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2,029 results on '"Vogelstein, Bert"'

1. TRBC1-targeting antibody–drug conjugates for the treatment of T cell cancers

Author

Nichakawade, Tushar D., Ge, Jiaxin, Mog, Brian J., Lee, Bum Seok, Pearlman, Alexander H., Hwang, Michael S., DiNapoli, Sarah R., Wyhs, Nicolas, Marcou, Nikita, Glavaris, Stephanie, Konig, Maximilian F., Gabelli, Sandra B., Watson, Evangeline, Sterling, Cole, Wagner-Johnston, Nina, Rozati, Sima, Swinnen, Lode, Fuchs, Ephraim, Pardoll, Drew M., Gabrielson, Kathy, Papadopoulos, Nickolas, Bettegowda, Chetan, Kinzler, Kenneth W., Zhou, Shibin, Sur, Surojit, Vogelstein, Bert, and Paul, Suman

Published
2024
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2. Hydrophobic interactions dominate the recognition of a KRAS G12V neoantigen

Author

Wright, Katharine M., DiNapoli, Sarah R., Miller, Michelle S., Aitana Azurmendi, P., Zhao, Xiaowei, Yu, Zhiheng, Chakrabarti, Mayukh, Shi, WuXian, Douglass, Jacqueline, Hwang, Michael S., Hsiue, Emily Han-Chung, Mog, Brian J., Pearlman, Alexander H., Paul, Suman, Konig, Maximilian F., Pardoll, Drew M., Bettegowda, Chetan, Papadopoulos, Nickolas, Kinzler, Kenneth W., Vogelstein, Bert, Zhou, Shibin, and Gabelli, Sandra B.

Published
2023
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4. Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from lower respiratory tract infection

Author

Koenecke, Allison, Powell, Michael, Xiong, Ruoxuan, Shen, Zhu, Fischer, Nicole, Huq, Sakibul, Khalafallah, Adham M., Trevisan, Marco, Sparen, Pär, Carrero, Juan J, Nishimura, Akihiko, Caffo, Brian, Stuart, Elizabeth A., Bai, Renyuan, Staedtke, Verena, Thomas, David L., Papadopoulos, Nickolas, Kinzler, Kenneth W., Vogelstein, Bert, Zhou, Shibin, Bettegowda, Chetan, Konig, Maximilian F., Mensh, Brett, Vogelstein, Joshua T., and Athey, Susan

Subjects
Quantitative Biology - Tissues and Organs, Quantitative Biology - Quantitative Methods
Abstract

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor ($\alpha_1$-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n=18,547) and three cohorts with pneumonia (n=400,907). Federated across two ARD cohorts, we find that patients exposed to $\alpha_1$-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR=0.70, p=0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of $\alpha_1$-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19., Comment: 31 pages, 10 figures

Published
2020
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6. Classification of pancreatic cystic neoplasms using radiomic feature analysis is equivalent to an experienced academic radiologist: a step toward computer-augmented diagnostics for radiologists

Author

Chu, Linda C., Park, Seyoun, Soleimani, Sahar, Fouladi, Daniel F., Shayesteh, Shahab, He, Jin, Javed, Ammar A., Wolfgang, Christopher L., Vogelstein, Bert, Kinzler, Kenneth W., Hruban, Ralph H., Afghani, Elham, Lennon, Anne Marie, Fishman, Elliot K., and Kawamoto, Satomi

Published
2022
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8. An analysis of genetic heterogeneity in untreated cancers

Author

Reiter, Johannes G, Baretti, Marina, Gerold, Jeffrey M, Makohon-Moore, Alvin P, Daud, Adil, Iacobuzio-Donahue, Christine A, Azad, Nilofer S, Kinzler, Kenneth W, Nowak, Martin A, and Vogelstein, Bert

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Genetics, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Aetiology, 2.1 Biological and endogenous factors, Animals, Biopsy, Clinical Trials as Topic, Epigenesis, Genetic, Genetic Heterogeneity, Humans, Medical Oncology, Mutation, Neoplasm Metastasis, Skin Neoplasms, Medical and Health Sciences, Oncology & Carcinogenesis, Biomedical and clinical sciences, Health sciences
Abstract

