs. Obesity’s Negative Effects (BE GONE) trial will test whether and how an increase in the consumption of pre-cooked, canned dry beans within the context of usual diet and lifestyle can enhance the gut landscape to improve metabolic health and reduce cancer risk. Methods/design This randomized crossover trial is designed to characterize changes in (1) host markers spanning lipid metabolism, inflammation, and obesity-related cancer risk; (2) compositional and functional profiles of the fecal microbiome; and (3) host and microbial metabolites. With each subject serving as their own control, the trial will compare the participant’s usual diet with (intervention) and without (control) dry beans. Canned, pre-cooked dry beans are provided to participants and the usual diet continually assessed and monitored. Following a 4-week run-in and equilibration period, each participant provides a total of 5 fasting blood and 6 stool samples over a total period of 16 weeks. The intervention consists of a 2-week ramp-up of dry bean intake to 1 cup/d, which is then continued for an additional 6 weeks. Intra- and inter-individual outcomes are assessed across each crossover period with consideration of the joint or modifying effects of the usual diet and baseline microbiome. Discussion The BE GONE trial is evaluating a scalable dietary prevention strategy targeting the gut microbiome of high-risk patients to mitigate the metabolic and inflammatory effects of adiposity that influence colorectal cancer risk, recurrence, and survival. The overarching scientific goal is to further elucidate interactions between diet, the gut microbiome, and host metabolism. Improved understanding of the diet-microbiota interplay and effective means to target these relationships will be key to the future of clinical and public health approaches to cancer and other major diet- and obesity-related diseases. Trial registration This protocol is registered with the U.S. National Institutes of Health trial registry, ClinicalTrials.gov, under the identifier NCT02843425. First posted July 25, 2016; last verified January 25, 2019.
Published: 2019
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7. Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma

Author: Xin Hu, Junya Fujimoto, Lisha Ying, Junya Fukuoka, Kazuto Ashizawa, Wenyong Sun, Alexandre Reuben, Chi-Wan Chow, Nicholas McGranahan, Runzhe Chen, Jinlin Hu, Myrna C. Godoy, Kazuhiro Tabata, Kishio Kuroda, Lei Shi, Jun Li, Carmen Behrens, Edwin Roger Parra, Latasha D. Little, Curtis Gumbs, Xizeng Mao, Xingzhi Song, Samantha Tippen, Rebecca L. Thornton, Humam Kadara, Paul Scheet, Emily Roarty, Edwin Justin Ostrin, Xu Wang, Brett W. Carter, Mara B. Antonoff, Jianhua Zhang, Ara A. Vaporciyan, Harvey Pass, Stephen G. Swisher, John V. Heymach, J. Jack Lee, Ignacio I. Wistuba, Waun Ki Hong, P. Andrew Futreal, Dan Su, and Jianjun Zhang
Subjects: Science
Abstract: There has been a drastic increase in detection of lung nodules, many of which are precancers, preinvasive, minimally invasive or sometimes invasive lung cancers. Here, Hu et al. perform multi-region exome sequencing to discern the evolutional trajectory from precancers to invasive lung cancers.
Published: 2019
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8. Genomic landscape of allelic imbalance in premalignant atypical adenomatous hyperplasias of the lungResearch in context

Author: Smruthy Sivakumar, F. Anthony San Lucas, Yasminka A. Jakubek, Tina L. McDowell, Wenhua Lang, Noah Kallsen, Shanna Peyton, Gareth E. Davies, Junya Fukuoka, Yasushi Yatabe, Jianjun Zhang, P. Andrew Futreal, Jerry Fowler, Junya Fujimoto, Erik A. Ehli, Ernest T. Hawk, Ignacio I. Wistuba, Humam Kadara, and Paul Scheet
Subjects: Medicine, Medicine (General), R5-920
Abstract: Background: Genomic investigation of atypical adenomatous hyperplasia (AAH), the only known precursor lesion to lung adenocarcinomas (LUAD), presents challenges due to the low mutant cell fractions. This necessitates sensitive methods for detection of chromosomal aberrations to better study the role of critical alterations in early lung cancer pathogenesis and the progression from AAH to LUAD. Methods: We applied a sensitive haplotype-based statistical technique to detect chromosomal alterations leading to allelic imbalance (AI) from genotype array profiling of 48 matched normal lung parenchyma, AAH and tumor tissues from 16 stage-I LUAD patients. To gain insights into shared developmental trajectories among tissues, we performed phylogenetic analyses and integrated our results with point mutation data, highlighting significantly-mutated driver genes in LUAD pathogenesis. Findings: AI was detected in nine AAHs (56%). Six cases exhibited recurrent loss of 17p. AI and the enrichment of 17p events were predominantly identified in patients with smoking history. Among the nine AAH tissues with detected AI, seven exhibited evidence for shared chromosomal aberrations with matched LUAD specimens, including losses harboring tumor suppressors on 17p, 8p, 9p, 9q, 19p, and gains encompassing oncogenes on 8q, 12p and 1q. Interpretation: Chromosomal aberrations, particularly 17p loss, appear to play critical roles early in AAH pathogenesis. Genomic instability in AAH, as well as truncal chromosomal aberrations shared with LUAD, provide evidence for mutation accumulation and are suggestive of a cancerized field contributing to the clonal selection and expansion of these premalignant lesions. Fund: Supported in part by Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150079 (PS and HK), NIH grant R01HG005859 (PS) and The University of Texas MD Anderson Cancer Center Core Support Grant. Keywords: Atypical adenomatous hyperplasia, Lung adenocarcinoma, Preneoplasia, Pathogenesis, Allelic imbalance, Chromosomal instability
Published: 2019
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9. Strategies for identification of somatic variants using the Ion Torrent deep targeted sequencing platform

Author: Aditya Deshpande, Wenhua Lang, Tina McDowell, Smruthy Sivakumar, Jiexin Zhang, Jing Wang, F. Anthony San Lucas, Jerry Fowler, Humam Kadara, and Paul Scheet
Subjects: Next-generation sequencing, Ion torrent, Variant calling strategies, Ion Reporter, Varscan2, MuTect, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract: Abstract Background ‘Next-generation’ (NGS) sequencing has wide application in medical genetics, including the detection of somatic variation in cancer. The Ion Torrent-based (IONT) platform is among NGS technologies employed in clinical, research and diagnostic settings. However, identifying mutations from IONT deep sequencing with high confidence has remained a challenge. We compared various computational variant-calling methods to derive a variant identification pipeline that may improve the molecular diagnostic and research utility of IONT. Results Using IONT, we surveyed variants from the 409-gene Comprehensive Cancer Panel in whole-section tumors, intra-tumoral biopsies and matched normal samples obtained from frozen tissues and blood from four early-stage non-small cell lung cancer (NSCLC) patients. We used MuTect, Varscan2, IONT’s proprietary Ion Reporter, and a simple subtraction we called “Poor Man’s Caller.” Together these produced calls at 637 loci across all samples. Visual validation of 434 called variants was performed, and performance of the methods assessed individually and in combination. Of the subset of inspected putative variant calls (n=223) in genomic regions that were not intronic or intergenic, 68 variants (30%) were deemed valid after visual inspection. Among the individual methods, the Ion Reporter method offered perhaps the most reasonable tradeoffs. Ion Reporter captured 83% of all discovered variants; 50% of its variants were visually validated. Aggregating results from multiple packages offered varied improvements in performance. Conclusions Overall, Ion Reporter offered the most attractive performance among the individual callers. This study suggests combined strategies to maximize sensitivity and positive predictive value in variant calling using IONT deep sequencing.
Published: 2018
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10. Author Correction: Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma

Author: Xin Hu, Junya Fujimoto, Lisha Ying, Junya Fukuoka, Kazuto Ashizawa, Wenyong Sun, Alexandre Reuben, Chi-Wan Chow, Nicholas McGranahan, Runzhe Chen, Jinlin Hu, Myrna C. Godoy, Kazuhiro Tabata, Kishio Kuroda, Lei Shi, Jun Li, Carmen Behrens, Edwin Roger Parra, Latasha D. Little, Curtis Gumbs, Xizeng Mao, Xingzhi Song, Samantha Tippen, Rebecca L. Thornton, Humam Kadara, Paul Scheet, Emily Roarty, Edwin Justin Ostrin, Xu Wang, Brett W. Carter, Mara B. Antonoff, Jianhua Zhang, Ara A. Vaporciyan, Harvey Pass, Stephen G. Swisher, John V. Heymach, J. Jack Lee, Ignacio I. Wistuba, Waun Ki Hong, P. Andrew Futreal, Dan Su, and Jianjun Zhang
Subjects: Science
Published: 2021
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11. Oral microbiota reveals signs of acculturation in Mexican American women.

Author: Kristi L Hoffman, Diane S Hutchinson, Jerry Fowler, Daniel P Smith, Nadim J Ajami, Hua Zhao, Paul Scheet, Wong-Ho Chow, Joseph F Petrosino, and Carrie R Daniel
Subjects: Medicine, Science
Abstract: The oral microbiome has been linked to a number of chronic inflammatory conditions, including obesity, diabetes, periodontitis, and cancers of the stomach and liver. These conditions disproportionately affect Mexican American women, yet few studies have examined the oral microbiota in this at-risk group. We characterized the 16S rDNA oral microbiome in 369 non-smoking women enrolled in the MD Anderson Mano a Mano Mexican American Cohort Study. Lower bacterial diversity, a potential indicator of oral health, was associated with increased age and length of US residency among recent immigrants. Grouping women by overarching bacterial community type (e.g., "Streptococcus," "Fusobacterium," and "Prevotella" clusters), we observed differences across a number of acculturation-related variables, including nativity, age at immigration, time in the US, country of longest residence, and a multi-dimensional acculturation scale. Participants in the cluster typified by higher abundance of Streptococcus spp. exhibited the lowest bacterial diversity and appeared the most acculturated as compared to women in the "Prevotella" group. Computationally-predicted functional analysis suggested the Streptococcus-dominated bacterial community had greater potential for carbohydrate metabolism while biosynthesis of essential amino acids and nitrogen metabolism prevailed among the Prevotella-high group. Findings suggest immigration and adaption to life in the US, a well-established mediator of disease risk, is associated with differences in oral microbial profiles in Mexican American women. These results warrant further investigation into the joint and modifying effects of acculturation and oral bacteria on the health of Mexican American women and other immigrant populations. The oral microbiome presents an easily accessible biomarker of disease risk, spanning biological, behavioral, and environmental factors.
Published: 2018
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12. Identification of allelic imbalance with a statistical model for subtle genomic mosaicism.