Genetic intratumoural heterogeneity is a natural consequence of imperfect DNA replication. Any two randomly selected cells, whether normal or cancerous, are therefore genetically different. Here, we review the different forms of genetic heterogeneity in cancer and re-analyse the extent of genetic heterogeneity within seven types of untreated epithelial cancers, with particular regard to its clinical relevance. We find that the homogeneity of predicted functional mutations in driver genes is the rule rather than the exception. In primary tumours with multiple samples, 97% of driver-gene mutations in 38 patients were homogeneous. Moreover, among metastases from the same primary tumour, 100% of the driver mutations in 17 patients were homogeneous. With a single biopsy of a primary tumour in 14 patients, the likelihood of missing a functional driver-gene mutation that was present in all metastases was 2.6%. Furthermore, all functional driver-gene mutations detected in these 14 primary tumours were present among all their metastases. Finally, we found that individual metastatic lesions responded concordantly to targeted therapies in 91% of 44 patients. These analyses indicate that the cells within the primary tumours that gave rise to metastases are genetically homogeneous with respect to functional driver-gene mutations, and we suggest that future efforts to develop combination therapies have the potential to be curative.

Published
2019

9. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer: Overall survival and updated 5-year results from the randomized DYNAMIC trial.

Author

Tie, Jeanne, primary, Wang, Yuxuan, additional, Lo, Serigne N, additional, Lahouel, Kamel, additional, Cohen, Joshua D., additional, Wong, Rachel, additional, Shapiro, Jeremy David, additional, Harris, Samuel John, additional, Khattak, Adnan, additional, Burge, Matthew E., additional, Lee, Margaret, additional, Harris, Marion, additional, McLachlan, Sue-Anne, additional, Ananda, Sumitra, additional, UNDERHILL, CRAIG R, additional, Papadopoulos, Nickolas, additional, Tomasetti, Cristian, additional, Kinzler, Kenneth W., additional, Vogelstein, Bert, additional, and Gibbs, Peter, additional

Published
2024
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10. Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape

Author

Cook, Ashley L, primary, Sur, Surojit, additional, Dobbyn, Laura, additional, Watson, Evangeline, additional, Cohen, Joshua D, additional, Ptak, Blair, additional, Lee, Bum Seok, additional, Paul, Suman, additional, Hsiue, Emily, additional, Popoli, Maria, additional, Vogelstein, Bert, additional, Papadopoulos, Nickolas, additional, Bettegowda, Chetan, additional, Gabrielson, Kathy, additional, Zhou, Shibin, additional, Kinzler, Kenneth W, additional, and Wyhs, Nicolas, additional

Published
2024
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12. Targeting loss of heterozygosity for cancer-specific immunotherapy

Author

Hwang, Michael S., Mog, Brian J., Douglass, Jacqueline, Pearlman, Alexander H., Hsiue, Emily Han-Chung, Paul, Suman, DiNapoli, Sarah R., Konig, Maximilian F., Pardoll, Drew M., Gabelli, Sandra B., Bettegowda, Chetan, Papadopoulos, Nickolas, Vogelstein, Bert, Zhou, Shibin, and Kinzler, Kenneth W.

Published
2021

14. Precancerous neoplastic cells can move through the pancreatic ductal system

Author

Makohon-Moore, Alvin P, Matsukuma, Karen, Zhang, Ming, Reiter, Johannes G, Gerold, Jeffrey M, Jiao, Yuchen, Sikkema, Lisa, Attiyeh, Marc A, Yachida, Shinichi, Sandone, Corinne, Hruban, Ralph H, Klimstra, David S, Papadopoulos, Nickolas, Nowak, Martin A, Kinzler, Kenneth W, Vogelstein, Bert, and Iacobuzio-Donahue, Christine A

Subjects
Rare Diseases, Cancer, Digestive Diseases, Pancreatic Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Carcinoma, Pancreatic Ductal, Cell Lineage, Disease Progression, Evolution, Molecular, Humans, INDEL Mutation, Models, Biological, Mutagenesis, Neoplasm Invasiveness, Pancreatic Ducts, Pancreatic Neoplasms, Polymorphism, Single Nucleotide, Precancerous Conditions, Time Factors, Exome Sequencing, General Science & Technology
Abstract

Most adult carcinomas develop from noninvasive precursor lesions, a progression that is supported by genetic analysis. However, the evolutionary and genetic relationships among co-existing lesions are unclear. Here we analysed the somatic variants of pancreatic cancers and precursor lesions sampled from distinct regions of the same pancreas. After inferring evolutionary relationships, we found that the ancestral cell had initiated and clonally expanded to form one or more lesions, and that subsequent driver gene mutations eventually led to invasive pancreatic cancer. We estimate that this multi-step progression generally spans many years. These new data reframe the step-wise progression model of pancreatic cancer by illustrating that independent, high-grade pancreatic precursor lesions observed in a single pancreas often represent a single neoplasm that has colonized the ductal system, accumulating spatial and genetic divergence over time.

Published
2018

15. ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1

Author

Rincon-Torroella, Jordina, primary, Molin, Marco Dal, additional, Mog, Brian, additional, Han, Gyuri, additional, Watson, Evangeline, additional, Wyhs, Nicolas, additional, Ishiyama, Shun, additional, Ahmedna, Taha, additional, Minn, Il, additional, Azad, Nilofer S., additional, Bettegowda, Chetan, additional, Papadopoulos, Nickolas, additional, Kinzler, Kenneth W., additional, Zhou, Shibin, additional, Vogelstein, Bert, additional, Gabrielson, Kathleen, additional, and Sur, Surojit, additional

Published
2024
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16. Circulating tumor DNA analysis informing adjuvant chemotherapy in locally advanced rectal cancer: The randomized AGITG DYNAMIC-Rectal study.

Author

Tie, Jeanne, primary, Cohen, Joshua D., additional, Wang, Yuxuan, additional, Ginestet, Pablo Gonzalez, additional, Wong, Rachel, additional, Shapiro, Jeremy David, additional, Campbell, Rob, additional, Day, Fiona, additional, Hayes, Theresa M., additional, Aghmesheh, Morteza, additional, Karapetis, Christos Stelios, additional, Popoli, Maria, additional, Dobbyn, Lisa, additional, Ptak, Janine, additional, Silliman, Natalie, additional, Douville, Christopher B., additional, Papadopoulos, Nickolas, additional, Kinzler, Kenneth W., additional, Vogelstein, Bert, additional, and Gibbs, Peter, additional

Published
2024
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17. Assessing aneuploidy with repetitive element sequencing

Author

Douville, Christopher, Cohen, Joshua D., Ptak, Janine, Popoli, Maria, Schaefer, Joy, Silliman, Natalie, Dobbyn, Lisa, Schoen, Robert E., Tie, Jeanne, Gibbs, Peter, Goggins, Michael, Wolfgang, Christopher L., Wang, Tian-Li, Shih, Ie-Ming, Karchin, Rachel, Lennon, Anne Marie, Hruban, Ralph H., Tomasetti, Cristian, Bettegowda, Chetan, Kinzler, Kenneth W., Papadopoulos, Nickolas, and Vogelstein, Bert

Published
2020

19. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers

Author

Caushi, Justina X., Zhang, Jiajia, Ji, Zhicheng, Vaghasia, Ajay, Zhang, Boyang, Hsiue, Emily Han-Chung, Mog, Brian J., Hou, Wenpin, Justesen, Sune, Blosser, Richard, Tam, Ada, Anagnostou, Valsamo, Cottrell, Tricia R., Guo, Haidan, Chan, Hok Yee, Singh, Dipika, Thapa, Sampriti, Dykema, Arbor G., Burman, Poromendro, Choudhury, Begum, Aparicio, Luis, Cheung, Laurene S., Lanis, Mara, Belcaid, Zineb, El Asmar, Margueritta, Illei, Peter B., Wang, Rulin, Meyers, Jennifer, Schuebel, Kornel, Gupta, Anuj, Skaist, Alyza, Wheelan, Sarah, Naidoo, Jarushka, Marrone, Kristen A., Brock, Malcolm, Ha, Jinny, Bush, Errol L., Park, Bernard J., Bott, Matthew, Jones, David R., Reuss, Joshua E., Velculescu, Victor E., Chaft, Jamie E., Kinzler, Kenneth W., Zhou, Shibin, Vogelstein, Bert, Taube, Janis M., Hellmann, Matthew D., Brahmer, Julie R., Merghoub, Taha, Forde, Patrick M., Yegnasubramanian, Srinivasan, Ji, Hongkai, Pardoll, Drew M., and Smith, Kellie N.