Author: Rui Xia, Selina Vattathil, and Paul Scheet
Subjects: Biology (General), QH301-705.5
Abstract: Genetic heterogeneity in a mixed sample of tumor and normal DNA can confound characterization of the tumor genome. Numerous computational methods have been proposed to detect aberrations in DNA samples from tumor and normal tissue mixtures. Most of these require tumor purities to be at least 10-15%. Here, we present a statistical model to capture information, contained in the individual's germline haplotypes, about expected patterns in the B allele frequencies from SNP microarrays while fully modeling their magnitude, the first such model for SNP microarray data. Our model consists of a pair of hidden Markov models--one for the germline and one for the tumor genome--which, conditional on the observed array data and patterns of population haplotype variation, have a dependence structure induced by the relative imbalance of an individual's inherited haplotypes. Together, these hidden Markov models offer a powerful approach for dealing with mixtures of DNA where the main component represents the germline, thus suggesting natural applications for the characterization of primary clones when stromal contamination is extremely high, and for identifying lesions in rare subclones of a tumor when tumor purity is sufficient to characterize the primary lesions. Our joint model for germline haplotypes and acquired DNA aberration is flexible, allowing a large number of chromosomal alterations, including balanced and imbalanced losses and gains, copy-neutral loss-of-heterozygosity (LOH) and tetraploidy. We found our model (which we term J-LOH) to be superior for localizing rare aberrations in a simulated 3% mixture sample. More generally, our model provides a framework for full integration of the germline and tumor genomes to deal more effectively with missing or uncertain features, and thus extract maximal information from difficult scenarios where existing methods fail.
Published: 2014
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13. The molecular genetic architecture of self-employment.

Author: Matthijs J H M van der Loos, Cornelius A Rietveld, Niina Eklund, Philipp D Koellinger, Fernando Rivadeneira, Gonçalo R Abecasis, Georgina A Ankra-Badu, Sebastian E Baumeister, Daniel J Benjamin, Reiner Biffar, Stefan Blankenberg, Dorret I Boomsma, David Cesarini, Francesco Cucca, Eco J C de Geus, George Dedoussis, Panos Deloukas, Maria Dimitriou, Guðny Eiriksdottir, Johan Eriksson, Christian Gieger, Vilmundur Gudnason, Birgit Höhne, Rolf Holle, Jouke-Jan Hottenga, Aaron Isaacs, Marjo-Riitta Järvelin, Magnus Johannesson, Marika Kaakinen, Mika Kähönen, Stavroula Kanoni, Maarit A Laaksonen, Jari Lahti, Lenore J Launer, Terho Lehtimäki, Marisa Loitfelder, Patrik K E Magnusson, Silvia Naitza, Ben A Oostra, Markus Perola, Katja Petrovic, Lydia Quaye, Olli Raitakari, Samuli Ripatti, Paul Scheet, David Schlessinger, Carsten O Schmidt, Helena Schmidt, Reinhold Schmidt, Andrea Senft, Albert V Smith, Timothy D Spector, Ida Surakka, Rauli Svento, Antonio Terracciano, Emmi Tikkanen, Cornelia M van Duijn, Jorma Viikari, Henry Völzke, H-Erich Wichmann, Philipp S Wild, Sara M Willems, Gonneke Willemsen, Frank J A van Rooij, Patrick J F Groenen, André G Uitterlinden, Albert Hofman, and A Roy Thurik
Subjects: Medicine, Science
Abstract: Economic variables such as income, education, and occupation are known to affect mortality and morbidity, such as cardiovascular disease, and have also been shown to be partly heritable. However, very little is known about which genes influence economic variables, although these genes may have both a direct and an indirect effect on health. We report results from the first large-scale collaboration that studies the molecular genetic architecture of an economic variable-entrepreneurship-that was operationalized using self-employment, a widely-available proxy. Our results suggest that common SNPs when considered jointly explain about half of the narrow-sense heritability of self-employment estimated in twin data (σ(g)(2)/σ(P)(2) = 25%, h(2) = 55%). However, a meta-analysis of genome-wide association studies across sixteen studies comprising 50,627 participants did not identify genome-wide significant SNPs. 58 SNPs with p
Published: 2013
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14. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Author: Zari Dastani, Marie-France Hivert, Nicholas Timpson, John R B Perry, Xin Yuan, Robert A Scott, Peter Henneman, Iris M Heid, Jorge R Kizer, Leo-Pekka Lyytikäinen, Christian Fuchsberger, Toshiko Tanaka, Andrew P Morris, Kerrin Small, Aaron Isaacs, Marian Beekman, Stefan Coassin, Kurt Lohman, Lu Qi, Stavroula Kanoni, James S Pankow, Hae-Won Uh, Ying Wu, Aurelian Bidulescu, Laura J Rasmussen-Torvik, Celia M T Greenwood, Martin Ladouceur, Jonna Grimsby, Alisa K Manning, Ching-Ti Liu, Jaspal Kooner, Vincent E Mooser, Peter Vollenweider, Karen A Kapur, John Chambers, Nicholas J Wareham, Claudia Langenberg, Rune Frants, Ko Willems-Vandijk, Ben A Oostra, Sara M Willems, Claudia Lamina, Thomas W Winkler, Bruce M Psaty, Russell P Tracy, Jennifer Brody, Ida Chen, Jorma Viikari, Mika Kähönen, Peter P Pramstaller, David M Evans, Beate St Pourcain, Naveed Sattar, Andrew R Wood, Stefania Bandinelli, Olga D Carlson, Josephine M Egan, Stefan Böhringer, Diana van Heemst, Lyudmyla Kedenko, Kati Kristiansson, Marja-Liisa Nuotio, Britt-Marie Loo, Tamara Harris, Melissa Garcia, Alka Kanaya, Margot Haun, Norman Klopp, H-Erich Wichmann, Panos Deloukas, Efi Katsareli, David J Couper, Bruce B Duncan, Margreet Kloppenburg, Linda S Adair, Judith B Borja, DIAGRAM+ Consortium, MAGIC Consortium, GLGC Investigators, MuTHER Consortium, James G Wilson, Solomon Musani, Xiuqing Guo, Toby Johnson, Robert Semple, Tanya M Teslovich, Matthew A Allison, Susan Redline, Sarah G Buxbaum, Karen L Mohlke, Ingrid Meulenbelt, Christie M Ballantyne, George V Dedoussis, Frank B Hu, Yongmei Liu, Bernhard Paulweber, Timothy D Spector, P Eline Slagboom, Luigi Ferrucci, Antti Jula, Markus Perola, Olli Raitakari, Jose C Florez, Veikko Salomaa, Johan G Eriksson, Timothy M Frayling, Andrew A Hicks, Terho Lehtimäki, George Davey Smith, David S Siscovick, Florian Kronenberg, Cornelia van Duijn, Ruth J F Loos, Dawn M Waterworth, James B Meigs, Josee Dupuis, J Brent Richards, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Oliver M Hofmann, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Andrew D Morris, Colin N A Palmer, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Oluf Pedersen, Inês Barroso, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Paul Elliott, Denis Rybin, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Taina Lajunen, Alex Doney, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Gunnar Sigurðsson, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, DIAGRAM Consortium, GIANT Consortium, Global B Pgen Consortium, Ingrid B Borecki, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Procardis Consortium, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, Brenda W J H Penninx, Dorret I Boomsma, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Leena Peltonen, Vincent Mooser, Robert Sladek, MAGIC investigators, GLGC Consortium, Kiran Musunuru, Albert V Smith, Andrew C Edmondson, Ioannis M Stylianou, Masahiro Koseki, James P Pirruccello, Daniel I Chasman, Christopher T Johansen, Sigrid W Fouchier, Gina M Peloso, Maja Barbalic, Sally L Ricketts, Joshua C Bis, Mary F Feitosa, Marju Orho-Melander, Olle Melander, Xiaohui Li, Mingyao Li, Yoon Shin Cho, Min Jin Go, Young Jin Kim, Jong-Young Lee, Taesung Park, Kyunga Kim, Xueling Sim, Rick Twee-Hee Ong, Damien C Croteau-Chonka, Leslie A Lange, Joshua D Smith, Andreas Ziegler, Weihua Zhang, Robert Y L Zee, John B Whitfield, John R Thompson, Ida Surakka, Tim D Spector, Johannes H Smit, Juha Sinisalo, James Scott, Juha Saharinen, Chiara Sabatti, Lynda M Rose, Robert Roberts, Mark Rieder, Alex N Parker, Guillaume Pare, Christopher J O'Donnell, Markku S Nieminen, Deborah A Nickerson, Grant W Montgomery, Wendy McArdle, David Masson, Nicholas G Martin, Fabio Marroni, Gavin Lucas, Robert Luben, Marja-Liisa Lokki, Guillaume Lettre, Lenore J Launer, Edward G Lakatta, Reijo Laaksonen, Kirsten O Kyvik, Inke R König, Kay-Tee Khaw, Lee M Kaplan, Åsa Johansson, A Cecile J W Janssens, Wilmar Igl, G Kees Hovingh, Christian Hengstenberg, Aki S Havulinna, Nicholas D Hastie, Tamara B Harris, Talin Haritunians, Alistair S Hall, Leif C Groop, Elena Gonzalez, Nelson B Freimer, Jeanette Erdmann, Kenechi G Ejebe, Angela Döring, Anna F Dominiczak, Serkalem Demissie, Panagiotis Deloukas, Ulf de Faire, Gabriel Crawford, Yii-der I Chen, Mark J Caulfield, S Matthijs Boekholdt, Themistocles L Assimes, Thomas Quertermous, Mark Seielstad, Tien Y Wong, E-Shyong Tai, Alan B Feranil, Christopher W Kuzawa, Herman A Taylor, Stacey B Gabriel, Hilma Holm, Vilmundur Gudnason, Ronald M Krauss, Jose M Ordovas, Patricia B Munroe, Jaspal S Kooner, Alan R Tall, Robert A Hegele, John J P Kastelein, Eric E Schadt, David P Strachan, Muredach P Reilly, Nilesh J Samani, Heribert Schunkert, L Adrienne Cupples, Manjinder S Sandhu, Paul M Ridker, Daniel J Rader, and Sekar Kathiresan
Subjects: Genetics, QH426-470
Abstract: Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p
Published: 2012
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15. A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation.