Published
2021
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21. Targeting public neoantigens for cancer immunotherapy

Author

Pearlman, Alexander H., Hwang, Michael S., Konig, Maximilian F., Hsiue, Emily Han-Chung, Douglass, Jacqueline, DiNapoli, Sarah R., Mog, Brian J., Bettegowda, Chetan, Pardoll, Drew M., Gabelli, Sandra B., Papadopoulos, Nicholas, Kinzler, Kenneth W., Vogelstein, Bert, and Zhou, Shibin

Published
2021
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22. Spatial model predicts dispersal and cell turnover cause reduced intra-tumor heterogeneity

Author

Waclaw, Bartlomiej, Bozic, Ivana, Pittman, Meredith E., Hruban, Ralph H., Vogelstein, Bert, and Nowak, Martin A.

Subjects
Quantitative Biology - Populations and Evolution, Quantitative Biology - Tissues and Organs
Abstract

Most cancers in humans are large, measuring centimeters in diameter, composed of many billions of cells. An equivalent mass of normal cells would be highly heterogeneous as a result of the mutations that occur during each cell division. What is remarkable about cancers is their homogeneity - virtually every neoplastic cell within a large cancer contains the same core set of genetic alterations, with heterogeneity confined to mutations that have emerged after the last clonal expansions. How such clones expand within the spatially-constrained three dimensional architecture of a tumor, and come to dominate a large, pre-existing lesion, has never been explained. We here describe a model for tumor evolution that shows how short-range migration and cell turnover can account for rapid cell mixing inside the tumor. With it, we show that even a small selective advantage of a single cell within a large tumor allows the descendants of that cell to replace the precursor mass in a clinically relevant time frame. We also demonstrate that the same mechanisms can be responsible for the rapid onset of resistance to chemotherapy. Our model not only provides novel insights into spatial and temporal aspects of tumor growth but also suggests that targeting short range cellular migratory activity could have dramatic effects on tumor growth rates., Comment: 37 pages, 14 figures

Published
2015
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23. Musings on the theory that variation in cancer risk among tissues can be explained by the number of divisions of normal stem cells

Author

Tomasetti, Cristian and Vogelstein, Bert

Subjects
Statistics - Applications, Quantitative Biology - Genomics, Quantitative Biology - Tissues and Organs
Abstract

This manuscript has been written to address questions related to our recent publication (Science 347:78-81, 2015). We appreciate the many reactions to this paper that have been communicated to us, either privately or publicly. The following addresses several of the most important statistical and technical issues related to our analysis and conclusions. Our responses to non-technical questions are available at http://www.hopkinsmedicine.org/news/media/releases/bad_luck_of_random_mutations_plays_predominant_role_in_cancer_study_shows

Published
2015

25. Figure S7 from The Origin of Highly Elevated Cell-Free DNA in Healthy Individuals and Patients with Pancreatic, Colorectal, Lung, or Ovarian Cancer

Author

Mattox, Austin K., primary, Douville, Christopher, primary, Wang, Yuxuan, primary, Popoli, Maria, primary, Ptak, Janine, primary, Silliman, Natalie, primary, Dobbyn, Lisa, primary, Schaefer, Joy, primary, Lu, Steve, primary, Pearlman, Alexander H., primary, Cohen, Joshua D., primary, Tie, Jeanne, primary, Gibbs, Peter, primary, Lahouel, Kamel, primary, Bettegowda, Chetan, primary, Hruban, Ralph H., primary, Tomasetti, Cristian, primary, Jiang, Peiyong, primary, Chan, K.C. Allen, primary, Lo, Yuk Ming Dennis, primary, Papadopoulos, Nickolas, primary, Kinzler, Kenneth W., primary, and Vogelstein, Bert, primary

Published
2023
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26. Clinical, genomic, and metagenomic characterization of oral tongue squamous cell carcinoma in patients who do not smoke

Author

Li, Ryan, Faden, Daniel L, Fakhry, Carole, Langelier, Chaz, Jiao, Yuchen, Wang, Yuxuan, Wilkerson, Matthew D, Pedamallu, Chandra Sekhar, Old, Matthew, Lang, James, Loyo, Myriam, Ahn, Sun Mi, Tan, Marietta, Gooi, Zhen, Chan, Jason, Richmon, Jeremy, Wood, Laura D, Hruban, Ralph H, Bishop, Justin, Westra, William H, Chung, Christine H, Califano, Joseph, Gourin, Christine G, Bettegowda, Chetan, Meyerson, Matthew, Papadopoulos, Nickolas, Kinzler, Kenneth W, Vogelstein, Bert, DeRisi, Joseph L, Koch, Wayne M, and Agrawal, Nishant

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Cancer, Dental/Oral and Craniofacial Disease, Genetics, Tobacco, Cancer Genomics, Tobacco Smoke and Health, Digestive Diseases, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Adult, Age Distribution, Carcinoma, Squamous Cell, Cohort Studies, DNA, Neoplasm, Databases, Factual, Female, Genetic Predisposition to Disease, Genomics, Humans, Incidence, Male, Metagenome, Middle Aged, Mutation, Neoplasm Invasiveness, Neoplasm Staging, Prognosis, RNA, Messenger, Retrospective Studies, Risk Assessment, Sex Distribution, Smoking, Tongue Neoplasms, Tumor Suppressor Protein p53, head and neck cancer, oral tongue, squamous cell carcinoma, next-generation sequencing, nonsmokers, Dentistry, Otorhinolaryngology, Clinical sciences
Abstract

BackgroundEvidence suggests the incidence of oral tongue squamous cell carcinoma is increasing in young patients, many who have no history of tobacco use.MethodsWe clinically reviewed 89 patients with oral tongue cancer. Exomic sequencing of tumor DNA from 6 nonsmokers was performed and compared to previously sequenced cases. RNA from 20 tumors was evaluated by massively parallel sequencing to search for potentially oncogenic viruses.ResultsNon-smokers (53 of 89) were younger than smokers (36 of 89; mean, 50.4 vs 61.9 years; p

Published
2015

27. Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens

Author

Hwang, Michael S., Miller, Michelle S., Thirawatananond, Puchong, Douglass, Jacqueline, Wright, Katharine M., Hsiue, Emily Han-Chung, Mog, Brian J., Aytenfisu, Tihitina Y., Murphy, Michael B., Aitana Azurmendi, P., Skora, Andrew D., Pearlman, Alexander H., Paul, Suman, DiNapoli, Sarah R., Konig, Maximilian F., Bettegowda, Chetan, Pardoll, Drew M., Papadopoulos, Nickolas, Kinzler, Kenneth W., Vogelstein, Bert, Zhou, Shibin, and Gabelli, Sandra B.

Published
2021
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28. Incidence and distribution of UroSEEK gene panel in a multi-institutional cohort of bladder urothelial carcinoma

Author

Eich, Marie-Lisa, Rodriguez Pena, Maria Del Carmen, Springer, Simeon U., Taheri, Diana, Tregnago, Aline C., Salles, Daniela C., Bezerra, Stephania Martins, Cunha, Isabela W., Fujita, Kazutoshi, Ertoy, Dilek, Bivalacqua, Trinity J., Tomasetti, Cristian, Papadopoulos, Nickolas, Kinzler, Ken W., Vogelstein, Bert, and Netto, George J.