Author: Silvia Naitza, Eleonora Porcu, Maristella Steri, Dennis D Taub, Antonella Mulas, Xiang Xiao, James Strait, Mariano Dei, Sandra Lai, Fabio Busonero, Andrea Maschio, Gianluca Usala, Magdalena Zoledziewska, Carlo Sidore, Ilenia Zara, Maristella Pitzalis, Alessia Loi, Francesca Virdis, Roberta Piras, Francesca Deidda, Michael B Whalen, Laura Crisponi, Antonio Concas, Carlo Podda, Sergio Uzzau, Paul Scheet, Dan L Longo, Edward Lakatta, Gonçalo R Abecasis, Antonio Cao, David Schlessinger, Manuela Uda, Serena Sanna, and Francesco Cucca
Subjects: Genetics, QH426-470
Abstract: Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals-5 of which were identified only with the custom arrays-and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(-29)); for ESR, at the HBB (rs4910472, p = 2.31×10(-11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(-10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(-13)) and in CADM3 (rs3026968, p = 7.63×10(-13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(-21)), near DARC (rs3845624, p = 1.43×10(-10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(-14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(-08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process.
Published: 2012
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16. A genome-wide association search for type 2 diabetes genes in African Americans.

Author: Nicholette D Palmer, Caitrin W McDonough, Pamela J Hicks, Bong H Roh, Maria R Wing, S Sandy An, Jessica M Hester, Jessica N Cooke, Meredith A Bostrom, Megan E Rudock, Matthew E Talbert, Joshua P Lewis, DIAGRAM Consortium, MAGIC Investigators, Assiamira Ferrara, Lingyi Lu, Julie T Ziegler, Michele M Sale, Jasmin Divers, Daniel Shriner, Adebowale Adeyemo, Charles N Rotimi, Maggie C Y Ng, Carl D Langefeld, Barry I Freedman, Donald W Bowden, Benjamin F Voight, Laura J Scott, Valgerdur Steinthorsdottir, Andrew P Morris, Christian Dina, Ryan P Welch, Eleftheria Zeggini, Cornelia Huth, Yurii S Aulchenko, Gudmar Thorleifsson, Laura J McCulloch, Teresa Ferreira, Harald Grallert, Najaf Amin, Guanming Wu, Cristen J Willer, Soumya Raychaudhuri, Steve A McCarroll, Claudia Langenberg, Oliver M Hofmann, Josée Dupuis, Lu Qi, Ayellet V Segrè, Mandy van Hoek, Pau Navarro, Kristin Ardlie, Beverley Balkau, Rafn Benediktsson, Amanda J Bennett, Roza Blagieva, Eric Boerwinkle, Lori L Bonnycastle, Kristina Bengtsson Boström, Bert Bravenboer, Suzannah Bumpstead, Noël P Burtt, Guillaume Charpentier, Peter S Chines, Marilyn Cornelis, David J Couper, Gabe Crawford, Alex S F Doney, Katherine S Elliott, Amanda L Elliott, Michael R Erdos, Caroline S Fox, Christopher S Franklin, Martha Ganser, Christian Gieger, Niels Grarup, Todd Green, Simon Griffin, Christopher J Groves, Candace Guiducci, Samy Hadjadj, Neelam Hassanali, Christian Herder, Bo Isomaa, Anne U Jackson, Paul R V Johnson, Torben Jørgensen, Wen H L Kao, Norman Klopp, Augustine Kong, Peter Kraft, Johanna Kuusisto, Torsten Lauritzen, Man Li, Aloysius Lieverse, Cecilia M Lindgren, Valeriya Lyssenko, Michel Marre, Thomas Meitinger, Kristian Midthjell, Mario A Morken, Narisu Narisu, Peter Nilsson, Katharine R Owen, Felicity Payne, John R B Perry, Ann-Kristin Petersen, Carl Platou, Christine Proença, Inga Prokopenko, Wolfgang Rathmann, N William Rayner, Neil R Robertson, Ghislain Rocheleau, Michael Roden, Michael J Sampson, Richa Saxena, Beverley M Shields, Peter Shrader, Gunnar Sigurdsson, Thomas Sparsø, Klaus Strassburger, Heather M Stringham, Qi Sun, Amy J Swift, Barbara Thorand, Jean Tichet, Tiinamaija Tuomi, Rob M van Dam, Timon W van Haeften, Thijs van Herpt, Jana V van Vliet-Ostaptchouk, G Bragi Walters, Michael N Weedon, Cisca Wijmenga, Jacqueline Witteman, Richard N Bergman, Stephane Cauchi, Francis S Collins, Anna L Gloyn, Ulf Gyllensten, Torben Hansen, Winston A Hide, Graham A Hitman, Albert Hofman, David J Hunter, Kristian Hveem, Markku Laakso, Karen L Mohlke, Andrew D Morris, Colin N A Palmer, Peter P Pramstaller, Igor Rudan, Eric Sijbrands, Lincoln D Stein, Jaakko Tuomilehto, Andre Uitterlinden, Mark Walker, Nicholas J Wareham, Richard M Watanabe, Goncalo R Abecasis, Bernhard O Boehm, Harry Campbell, Mark J Daly, Andrew T Hattersley, Frank B Hu, James B Meigs, James S Pankow, Oluf Pedersen, H-Erich Wichmann, Inês Barroso, Jose C Florez, Timothy M Frayling, Leif Groop, Rob Sladek, Unnur Thorsteinsdottir, James F Wilson, Thomas Illig, Philippe Froguel, Cornelia M van Duijn, Kari Stefansson, David Altshuler, Michael Boehnke, Mark I McCarthy, Nicole Soranzo, Eleanor Wheeler, Nicole L Glazer, Nabila Bouatia-Naji, Reedik Mägi, Joshua Randall, Toby Johnson, Paul Elliott, Denis Rybin, Peter Henneman, Abbas Dehghan, Jouke Jan Hottenga, Kijoung Song, Anuj Goel, Josephine M Egan, Taina Lajunen, Alex Doney, Stavroula Kanoni, Christine Cavalcanti-Proença, Meena Kumari, Nicholas J Timpson, Carina Zabena, Erik Ingelsson, Ping An, Jeffrey O'Connell, Jian'an Luan, Amanda Elliott, Steven A McCarroll, Rosa Maria Roccasecca, François Pattou, Praveen Sethupathy, Yavuz Ariyurek, Philip Barter, John P Beilby, Yoav Ben-Shlomo, Sven Bergmann, Murielle Bochud, Amélie Bonnefond, Knut Borch-Johnsen, Yvonne Böttcher, Eric Brunner, Suzannah J Bumpstead, Yii-Der Ida Chen, Peter Chines, Robert Clarke, Lachlan J M Coin, Matthew N Cooper, Laura Crisponi, Ian N M Day, Eco J C de Geus, Jerome Delplanque, Annette C Fedson, Antje Fischer-Rosinsky, Nita G Forouhi, Rune Frants, Maria Grazia Franzosi, Pilar Galan, Mark O Goodarzi, Jürgen Graessler, Scott Grundy, Rhian Gwilliam, Göran Hallmans, Naomi Hammond, Xijing Han, Anna-Liisa Hartikainen, Caroline Hayward, Simon C Heath, Serge Hercberg, Andrew A Hicks, David R Hillman, Aroon D Hingorani, Jennie Hui, Joe Hung, Antti Jula, Marika Kaakinen, Jaakko Kaprio, Y Antero Kesaniemi, Mika Kivimaki, Beatrice Knight, Seppo Koskinen, Peter Kovacs, Kirsten Ohm Kyvik, G Mark Lathrop, Debbie A Lawlor, Olivier Le Bacquer, Cécile Lecoeur, Yun Li, Robert Mahley, Massimo Mangino, Alisa K Manning, María Teresa Martínez-Larrad, Jarred B McAteer, Ruth McPherson, Christa Meisinger, David Melzer, David Meyre, Braxton D Mitchell, Sutapa Mukherjee, Silvia Naitza, Matthew J Neville, Ben A Oostra, Marco Orrù, Ruth Pakyz, Giuseppe Paolisso, Cristian Pattaro, Daniel Pearson, John F Peden, Nancy L Pedersen, Markus Perola, Andreas F H Pfeiffer, Irene Pichler, Ozren Polasek, Danielle Posthuma, Simon C Potter, Anneli Pouta, Michael A Province, Bruce M Psaty, Nigel W Rayner, Kenneth Rice, Samuli Ripatti, Fernando Rivadeneira, Olov Rolandsson, Annelli Sandbaek, Manjinder Sandhu, Serena Sanna, Avan Aihie Sayer, Paul Scheet, Udo Seedorf, Stephen J Sharp, Beverley Shields, Eric J G Sijbrands, Angela Silveira, Laila Simpson, Andrew Singleton, Nicholas L Smith, Ulla Sovio, Amy Swift, Holly Syddall, Ann-Christine Syvänen, Toshiko Tanaka, Anke Tönjes, André G Uitterlinden, Ko Willems van Dijk, Dhiraj Varma, Sophie Visvikis-Siest, Veronique Vitart, Nicole Vogelzangs, Gérard Waeber, Peter J Wagner, Andrew Walley, Kim L Ward, Hugh Watkins, Sarah H Wild, Gonneke Willemsen, Jaqueline C M Witteman, John W G Yarnell, Diana Zelenika, Björn Zethelius, Guangju Zhai, Jing Hua Zhao, M Carola Zillikens, Ingrid B Borecki, Ruth J F Loos, Pierre Meneton, Patrik K E Magnusson, David M Nathan, Gordon H Williams, Kaisa Silander, Veikko Salomaa, George Davey Smith, Stefan R Bornstein, Peter Schwarz, Joachim Spranger, Fredrik Karpe, Alan R Shuldiner, Cyrus Cooper, George V Dedoussis, Manuel Serrano-Ríos, Lars Lind, Lyle J Palmer, Paul W Franks, Shah Ebrahim, Michael Marmot, W H Linda Kao, Peter Paul Pramstaller, Alan F Wright, Michael Stumvoll, Anders Hamsten, Thomas A Buchanan, Timo T Valle, Jerome I Rotter, David S Siscovick, Brenda W J H Penninx, Dorret I Boomsma, Panos Deloukas, Timothy D Spector, Luigi Ferrucci, Antonio Cao, Angelo Scuteri, David Schlessinger, Manuela Uda, Aimo Ruokonen, Marjo-Riitta Jarvelin, Dawn M Waterworth, Peter Vollenweider, Leena Peltonen, Vincent Mooser, and Robert Sladek
Subjects: Medicine, Science
Abstract: African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P
Published: 2012
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17. Correction: Genome-Wide Association Scan Meta-Analysis Identifies Three Loci Influencing Adiposity and Fat Distribution.