Published
2019
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30. Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas

Author

Wang, Yuxuan, Springer, Simeon, Mulvey, Carolyn L, Silliman, Natalie, Schaefer, Joy, Sausen, Mark, James, Nathan, Rettig, Eleni M, Guo, Theresa, Pickering, Curtis R, Bishop, Justin A, Chung, Christine H, Califano, Joseph A, Eisele, David W, Fakhry, Carole, Gourin, Christine G, Ha, Patrick K, Kang, Hyunseok, Kiess, Ana, Koch, Wayne M, Myers, Jeffrey N, Quon, Harry, Richmon, Jeremy D, Sidransky, David, Tufano, Ralph P, Westra, William H, Bettegowda, Chetan, Diaz, Luis A, Papadopoulos, Nickolas, Kinzler, Kenneth W, Vogelstein, Bert, and Agrawal, Nishant

Subjects
Genetics, Clinical Research, Rare Diseases, Dental/Oral and Craniofacial Disease, Genetic Testing, Cancer, Carcinoma, Squamous Cell, DNA, Neoplasm, Female, Head and Neck Neoplasms, Humans, Male, Middle Aged, Mutation, Neoplasm Staging, Papillomaviridae, Saliva, Biological Sciences, Medical and Health Sciences
Abstract

To explore the potential of tumor-specific DNA as a biomarker for head and neck squamous cell carcinomas (HNSCC), we queried DNA from saliva or plasma of 93 HNSCC patients. We searched for somatic mutations or human papillomavirus genes, collectively referred to as tumor DNA. When both plasma and saliva were tested, tumor DNA was detected in 96% of 47 patients. The fractions of patients with detectable tumor DNA in early- and late-stage disease were 100% (n = 10) and 95% (n = 37), respectively. When segregated by site, tumor DNA was detected in 100% (n = 15), 91% (n = 22), 100% (n = 7), and 100% (n = 3) of patients with tumors of the oral cavity, oropharynx, larynx, and hypopharynx, respectively. In saliva, tumor DNA was found in 100% of patients with oral cavity cancers and in 47 to 70% of patients with cancers of the other sites. In plasma, tumor DNA was found in 80% of patients with oral cavity cancers, and in 86 to 100% of patients with cancers of the other sites. Thus, saliva is preferentially enriched for tumor DNA from the oral cavity, whereas plasma is preferentially enriched for tumor DNA from the other sites. Tumor DNA in saliva was found postsurgically in three patients before clinical diagnosis of recurrence, but in none of the five patients without recurrence. Tumor DNA in the saliva and plasma appears to be a potentially valuable biomarker for detection of HNSCC.

Published
2015

31. Microbiota organization is a distinct feature of proximal colorectal cancers.

Author

Dejea, Christine, Wick, Elizabeth, Hechenbleikner, Elizabeth, White, James, Mark Welch, Jessica, Rossetti, Blair, Peterson, Scott, Snesrud, Erik, Borisy, Gary, Lazarev, Mark, Stein, Ellen, Vadivelu, Jamuna, Roslani, April, Malik, Ausuma, Wanyiri, Jane, Goh, Khean, Thevambiga, Iyadorai, Fu, Kai, Wan, Fengyi, Llosa, Nicolas, Housseau, Franck, Romans, Katharine, Wu, XinQun, McAllister, Florencia, Wu, Shaoguang, Vogelstein, Bert, Kinzler, Kenneth, Pardoll, Drew, and Sears, Cynthia

Subjects
adenoma, bacterial communities, biofilm, colorectal cancer, microbiome, Bacteria, Biofilms, Colonoscopy, Colorectal Neoplasms, Humans, Microbiota
Abstract

Environmental factors clearly affect colorectal cancer (CRC) incidence, but the mechanisms through which these factors function are unknown. One prime candidate is an altered colonic microbiota. Here we show that the mucosal microbiota organization is a critical factor associated with a subset of CRC. We identified invasive polymicrobial bacterial biofilms (bacterial aggregates), structures previously associated with nonmalignant intestinal pathology, nearly universally (89%) on right-sided tumors (13 of 15 CRCs, 4 of 4 adenomas) but on only 12% of left-sided tumors (2 of 15 CRCs, 0 of 2 adenomas). Surprisingly, patients with biofilm-positive tumors, whether cancers or adenomas, all had biofilms on their tumor-free mucosa far distant from their tumors. Bacterial biofilms were associated with diminished colonic epithelial cell E-cadherin and enhanced epithelial cell IL-6 and Stat3 activation, as well as increased crypt epithelial cell proliferation in normal colon mucosa. High-throughput sequencing revealed no consistent bacterial genus associated with tumors, regardless of biofilm status. However, principal coordinates analysis revealed that biofilm communities on paired normal mucosa, distant from the tumor itself, cluster with tumor microbiomes as opposed to biofilm-negative normal mucosa bacterial communities also from the tumor host. Colon mucosal biofilm detection may predict increased risk for development of sporadic CRC.