Author: Cecilia M. Lindgren, Iris M. Heid, Joshua C. Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K. Speliotes, Gudmar Thorleifsson, Cristen J. Willer, Blanca M. Herrera, Anne U. Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S. Aulchenko, John C. Chambers, Alexander Drong, Jian'an Luan, Helen N. Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J. Timpson, M. Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J. Bennett, Richard N. Bergman, Lori L. Bonnycastle, Suzannah J. Bumpstead, Stephen J. Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S. F. Doney, Shah Ebrahim, Paul Elliott, Michael R. Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G. Forouhi, Christian Gieger, Harald Grallert, Christopher J. Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S. Havulinna, Albert Hofman, Rolf Holle, John W. Holloway, Thomas Illig, Bo Isomaa, Leonie C. Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G. Mark Lathrop, Debbie A. Lawlor, Massimo Mangino, Wendy L. McArdle, Thomas Meitinger, Mario A. Morken, Andrew P. Morris, Patricia Munroe, Narisu Narisu, Anna Nordström, Peter Nordström, Ben A. Oostra, Colin N. A. Palmer, Felicity Payne, John F. Peden, Inga Prokopenko, Frida Renström, Aimo Ruokonen, Veikko Salomaa, Manjinder S. Sandhu, Laura J. Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M. Stringham, Amy J. Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gerard Waeber, Chris Wallace, G. Bragi Walters, Michael N. Weedon, Jacqueline C. M. Witteman, Cuilin Zhang, Weihua Zhang, Mark J. Caulfield, Francis S. Collins, George Davey Smith, Ian N. M. Day, Paul W. Franks, Andrew T. Hattersley, Frank B. Hu, Marjo-Riitta Jarvelin, Augustine Kong, Jaspal S. Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D. Morris, Leena Peltonen, Nilesh J. Samani, Timothy D. Spector, David P. Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G. Uitterlinden, Cornelia M. van Duijn, Nicholas J. Wareham, Hugh Watkins for the PROCARDIS consortia, Dawn M. Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J. Hunter, Unnur Thorsteinsdottir, David Schlessinger, H.-Erich Wichmann, Timothy M. Frayling, Gonçalo R. Abecasis, Joel N. Hirschhorn, Ruth J. F. Loos, Kari Stefansson, Karen L. Mohlke, Inês Barroso, and Mark I. McCarthy for the GIANT consortium
Subjects: Genetics, QH426-470
Published: 2009
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18. Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

Author: Cecilia M Lindgren, Iris M Heid, Joshua C Randall, Claudia Lamina, Valgerdur Steinthorsdottir, Lu Qi, Elizabeth K Speliotes, Gudmar Thorleifsson, Cristen J Willer, Blanca M Herrera, Anne U Jackson, Noha Lim, Paul Scheet, Nicole Soranzo, Najaf Amin, Yurii S Aulchenko, John C Chambers, Alexander Drong, Jian'an Luan, Helen N Lyon, Fernando Rivadeneira, Serena Sanna, Nicholas J Timpson, M Carola Zillikens, Jing Hua Zhao, Peter Almgren, Stefania Bandinelli, Amanda J Bennett, Richard N Bergman, Lori L Bonnycastle, Suzannah J Bumpstead, Stephen J Chanock, Lynn Cherkas, Peter Chines, Lachlan Coin, Cyrus Cooper, Gabriel Crawford, Angela Doering, Anna Dominiczak, Alex S F Doney, Shah Ebrahim, Paul Elliott, Michael R Erdos, Karol Estrada, Luigi Ferrucci, Guido Fischer, Nita G Forouhi, Christian Gieger, Harald Grallert, Christopher J Groves, Scott Grundy, Candace Guiducci, David Hadley, Anders Hamsten, Aki S Havulinna, Albert Hofman, Rolf Holle, John W Holloway, Thomas Illig, Bo Isomaa, Leonie C Jacobs, Karen Jameson, Pekka Jousilahti, Fredrik Karpe, Johanna Kuusisto, Jaana Laitinen, G Mark Lathrop, Debbie A Lawlor, Massimo Mangino, Wendy L McArdle, Thomas Meitinger, Mario A Morken, Andrew P Morris, Patricia Munroe, Narisu Narisu, Anna Nordström, Peter Nordström, Ben A Oostra, Colin N A Palmer, Felicity Payne, John F Peden, Inga Prokopenko, Frida Renström, Aimo Ruokonen, Veikko Salomaa, Manjinder S Sandhu, Laura J Scott, Angelo Scuteri, Kaisa Silander, Kijoung Song, Xin Yuan, Heather M Stringham, Amy J Swift, Tiinamaija Tuomi, Manuela Uda, Peter Vollenweider, Gerard Waeber, Chris Wallace, G Bragi Walters, Michael N Weedon, Wellcome Trust Case Control Consortium, Jacqueline C M Witteman, Cuilin Zhang, Weihua Zhang, Mark J Caulfield, Francis S Collins, George Davey Smith, Ian N M Day, Paul W Franks, Andrew T Hattersley, Frank B Hu, Marjo-Riitta Jarvelin, Augustine Kong, Jaspal S Kooner, Markku Laakso, Edward Lakatta, Vincent Mooser, Andrew D Morris, Leena Peltonen, Nilesh J Samani, Timothy D Spector, David P Strachan, Toshiko Tanaka, Jaakko Tuomilehto, André G Uitterlinden, Cornelia M van Duijn, Nicholas J Wareham, Hugh Watkins, Procardis Consortia, Dawn M Waterworth, Michael Boehnke, Panos Deloukas, Leif Groop, David J Hunter, Unnur Thorsteinsdottir, David Schlessinger, H-Erich Wichmann, Timothy M Frayling, Gonçalo R Abecasis, Joel N Hirschhorn, Ruth J F Loos, Kari Stefansson, Karen L Mohlke, Inês Barroso, Mark I McCarthy, and Giant Consortium
Subjects: Genetics, QH426-470
Abstract: To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity.
Published: 2009
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19. STrengthening the REporting of Genetic Association Studies (STREGA): an extension of the STROBE statement.

Author: Julian Little, Julian P T Higgins, John P A Ioannidis, David Moher, France Gagnon, Erik von Elm, Muin J Khoury, Barbara Cohen, George Davey-Smith, Jeremy Grimshaw, Paul Scheet, Marta Gwinn, Robin E Williamson, Guang Yong Zou, Kim Hutchings, Candice Y Johnson, Valerie Tait, Miriam Wiens, Jean Golding, Cornelia van Duijn, John McLaughlin, Andrew Paterson, George Wells, Isabel Fortier, Matthew Freedman, Maja Zecevic, Richard King, Claire Infante-Rivard, Alex Stewart, Nick Birkett, and STrengthening the REporting of Genetic Association Studies
Subjects: Medicine
Abstract: Making sense of rapidly evolving evidence on genetic associations is crucial to making genuine advances in human genomics and the eventual integration of this information in the practice of medicine and public health. Assessment of the strengths and weaknesses of this evidence, and hence the ability to synthesize it, has been limited by inadequate reporting of results. The STrengthening the REporting of Genetic Association studies (STREGA) initiative builds on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and provides additions to 12 of the 22 items on the STROBE checklist. The additions concern population stratification, genotyping errors, modelling haplotype variation, Hardy-Weinberg equilibrium, replication, selection of participants, rationale for choice of genes and variants, treatment effects in studying quantitative traits, statistical methods, relatedness, reporting of descriptive and outcome data, and the volume of data issues that are important to consider in genetic association studies. The STREGA recommendations do not prescribe or dictate how a genetic association study should be designed but seek to enhance the transparency of its reporting, regardless of choices made during design, conduct, or analysis.
Published: 2009
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20. Linkage disequilibrium-based quality control for large-scale genetic studies.

Author: Paul Scheet and Matthew Stephens
Subjects: Genetics, QH426-470
Abstract: Quality control (QC) is a critical step in large-scale studies of genetic variation. While, on average, high-throughput single nucleotide polymorphism (SNP) genotyping assays are now very accurate, the errors that remain tend to cluster into a small percentage of "problem" SNPs, which exhibit unusually high error rates. Because most large-scale studies of genetic variation are searching for phenomena that are rare (e.g., SNPs associated with a phenotype), even this small percentage of problem SNPs can cause important practical problems. Here we describe and illustrate how patterns of linkage disequilibrium (LD) can be used to improve QC in large-scale, population-based studies. This approach has the advantage over existing filters (e.g., HWE or call rate) that it can actually reduce genotyping error rates by automatically correcting some genotyping errors. Applying this LD-based QC procedure to data from The International HapMap Project, we identify over 1,500 SNPs that likely have high error rates in the CHB and JPT samples and estimate corrected genotypes. Our method is implemented in the software package fastPHASE, available from the Stephens Lab website (http://stephenslab.uchicago.edu/software.html).
Published: 2008
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21. Cancer Epidemiology

Author: Veronika Fedirko, Kevin T. Nead, Carrie Daniel, and Paul Scheet
Published: 2022

22. Supplementary Fig S9 from Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

Author: Humam Kadara, Linghua Wang, Avrum Spira, Christopher S. Stevenson, Ignacio I. Wistuba, Junya Fujimoto, Steven M. Dubinett, Paul Scheet, John V. Heymach, Daniel Rosen, Edwin J. Ostrin, Seyed Javad Moghaddam, Jichao Chen, Don L. Gibbons, Lauren Averett Byers, Tina Cascone, Boris Sepesi, Jianjun Zhang, Junya Fukuoka, Luisa M. Solis, Maria Gabriela Raso, Edwin R. Parra, Dzifa Y. Duose, Carmen Behrens, Kostyantyn Krysan, Linh M. Tran, Samer Bazzi, Danielle R. Little, Kyle Chang, Beatriz Sanchez-Espiridion, Elena Bogatenkova, Jiexin Zhang, Hitoshi Dejima, Enyu Dai, Ruiping Wang, Dapeng Hao, Minghao Dang, Patrick M. Brennan, Kieko Hara, Warapen Treekitkarnmongkol, Guangchun Han, and Ansam Sinjab
Abstract: Supplementary Fig S9 and legend
Published: 2023