Published
2014

32. Accumulation of driver and passenger mutations during tumor progression

Author

Bozic, Ivana, Antal, Tibor, Ohtsuki, Hisashi, Carter, Hannah, Kim, Dewey, Chen, Sining, Karchin, Rachel, Kinzler, Kenneth W., Vogelstein, Bert, and Nowak, Martin A.

Subjects
Quantitative Biology - Populations and Evolution
Abstract

Major efforts to sequence cancer genomes are now occurring throughout the world. Though the emerging data from these studies are illuminating, their reconciliation with epidemiologic and clinical observations poses a major challenge. In the current study, we provide a novel mathematical model that begins to address this challenge. We model tumors as a discrete time branching process that starts with a single driver mutation and proceeds as each new driver mutation leads to a slightly increased rate of clonal expansion. Using the model, we observe tremendous variation in the rate of tumor development - providing an understanding of the heterogeneity in tumor sizes and development times that have been observed by epidemiologists and clinicians. Furthermore, the model provides a simple formula for the number of driver mutations as a function of the total number of mutations in the tumor. Finally, when applied to recent experimental data, the model allows us to calculate, for the first time, the actual selective advantage provided by typical somatic mutations in human tumors in situ. This selective advantage is surprisingly small, 0.005 +- 0.0005, and has major implications for experimental cancer research.

Published
2009
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33. The Origin of Highly Elevated Cell-Free DNA in Healthy Individuals and Patients with Pancreatic, Colorectal, Lung, or Ovarian Cancer

Author

Mattox, Austin K., primary, Douville, Christopher, additional, Wang, Yuxuan, additional, Popoli, Maria, additional, Ptak, Janine, additional, Silliman, Natalie, additional, Dobbyn, Lisa, additional, Schaefer, Joy, additional, Lu, Steve, additional, Pearlman, Alexander H., additional, Cohen, Joshua D., additional, Tie, Jeanne, additional, Gibbs, Peter, additional, Lahouel, Kamel, additional, Bettegowda, Chetan, additional, Hruban, Ralph H., additional, Tomasetti, Cristian, additional, Jiang, Peiyong, additional, Chan, K.C. Allen, additional, Lo, Yuk Ming Dennis, additional, Papadopoulos, Nickolas, additional, Kinzler, Kenneth W., additional, and Vogelstein, Bert, additional

Published
2023
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34. Seq-ing the SINEs of central nervous system tumors in cerebrospinal fluid

Author

Douville, Christopher, primary, Curtis, Samuel, additional, Summers, Mahmoud, additional, Azad, Tej D., additional, Rincon-Torroella, Jordina, additional, Wang, Yuxuan, additional, Mattox, Austin, additional, Avigdor, Bracha, additional, Dudley, Jonathan, additional, Materi, Joshua, additional, Raj, Divyaansh, additional, Nair, Sumil, additional, Bhanja, Debarati, additional, Tuohy, Kyle, additional, Dobbyn, Lisa, additional, Popoli, Maria, additional, Ptak, Janine, additional, Nehme, Nadine, additional, Silliman, Natalie, additional, Blair, Cherie, additional, Judge, Kathy, additional, Gallia, Gary L., additional, Groves, Mari, additional, Jackson, Christopher M., additional, Jackson, Eric M., additional, Laterra, John, additional, Lim, Michael, additional, Mukherjee, Debraj, additional, Weingart, Jon, additional, Naidoo, Jarushka, additional, Koschmann, Carl, additional, Smith, Natalya, additional, Schreck, Karisa C., additional, Pardo, Carlos A., additional, Glantz, Michael, additional, Holdhoff, Matthias, additional, Kinzler, Kenneth W., additional, Papadopoulos, Nickolas, additional, Vogelstein, Bert, additional, and Bettegowda, Chetan, additional