23. Supplementary Fig S10-S20 from Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

Author: Humam Kadara, Linghua Wang, Avrum Spira, Christopher S. Stevenson, Ignacio I. Wistuba, Junya Fujimoto, Steven M. Dubinett, Paul Scheet, John V. Heymach, Daniel Rosen, Edwin J. Ostrin, Seyed Javad Moghaddam, Jichao Chen, Don L. Gibbons, Lauren Averett Byers, Tina Cascone, Boris Sepesi, Jianjun Zhang, Junya Fukuoka, Luisa M. Solis, Maria Gabriela Raso, Edwin R. Parra, Dzifa Y. Duose, Carmen Behrens, Kostyantyn Krysan, Linh M. Tran, Samer Bazzi, Danielle R. Little, Kyle Chang, Beatriz Sanchez-Espiridion, Elena Bogatenkova, Jiexin Zhang, Hitoshi Dejima, Enyu Dai, Ruiping Wang, Dapeng Hao, Minghao Dang, Patrick M. Brennan, Kieko Hara, Warapen Treekitkarnmongkol, Guangchun Han, and Ansam Sinjab
Abstract: Supplementary Figures S10-S20 and figure legends
Published: 2023

24. Data from Genome-Wide Gene Expression Changes in the Normal-Appearing Airway during the Evolution of Smoking-Associated Lung Adenocarcinoma

Author: Humam Kadara, Avrum E. Spira, Junya Fujimoto, Paul Scheet, Ignacio I. Wistuba, Arafat Tfayli, Hassan Chami, Nadine Darwiche, Georges Nemer, Junya Fukuoka, Sayuri Nunomura-Nakamura, Wenhua Lang, Smruthy Sivakumar, Tina L. McDowell, Li Xu, Ansam Sinjab, and Jacob Kantrowitz
Abstract: Smoking perpetuates in cytologically normal airways a molecular “field of injury” that is pertinent to lung cancer and early detection. The evolution of airway field changes prior to lung oncogenesis is poorly understood largely due to the long latency of lung cancer in smokers. Here, we studied airway expression changes prior to lung cancer onset in mice with knockout of the Gprc5a gene (Gprc5a−/−) and tobacco carcinogen (NNK) exposure and that develop the most common type of lung cancer, lung adenocarcinoma, within 6 months following exposure. Airway epithelial brushings were collected from Gprc5a−/− mice before exposure and at multiple times post-NNK until time of lung adenocarcinoma development and then analyzed by RNA sequencing. Temporal airway profiles were identified by linear models and analyzed by comparative genomics in normal airways of human smokers with and without lung cancer. We identified significantly altered profiles (n = 926) in the NNK-exposed mouse normal airways relative to baseline epithelia, a subset of which were concordantly modulated with smoking status in the human airway. Among airway profiles that were significantly modulated following NNK, we found that expression changes (n = 22) occurring as early as 2 months following exposure were significantly associated with lung cancer status when examined in airways of human smokers. Furthermore, a subset of a recently reported human bronchial gene classifier (Percepta; n = 56) was enriched in the temporal mouse airway profiles. We underscore evolutionarily conserved profiles in the normal-appearing airway that develop prior to lung oncogenesis and that comprise viable markers for early lung cancer detection in suspect smokers. Cancer Prev Res; 11(4); 237–48. ©2018 AACR.
Published: 2023

25. Supplementary Figure Legends from Baseline Oral Microbiome and All-cancer Incidence in a Cohort of Nonsmoking Mexican American Women

Author: Carrie R. Daniel, Joseph F. Petrosino, Shine Chang, Paul Scheet, Fangyu Li, Reji Joseph, Kplola Y. Elhor Gbito, Peng Wei, Kristi L. Hoffman, and Xiaotao Zhang
Abstract: Legends for supplemental figures
Published: 2023

26. Supplementary Figure from Chronic Exposure to Waterpipe Smoke Elicits Immunomodulatory and Carcinogenic Effects in the Lung

Author: Humam Kadara, Alan L. Shihadeh, Hassan Chami, Junya Fujimoto, Luisa M. Solis, Maria Gabriela Raso, J. Jack Lee, Paul Scheet, Wei Lu, Justin W. Wong, Ansam Sinjab, Jiexin Zhang, Nareg Karaoghlanian, Zahraa Rahal, and Maya Hassane
Abstract: Supplementary Figure from Chronic Exposure to Waterpipe Smoke Elicits Immunomodulatory and Carcinogenic Effects in the Lung
Published: 2023

27. Supplementary Tables 1-5 from Genome-Wide Gene Expression Changes in the Normal-Appearing Airway during the Evolution of Smoking-Associated Lung Adenocarcinoma

Author: Humam Kadara, Avrum E. Spira, Junya Fujimoto, Paul Scheet, Ignacio I. Wistuba, Arafat Tfayli, Hassan Chami, Nadine Darwiche, Georges Nemer, Junya Fukuoka, Sayuri Nunomura-Nakamura, Wenhua Lang, Smruthy Sivakumar, Tina L. McDowell, Li Xu, Ansam Sinjab, and Jacob Kantrowitz
Abstract: Supplementary Tables Table S1. Early efffcts of NNK exposure on the mouse airway transcriptome. Table S2. Evolutionarily conserved decreased gene expression in the airway following NNK exposure. Table S3. Genes differentially regulated in the mouse airway at the indicated timepoints post NNK exposure. Table S4. Mouse genes downregulated as early as T2 vs T0 and enriched in airways of human smokers with lung cancer relative to cancer-free smokers. Table S5. Pathways analysis of Mouse genes enriched in airways of human smokers with lung cancer and modulated during in vivo lung oncogenesis
Published: 2023

28. Manuscript supplement from Genome-Wide Gene Expression Changes in the Normal-Appearing Airway during the Evolution of Smoking-Associated Lung Adenocarcinoma

Author: Humam Kadara, Avrum E. Spira, Junya Fujimoto, Paul Scheet, Ignacio I. Wistuba, Arafat Tfayli, Hassan Chami, Nadine Darwiche, Georges Nemer, Junya Fukuoka, Sayuri Nunomura-Nakamura, Wenhua Lang, Smruthy Sivakumar, Tina L. McDowell, Li Xu, Ansam Sinjab, and Jacob Kantrowitz
Abstract: Supplementary Methods and Supplementary Figure Legends
Published: 2023

29. Data from Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

Author: Humam Kadara, Linghua Wang, Avrum Spira, Christopher S. Stevenson, Ignacio I. Wistuba, Junya Fujimoto, Steven M. Dubinett, Paul Scheet, John V. Heymach, Daniel Rosen, Edwin J. Ostrin, Seyed Javad Moghaddam, Jichao Chen, Don L. Gibbons, Lauren Averett Byers, Tina Cascone, Boris Sepesi, Jianjun Zhang, Junya Fukuoka, Luisa M. Solis, Maria Gabriela Raso, Edwin R. Parra, Dzifa Y. Duose, Carmen Behrens, Kostyantyn Krysan, Linh M. Tran, Samer Bazzi, Danielle R. Little, Kyle Chang, Beatriz Sanchez-Espiridion, Elena Bogatenkova, Jiexin Zhang, Hitoshi Dejima, Enyu Dai, Ruiping Wang, Dapeng Hao, Minghao Dang, Patrick M. Brennan, Kieko Hara, Warapen Treekitkarnmongkol, Guangchun Han, and Ansam Sinjab
Abstract: Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8+ T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand–receptor interactome harbors increased expression of epithelial CD24, which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment.Significance:The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception.This article is highlighted in the In This Issue feature, p. 2355
Published: 2023

30. Supplementary Tables from Baseline Oral Microbiome and All-cancer Incidence in a Cohort of Nonsmoking Mexican American Women

Author: Carrie R. Daniel, Joseph F. Petrosino, Shine Chang, Paul Scheet, Fangyu Li, Reji Joseph, Kplola Y. Elhor Gbito, Peng Wei, Kristi L. Hoffman, and Xiaotao Zhang
Abstract: Supplemental tables 1 through 3
Published: 2023

31. Supplementary Methods from Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing

Author: Humam Kadara, Linghua Wang, Avrum Spira, Christopher S. Stevenson, Ignacio I. Wistuba, Junya Fujimoto, Steven M. Dubinett, Paul Scheet, John V. Heymach, Daniel Rosen, Edwin J. Ostrin, Seyed Javad Moghaddam, Jichao Chen, Don L. Gibbons, Lauren Averett Byers, Tina Cascone, Boris Sepesi, Jianjun Zhang, Junya Fukuoka, Luisa M. Solis, Maria Gabriela Raso, Edwin R. Parra, Dzifa Y. Duose, Carmen Behrens, Kostyantyn Krysan, Linh M. Tran, Samer Bazzi, Danielle R. Little, Kyle Chang, Beatriz Sanchez-Espiridion, Elena Bogatenkova, Jiexin Zhang, Hitoshi Dejima, Enyu Dai, Ruiping Wang, Dapeng Hao, Minghao Dang, Patrick M. Brennan, Kieko Hara, Warapen Treekitkarnmongkol, Guangchun Han, and Ansam Sinjab
Abstract: Supplementary Methods
Published: 2023

32. Supplementary Figures from Baseline Oral Microbiome and All-cancer Incidence in a Cohort of Nonsmoking Mexican American Women

Author: Carrie R. Daniel, Joseph F. Petrosino, Shine Chang, Paul Scheet, Fangyu Li, Reji Joseph, Kplola Y. Elhor Gbito, Peng Wei, Kristi L. Hoffman, and Xiaotao Zhang
Abstract: Supplemental Figures 1 through 4
Published: 2023

33. Supplementary Figures S1 - S4 from Genome-Wide Gene Expression Changes in the Normal-Appearing Airway during the Evolution of Smoking-Associated Lung Adenocarcinoma

Author: Humam Kadara, Avrum E. Spira, Junya Fujimoto, Paul Scheet, Ignacio I. Wistuba, Arafat Tfayli, Hassan Chami, Nadine Darwiche, Georges Nemer, Junya Fukuoka, Sayuri Nunomura-Nakamura, Wenhua Lang, Smruthy Sivakumar, Tina L. McDowell, Li Xu, Ansam Sinjab, and Jacob Kantrowitz
Abstract: S1. Lung tumor development in NNK-exposed Gprc5a-/- mice. S2. Evolutionarily conserved patterns of tobacco-carcinogen mediated gene expression in murine and human airway epithelia. S3. Early and persistent changes in mouse airway gene expression in vivo following tobacco carcinogen exposure and during lung oncogenesis. S4. Gene profiles downregulated in the mouse normal-appearing airway field of injury are overall suppressed in lung tumors relative to adjacent normal lung.
Published: 2023

34. Data from Chronic Exposure to Waterpipe Smoke Elicits Immunomodulatory and Carcinogenic Effects in the Lung

Author: Humam Kadara, Alan L. Shihadeh, Hassan Chami, Junya Fujimoto, Luisa M. Solis, Maria Gabriela Raso, J. Jack Lee, Paul Scheet, Wei Lu, Justin W. Wong, Ansam Sinjab, Jiexin Zhang, Nareg Karaoghlanian, Zahraa Rahal, and Maya Hassane
Abstract: Effects of waterpipe smoking on lung pathobiology and carcinogenesis remain sparse despite the worldwide emergence of this tobacco vector. To address this gap, we investigated the effects of chronic waterpipe smoke (WPS) exposure on lung pathobiology, host immunity, and tumorigenesis using an experimental animal model that is prone to tobacco carcinogens and an exploratory observational analysis of human waterpipe smokers and nonsmokers. Mice exhibited elevated incidence of lung tumors following heavy WPS exposure (5 days/week for 20 weeks) compared to littermates with light WPS (once/week for 20 weeks) or control air. Lungs of mice exposed to heavy WPS showed augmented CD8+ and CD4+ T cell counts along with elevated protumor immune phenotypes including increased IL17A in T/B cells, PD-L1 on tumor and immune cells, and the proinflammatory cytokine IL1β in myeloid cells. RNA-sequencing (RNA-seq) analysis showed reduced antitumor immune gene signatures in animals exposed to heavy WPS relative to control air. We also performed RNA-seq analysis of airway epithelia from bronchial brushings of cancer-free waterpipe smokers and nonsmokers undergoing diagnostic bronchoscopy. Transcriptomes of normal airway cells in waterpipe smokers, relative to waterpipe nonsmokers, harbored gene programs that were associated with poor clinical outcomes in patients with lung adenocarcinoma, alluding to a WPS-associated molecular injury, like that established in response to cigarette smoking. Our findings support the notion that WPS exhibits carcinogenic effects and constitutes a possible risk factor for lung cancer as well as warrant future studies that can guide evidence-based policies for mitigating waterpipe smoking.Prevention Relevance:Potential carcinogenic effects of waterpipe smoking are very poorly understood despite its emergence as a socially acceptable form of smoking. Our work highlights carcinogenic effects of waterpipe smoking in the lung and, thus, accentuate the need for inclusion of individuals with exclusive waterpipe smoking in prevention and smoking cessation studies.
Published: 2023

35. Data from Baseline Oral Microbiome and All-cancer Incidence in a Cohort of Nonsmoking Mexican American Women

Author: Carrie R. Daniel, Joseph F. Petrosino, Shine Chang, Paul Scheet, Fangyu Li, Reji Joseph, Kplola Y. Elhor Gbito, Peng Wei, Kristi L. Hoffman, and Xiaotao Zhang
Abstract: Given the increasing evidence that the oral microbiome is involved in obesity, diabetes, and cancer risk, we investigated baseline oral microbiota profiles in relation to all-cancer incidence among nonsmoking women enrolled in a Texas cohort of first- and second-generation immigrants of Mexican origin. We characterized the 16Sv4 rDNA microbiome in oral mouthwash samples collected at baseline from a representative subset of 305 nonsmoking women, ages 20–75 years. We evaluated within- (alpha) and between-sample (beta) diversity by incident cancer status and applied linear discriminant analysis (LDA) effect size analysis to assess differentially abundant taxa. Diversity and candidate taxa in relation to all-cancer incidence were evaluated in multivariable-adjusted Cox regression models. Over 8.8 median years of follow-up, 31 incident cancer cases were identified and verified. Advanced age, greater acculturation, and cardiometabolic risk factors were associated with all-cancer incidence. Higher alpha diversity (age-adjusted Pdifference < 0.01) and distinct biological communities (Pdifference = 0.002) were observed by incident cancer status. Each unit increase in the Shannon diversity index yielded >8-fold increase in all-cancer and obesity-related cancer risk [multivariable-adjusted HR (95% confidence interval), 8.11 (3.14–20.94) and 10.72 (3.30–34.84), respectively] with similar findings for the inverse Simpson index. Streptococcus was enriched among women who did not develop cancer, while Fusobacterium, Prevotella, Mogibacterium, Campylobacter, Lachnoanaerobaculum, Dialister, and Atopobium were higher among women who developed cancer (LDA score ≥ 3; q-value < 0.01). This initial study of oral microbiota and overall cancer risk in nonsmoking Mexican American women suggests the readily accessible oral microbiota as a promising biomarker.Prevention Relevance:Mexican American women suffer a disproportionate burden of chronic health conditions that increase cancer risk. Few investigations of the microbiome, a key determinant of host health, have been conducted among this group. Oral microbiota profiles may provide early and accessible cancer biomarker data on invasive bacteria or community disruptions.
Published: 2023

36. Supplementary Tables from Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

Author: Humam Kadara, Paul Scheet, Ignacio I. Wistuba, Ernest T. Hawk, Jerry Fowler, Avrum E. Spira, Steven M. Dubinett, Yasushi Yatabe, Junya Fukuoka, P. Andrew Futreal, Jianjun Zhang, Junya Fujimoto, Li Xu, Wenhua Lang, Tina L. McDowell, F. Anthony San Lucas, and Smruthy Sivakumar
Abstract: Table S1: Samples analyzed by DNA and RNA sequencing; Table S2: DNA (n=67) and RNA (n=48) sequencing quality metrics for each sample; Table S3: Exonic mutations in known lung adenocarcinoma drivers and other cancer associated genes; Table S4: Genes mutated in atypical adenomatous hyperplasias and lung adenocarcinomas; Table S5: Validation of specific BRAF, KRAS and EGFR mutations using digital PCR; Table S6: Genes differentially expressed among normal lung tissues, atypical adenomatous hyperplasias and lung adenocarcinomas; Table S7: Genes differentially expressed between BRAF-mutant, KRAS-mutant and BRAF/KRAS wild type atypical adenomatous hyperplasias; Table S8: Markers of immune signaling that are aberrantly expressed between normal lung tissues, atypical adenomatous hyperplasias and lung adenocarcinomas.
Published: 2023

37. Data from Can Microsatellite Status of Colorectal Cancer Be Reliably Assessed after Neoadjuvant Therapy?

Author: Eduardo Vilar, Y. Nancy You, Scott Kopetz, Paul Scheet, Ji Wu, Melissa W. Taggart, Miguel Rodriguez-Bigas, Patrick M. Lynch, Sarah A. Bannon, Maureen E. Mork, Amanda Cuddy, Gita Masand, Ester Borras, William Wu, and Jennifer B. Goldstein
Abstract: Purpose: Determination of microsatellite instability (MSI) by PCR is the gold standard; however, IHC of mismatch repair (MMR) proteins is frequently performed instead. The reliability of these methods on postneoadjuvant therapy specimens is unknown. We examined the effect of neoadjuvant therapy on MSI results by PCR and IHC.Experimental design: A total of 239 colorectal cancers resected after neoadjuvant therapy were assessed for MSI with PCR and IHC. PCR and IHC results for matched paired pre- and posttreatment specimens were compared. In parallel, 2 isogenic cell lines conditioned for MMR functioning and 2 different patient-derived xenografts (PDXs) were exposed to chemotherapy, radiation, or both. We also examined whether establishment of PDXs induced MSI changes in 5 tumors. IHC and MSI were tested after treatment to assess for changes.Results: We identified paired pre- and posttreatment specimens for 37 patients: 2 with PCR only, 34 with IHC only, and 1 with both. All 3 patients with PCR had microsatellite stable pre- and posttreatment specimens. Of the 35 patients with IHC, 30 had intact MMR proteins in pre- and posttreatment specimens, 1 had equivocal MLH1 staining in the pretreatment and loss in the posttreatment specimen, and 4 had intact pretreatment MSH6 but variable posttreatment staining. In the experimental setting, no changes in MSI status were detected after treatment or tumor implantation in animals.Conclusions: Our findings show that the expression of MMR proteins, commonly MSH6, can change after neoadjuvant therapy and confirm PCR as the gold-standard test for MSI after neoadjuvant therapy. Clin Cancer Res; 23(17); 5246–54. ©2017 AACR.
Published: 2023

38. Supplementary Figure Legend from Can Microsatellite Status of Colorectal Cancer Be Reliably Assessed after Neoadjuvant Therapy?

Author: Eduardo Vilar, Y. Nancy You, Scott Kopetz, Paul Scheet, Ji Wu, Melissa W. Taggart, Miguel Rodriguez-Bigas, Patrick M. Lynch, Sarah A. Bannon, Maureen E. Mork, Amanda Cuddy, Gita Masand, Ester Borras, William Wu, and Jennifer B. Goldstein
Abstract: Supplementary Figure Legend
Published: 2023

39. Data from DNA Sequencing of Small Bowel Adenocarcinomas Identifies Targetable Recurrent Mutations in the ERBB2 Signaling Pathway

Author: Michael J. Overman, Paul Scheet, Scott Kopetz, Chad Huff, Stefan T. Arold, Ganiraju Manyam, Joe Ensor, Michael T. Tetzlaff, David Menter, Huamin Wang, Yulun Liu, Wenhui Wu, Yao Yu, Richard Fowler, F. Anthony San Lucas, and Liana Adam
Abstract: Purpose:Little is known about the genetic alterations characteristic of small bowel adenocarcinoma (SBA). Our purpose was to identify targetable alterations and develop experimental models of this disease.Experimental Design: Whole-exome sequencing (WES) was completed on 17 SBA patient samples and targeted-exome sequencing (TES) on 27 samples to confirm relevant driver mutations. Two SBA models with ERBB2 kinase activating mutations were tested for sensitivity to anti-ERBB2 agents in vivo and in vitro. Biochemical changes were measured by reverse-phase protein arrays.Results:WES identified somatic mutations in 4 canonical pathways (WNT, ERBB2, STAT3, and chromatin remodeling), which were validated in the TES cohort. Although APC mutations were present in only 23% of samples, additional WNT-related alterations were seen in 12%. ERBB2 mutations and amplifications were present in 23% of samples. Patients with alterations in the ERBB2 signaling cascade (64%) demonstrated worse clinical outcomes (median survival 70.3 months vs. 109 months; log-rank HR = 2.4, P = 0.03). Two ERBB2-mutated (V842I and Y803H) cell lines were generated from SBA patient samples. Both demonstrated high sensitivity to ERBB2 inhibitor dacomitinib (IC50 < 2.5 nmol/L). In xenografts derived from these samples, treatment with dacomitinib reduced tumor growth by 39% and 59%, respectively, whereas it had no effect in an SBA wild-type ERBB2 model.Conclusions:The in vitro and in vivo models of SBA developed here provide a valuable resource for understanding targetable mutations in this disease. Our findings support clinical efforts to target activating ERBB2 mutations in patients with SBA that harbor these alterations.
Published: 2023

40. Supplementary Tables from Genomic Landscape Established by Allelic Imbalance in the Cancerization Field of a Normal Appearing Airway

Author: Humam Kadara, Paul Scheet, Ignacio I. Wistuba, Erik A. Ehli, Avrum E. Spira, Jerry Fowler, Jing Wang, Stephen G. Swisher, Randa El-Zein, Reza Mehran, Junya Fujimoto, Cesar Moran, Neda Kalhor, Carmen Behrens, Jing Huang, Gareth Davies, Zachary Weber, Chi-Wan Chow, Wei Lu, Li Shen, Suk-Young Yoo, Lili Huang, Li Xu, Melinda Garcia, Selina Vattathil, Wenhua Lang, and Yasminka Jakubek
Abstract: Supplementary Tables 1-3 Supplementary Table 1. Location and number of NSCLC, normal and field of cancerization specimens analyzed for genome-wide allelic imbalance Supplementary Table 2. Summary of identified allelic imbalance events in the normal-appearing airway field of cancerization in early-stage NSCLC Supplementary Table 3. Airway events with negative B-allele frequency correlations
Published: 2023

41. Supplementary information from Genomic Landscape Established by Allelic Imbalance in the Cancerization Field of a Normal Appearing Airway

Author: Humam Kadara, Paul Scheet, Ignacio I. Wistuba, Erik A. Ehli, Avrum E. Spira, Jerry Fowler, Jing Wang, Stephen G. Swisher, Randa El-Zein, Reza Mehran, Junya Fujimoto, Cesar Moran, Neda Kalhor, Carmen Behrens, Jing Huang, Gareth Davies, Zachary Weber, Chi-Wan Chow, Wei Lu, Li Shen, Suk-Young Yoo, Lili Huang, Li Xu, Melinda Garcia, Selina Vattathil, Wenhua Lang, and Yasminka Jakubek
Abstract: Supplementary information including supplementary methods, supplementary tables and figures as well as supplementary figure legends. Supplementary Figure 1. HapLOH results for matched normal large airway and NSCLC tumor from case 18 Supplementary Figure 2. Distribution of posterior probabilities for airway events called by hapLOH Supplementary Figure 3: Allelic imbalance events detected in normal-appearing airway brushings Supplementary Figure 4. Event classification using B-allele frequencies and log R ratios Supplementary Figure 5. Effect of allelic imbalance on B-allele frequencies Supplementary Figure 6: Distribution of focal and arm airway events
Published: 2023

42. Data from Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

Author: Humam Kadara, Paul Scheet, Ignacio I. Wistuba, Ernest T. Hawk, Jerry Fowler, Avrum E. Spira, Steven M. Dubinett, Yasushi Yatabe, Junya Fukuoka, P. Andrew Futreal, Jianjun Zhang, Junya Fujimoto, Li Xu, Wenhua Lang, Tina L. McDowell, F. Anthony San Lucas, and Smruthy Sivakumar
Abstract: There is a dearth of knowledge about the pathogenesis of premalignant lung lesions, especially for atypical adenomatous hyperplasia (AAH), the only known precursor for the major lung cancer subtype adenocarcinoma (LUAD). In this study, we performed deep DNA and RNA sequencing analyses of a set of AAH, LUAD, and normal tissues. Somatic BRAF variants were found in AAHs from 5 of 22 (23%) patients, 4 of 5 of whom had matched LUAD with driver EGFR mutations. KRAS mutations were present in AAHs from 4 of 22 (18%) of patients. KRAS mutations in AAH were only found in ever-smokers and were exclusive to BRAF-mutant cases. Integrative analysis revealed profiles expressed in KRAS-mutant cases (UBE2C, REL) and BRAF-mutant cases (MAX) of AAH, or common to both sets of cases (suppressed AXL). Gene sets associated with suppressed antitumor (Th1; IL12A, GZMB) and elevated protumor (CCR2, CTLA-4) immune signaling were enriched in AAH development and progression. Our results reveal potentially divergent BRAF or KRAS pathways in AAH as well as immune dysregulation in the pathogenesis of this premalignant lung lesion. Cancer Res; 77(22); 6119–30. ©2017 AACR.
Published: 2023

43. Supplementary Figures from Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

Author: Humam Kadara, Paul Scheet, Ignacio I. Wistuba, Ernest T. Hawk, Jerry Fowler, Avrum E. Spira, Steven M. Dubinett, Yasushi Yatabe, Junya Fukuoka, P. Andrew Futreal, Jianjun Zhang, Junya Fujimoto, Li Xu, Wenhua Lang, Tina L. McDowell, F. Anthony San Lucas, and Smruthy Sivakumar
Abstract: Figure S1: Mutation burden in atypical adenomatous hyperplasia and lung adenocarcinoma; Figure S2: Mutation burden in atypical adenomatous hyperplasia and lung adenocarcinoma based on tobacco history; Figure S3: Mutations in cancer driver genes in atypical adenomatous hyperplasia and lung adenocarcinoma; Figure S4: Representative validation of somatic mutations by digital PCR.
Published: 2023

44. Data from Genomic Landscape Established by Allelic Imbalance in the Cancerization Field of a Normal Appearing Airway

Author: Humam Kadara, Paul Scheet, Ignacio I. Wistuba, Erik A. Ehli, Avrum E. Spira, Jerry Fowler, Jing Wang, Stephen G. Swisher, Randa El-Zein, Reza Mehran, Junya Fujimoto, Cesar Moran, Neda Kalhor, Carmen Behrens, Jing Huang, Gareth Davies, Zachary Weber, Chi-Wan Chow, Wei Lu, Li Shen, Suk-Young Yoo, Lili Huang, Li Xu, Melinda Garcia, Selina Vattathil, Wenhua Lang, and Yasminka Jakubek
Abstract: Visually normal cells adjacent to, and extending from, tumors of the lung may carry molecular alterations characteristics of the tumor itself, an effect referred to as airway field of cancerization. This airway field has been postulated as a model for early events in lung cancer pathogenesis. Yet the genomic landscape of somatically acquired molecular alterations in airway epithelia of lung cancer patients has remained unknown. To begin to fill this void, we sought to comprehensively characterize the genomic architecture of chromosomal alterations inducing allelic imbalance (AI) in the airway field of the most common type of lung tumors, non–small cell lung cancer (NSCLC). To do so, we conducted a genome-wide survey of multiple spatially distributed normal-appearing airways, multiregion tumor specimens, and uninvolved normal tissues or blood from 45 patients with early-stage NSCLC. We detected alterations in airway epithelia from 22 patients, with an increased frequency in NSCLCs of squamous histology. Our data also indicated a spatial gradient of AI in samples at closer proximity to the NSCLC. Chromosome 9 displayed the highest levels of AI and comprised recurrent independent events. Furthermore, the airway field AI included oncogenic gains and tumor suppressor losses in known NSCLC drivers. Our results demonstrate that genome-wide AI is common in the airway field of cancerization, providing insights into early events in the pathogenesis of NSCLC that may comprise targets for early treatment and chemoprevention. Cancer Res; 76(13); 3676–83. ©2016 AACR.
Published: 2023

45. Supplementary Tables and Figures from Can Microsatellite Status of Colorectal Cancer Be Reliably Assessed after Neoadjuvant Therapy?

Author: Eduardo Vilar, Y. Nancy You, Scott Kopetz, Paul Scheet, Ji Wu, Melissa W. Taggart, Miguel Rodriguez-Bigas, Patrick M. Lynch, Sarah A. Bannon, Maureen E. Mork, Amanda Cuddy, Gita Masand, Ester Borras, William Wu, and Jennifer B. Goldstein
Abstract: Supplementary Table 1. Patient Demographic Characteristics. *2 patients with metachronous tumors, 1 poor and 1 moderate; **One patient with both pre- and posttreatment IHC and MSI testing. Supplementary Table 2. Tumor characteristics and results of the IHC and MSI analysis of those cases exhibiting loss of MSH6 after neoadjuvant treatment. Abbreviations: yp, pathologic stage after neoadjuvant treatment; NT, not tested; pre-tx, pre-treatment; post-tx, post-treatment; MSS, microsatellite stable; MSI-L, microsatellite low. Supplementary Table 3. MSI and IHC Analysis of in vivo pre- and post-treatment data. Abbreviations: yp, pathologic stage after neoadjuvant treatment; pre-tx, pre-treatment; post-tx, post-treatment; MSS, microsatellite stable; MSI-L, microsatellite low. Supplementary Table 4. PDX Patient Demographic Characteristics (n = 5) Supplementary Figure 1. Confirmation of MLH1 loss in the cell line HCT116 was performed via Sanger sequencing (A) and Western Blot (B) Supplementary Figure 2. In vitro treatment method. MMR deficient (HCT116) and proficient (HCT116+Ch3) isogenic cell lines were exposed to treatment every 48 hours for 3 cycles. On Day 1, 500,000 cells/10 mm plate were seeded and allowed to grow exponentially for 24-48 hours. Cells were then treated with radiation or drug. After 48hrs, the cells were allowed to grow in drug-free medium until confluency. Cells were split and allowed to grow again in drug-free medium for 48 hours before being treated with the next round of treatment. This process was repeated for 3 cycles. After 48 hours of the 3rd treatment, the slides were fixed with 4% paraformaldehyde.
Published: 2023

46. Supplementary Methods from Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

Author: Humam Kadara, Paul Scheet, Ignacio I. Wistuba, Ernest T. Hawk, Jerry Fowler, Avrum E. Spira, Steven M. Dubinett, Yasushi Yatabe, Junya Fukuoka, P. Andrew Futreal, Jianjun Zhang, Junya Fujimoto, Li Xu, Wenhua Lang, Tina L. McDowell, F. Anthony San Lucas, and Smruthy Sivakumar
Abstract: Supplementary methods including detailed methods on specimen collection and evaluation; DNA and RNA isolation; deep DNA targeted sequencing and transcriptome sequencing; identification and validation of somatic mutations; and expression analysis.
Published: 2023

47. Germline genetic variants and pediatric rhabdomyosarcoma outcomes: a report from the Children’s Oncology Group

Author: Bailey A Martin-Giacalone, Melissa A Richard, Michael E Scheurer, Javed Khan, Pagna Sok, Priya B Shetty, Stephen J Chanock, Shengchao Alfred Li, Meredith Yeager, Deborah A Marquez-Do, Donald A Barkauskas, David Hall, Matthew T McEvoy, Austin L Brown, Aniko Sabo, Paul Scheet, Chad D Huff, Stephen X Skapek, Douglas S Hawkins, Rajkumar Venkatramani, Lisa Mirabello, and Philip J Lupo
Subjects: Cancer Research, Oncology
Abstract: Background Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS. Methods The study included 920 individuals with newly diagnosed RMS who were enrolled in Children’s Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical covariates. All statistical tests were two sided. We also performed stratified analyses by histological subtype (alveolar and embryonal RMS) and carried out sensitivity analyses of statistically significant SNPs by PAX3/7-FOXO1 fusion status and genetic ancestry group. Results We identified that rs17321084 was associated with worse EFS (HR = 2.01, 95% CI = 1.59 to 2.53, P = 5.39 × 10−9) and rs10094840 was associated with worse OS (HR = 1.84, 95% CI = 1.48 to 2.27, P = 2.13 × 10−8). Using publicly available data, we found that rs17321084 lies in a binding region for transcription factors GATA2 and GATA3, and rs10094840 is associated with SPAG1 and RNF19A expression. We also identified that CTNNA3 rs2135732 (HR = 3.75, 95% CI = 2.34 to 5.99, P = 3.54 × 10−8) and MED31 rs74504320 (HR = 3.21, 95% CI = 2.12 to 4.86, P = 3.60 × 10−8) were associated with worse OS among individuals with alveolar RMS. Conclusions We demonstrated that common germline variants are associated with EFS and OS among individuals with RMS. Additional replication and investigation of these SNP effects may further support their consideration in risk stratification protocols.
Published: 2023

48. Chronic Exposure to Waterpipe Smoke Elicits Immunomodulatory and Carcinogenic Effects in the Lung

Author: Maya Hassane, Zahraa Rahal, Nareg Karaoghlanian, Jiexin Zhang, Ansam Sinjab, Justin W. Wong, Wei Lu, Paul Scheet, J. Jack Lee, Maria Gabriela Raso, Luisa M. Solis, Junya Fujimoto, Hassan Chami, Alan L. Shihadeh, and Humam Kadara
Subjects: Mice, Cancer Research, Oncology, Neoplasms, Carcinogens, Animals, Water Pipe Smoking, Tobacco Products, Lung, Article, respiratory tract diseases
Abstract: Effects of waterpipe smoking on lung pathobiology and carcinogenesis remain sparse despite the worldwide emergence of this tobacco vector. To address this gap, we investigated the effects of chronic waterpipe smoke (WPS) exposure on lung pathobiology, host immunity, and tumorigenesis using an experimental animal model that is prone to tobacco carcinogens and an exploratory observational analysis of human waterpipe smokers and nonsmokers. Mice exhibited elevated incidence of lung tumors following heavy WPS exposure (5 days/week for 20 weeks) compared to littermates with light WPS (once/week for 20 weeks) or control air. Lungs of mice exposed to heavy WPS showed augmented CD8+ and CD4+ T cell counts along with elevated protumor immune phenotypes including increased IL17A in T/B cells, PD-L1 on tumor and immune cells, and the proinflammatory cytokine IL1β in myeloid cells. RNA-sequencing (RNA-seq) analysis showed reduced antitumor immune gene signatures in animals exposed to heavy WPS relative to control air. We also performed RNA-seq analysis of airway epithelia from bronchial brushings of cancer-free waterpipe smokers and nonsmokers undergoing diagnostic bronchoscopy. Transcriptomes of normal airway cells in waterpipe smokers, relative to waterpipe nonsmokers, harbored gene programs that were associated with poor clinical outcomes in patients with lung adenocarcinoma, alluding to a WPS-associated molecular injury, like that established in response to cigarette smoking. Our findings support the notion that WPS exhibits carcinogenic effects and constitutes a possible risk factor for lung cancer as well as warrant future studies that can guide evidence-based policies for mitigating waterpipe smoking. Prevention Relevance: Potential carcinogenic effects of waterpipe smoking are very poorly understood despite its emergence as a socially acceptable form of smoking. Our work highlights carcinogenic effects of waterpipe smoking in the lung and, thus, accentuate the need for inclusion of individuals with exclusive waterpipe smoking in prevention and smoking cessation studies.
Published: 2022

49. Chromosomal imbalances detected via RNA-sequencing in 28 cancers

Author: Zuhal Ozcan, Francis A San Lucas, Justin W Wong, Kyle Chang, Konrad H Stopsack, Jerry Fowler, Yasminka A Jakubek, and Paul Scheet
Subjects: Statistics and Probability, Computational Mathematics, Computational Theory and Mathematics, Molecular Biology, Biochemistry, Computer Science Applications
Abstract: Motivation RNA-sequencing (RNA-seq) of tumor tissue is typically only used to measure gene expression. Here, we present a statistical approach that leverages existing RNA-seq data to also detect somatic copy number alterations (SCNAs), a pervasive phenomenon in human cancers, without a need to sequence the corresponding DNA. Results We present an analysis of 4942 participant samples from 28 cancers in The Cancer Genome Atlas (TCGA), demonstrating robust detection of SCNAs from RNA-seq. Using genotype imputation and haplotype information, our RNA-based method had a median sensitivity of 85% to detect SCNAs defined by DNA analysis, at high specificity (∼95%). As an example of translational potential, we successfully replicated SCNA features associated with breast cancer subtypes. Our results credential haplotype-based inference based on RNA-seq to detect SCNAs in clinical and population-based settings. Availability and implementation The analyses presented use the data publicly available from TCGA Research Network (http://cancergenome.nih.gov/). See Methods for details regarding data downloads. hapLOHseq software is freely available under The MIT license and can be downloaded from http://scheet.org/software.html. Supplementary information Supplementary data are available at Bioinformatics online.
Published: 2022

50. Mosaic chromosomal alterations in blood across ancestries via whole-genome sequencing

Author: Yasminka A. Jakubek, Ying Zhou, Adrienne Stilp, Jason Bacon, Justin Wong, Zuhal Ozcan, Donna Arnett, Kathleen Barnes, Josh Bis, Eric Boerwinkle, April Carson, Daniel Chasman, Michael Cho, Matthew P. Conomos, Nancy Cox, Margaret Doyle, Myriam Fornage, Xiuqing Guo, Sharon Kardia, Joshua P. Lewis, Ruth J. Loos, Xiaolong Ma, Mitchell Machiela, Taralynn M. Mack, Rasika Mathias, Braxton D. Mitchell, Kari North, Nathan Pankratz, Patricia Peyser, Michael H. Preuss, Bruce Psaty, Laura M. Raffield, Ramachandran S. Vasan, Susan Redline, Stephen S. Rich, Jerome I. Rotter, Edwin Silverman, Jennifer Smith, Margaret Taub, Jeong Yun, Yun Li, Pinkal Desai, Alexander G. Bick, Alexander P. Reiner, Paul Scheet, and Paul L. Auer
Abstract: Mosaic mutations in blood are common with increasing age and are prognostic markers for cancer, cardiovascular dysfunction and other diseases. This group of acquired mutations include megabase-scale mosaic chromosomal alterations (mCAs). These large mutations have mainly been surveyed using SNP array data from individuals of European (EA) or Japanese genetic ancestry. To gain a better understanding of mCA rates and associated risk factors in genetically diverse populations, we surveyed whole genome sequencing data from 67,390 individuals, including 20,132 individuals of African ancestry (AA), and 7,608 of Hispanic ancestry (HA) with deep (30X) whole genome sequencing data from the NHLBI Trans Omics for Precision Medicine (TOPMed) program. We adapted an existing mCA calling algorithm for application to WGS data, and observed higher sensitivity with WGS data, compared with array-based data, in uncovering mCAs at low mutant cell fractions. As in previous reports, we observed a strong association with age and a non-uniform distribution of mCAs across the genome. The presence of autosomal (but not chromosome X) mCAs was associated with an increased risk of both lymphoid and myeloid malignancies. After adjusting for age, we found that individuals of European ancestry have the highest rates of autosomal mCAs, mirroring the higher rate of leukemia in this group. Our analysis also uncovered higher rates of chromosome X mCAs in AA and HA compared to EA, again after adjusting for age. Germline variants inATMandMPLshowed strong associations with mCAs incis, including ancestry specific variants. And rare variant gene-burden analysis confirmed the association of putatively protein altering variants inATMandMPLwith mCAs incis. Individual rare variants inDCPS, ADM17, PPP1R16B, andTET2were all associated with autosomal mCAs and rare variants inOR4C16were associated with chromosome X mCAs in females. There was significant enrichment of co-occurrence of CHIP mutations and mCAs both altering cancer associated genesTET2, DNMT3A, JAK2, CUX1, andTP53. Overall, our study demonstrates that rates of mCAs differ across populations and that rare inherited germline variants are strongly associated with mCAs across genetically diverse populations. These results strongly motivate further studies of mCAs in under-represented populations to better understand the causes and consequences of this class of somatic variation.
Published: 2022

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