Published
2023
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35. ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1

Author

Rincon-Torroella, Jordina, primary, Dal Molin, Marco, additional, Mog, Brian, additional, Han, Gyuri, additional, Watson, Evangeline, additional, Wyhs, Nicolas, additional, Ishiyama, Shun, additional, Ahmedna, Taha, additional, Minn, Il, additional, Azad, Nilofer S, additional, Bettegowda, Chetan, additional, Papadopoulos, Nickolas, additional, Kinzler, Kenneth W, additional, Zhou, Shibin, additional, Vogelstein, Bert, additional, Gabrielson, Kathleen L, additional, and Sur, Surojit, additional

Published
2023
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37. Minimal functional driver gene heterogeneity among untreated metastases

Author

Reiter, Johannes G., Makohon-Moore, Alvin P., Gerold, Jeffrey M., Heyde, Alexander, Attiyeh, Marc A., Kohutek, Zachary A., Tokheim, Collin J., Brown, Alexia, DeBlasio, Rayne M., Niyazov, Juliana, Zucker, Amanda, Karchin, Rachel, Kinzler, Kenneth W., Iacobuzio-Donahue, Christine A., Vogelstein, Bert, and Nowak, Martin A.

Published
2018

38. Detection and localization of surgically resectable cancers with a multi-analyte blood test

Author

Cohen, Joshua D., Li, Lu, Wang, Yuxuan, Thoburn, Christopher, Afsari, Bahman, Danilova, Ludmila, Douville, Christopher, Javed, Ammar A., Wong, Fay, Mattox, Austin, Hruban, Ralph. H., Wolfgang, Christopher L., Goggins, Michael G., Dal Molin, Marco, Wang, Tian-Li, Roden, Richard, Klein, Alison P., Ptak, Janine, Dobbyn, Lisa, Schaefer, Joy, Silliman, Natalie, Popoli, Maria, Vogelstein, Joshua T., Browne, James D., Schoen, Robert E., Brand, Randall E., Tie, Jeanne, Gibbs, Peter, Wong, Hui-Li, Mansfield, Aaron S., Jen, Jin, Hanash, Samir M., Falconi, Massimo, Allen, Peter J., Zhou, Shibin, Bettegowda, Chetan, Diaz, Luis A., Tomasetti, Cristian, Kinzler, Kenneth W., Vogelstein, Bert, Lennon, Anne Marie, and Papadopoulos, Nickolas

Published
2018

40. Genetic progression and the waiting time to cancer

Author

Beerenwinkel, Niko, Antal, Tibor, Dingli, David, Traulsen, Arne, Kinzler, Kenneth W., Velculescu, Victor E., Vogelstein, Bert, and Nowak, Martin A.

Subjects
Quantitative Biology - Populations and Evolution, Quantitative Biology - Quantitative Methods
Abstract

Cancer results from genetic alterations that disturb the normal cooperative behavior of cells. Recent high-throughput genomic studies of cancer cells have shown that the mutational landscape of cancer is complex and that individual cancers may evolve through mutations in as many as 20 different cancer-associated genes. We use data published by Sjoblom et al. (2006) to develop a new mathematical model for the somatic evolution of colorectal cancers. We employ the Wright-Fisher process for exploring the basic parameters of this evolutionary process and derive an analytical approximation for the expected waiting time to the cancer phenotype. Our results highlight the relative importance of selection over both the size of the cell population at risk and the mutation rate. The model predicts that the observed genetic diversity of cancer genomes can arise under a normal mutation rate if the average selective advantage per mutation is on the order of 1%. Increased mutation rates due to genetic instability would allow even smaller selective advantages during tumorigenesis. The complexity of cancer progression thus can be understood as the result of multiple sequential mutations, each of which has a relatively small but positive effect on net cell growth., Comment: Details available as supplementary material at http://www.people.fas.harvard.edu/~antal/publications.html

Published
2007
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48. A Survey of Homozygous Deletions in Human Cancer Genomes

Author

Cox, Charles, Bignell, Graham, Greenman, Chris, Stabenau, Arne, Warren, William, Stephens, Philip, Davies, Helen, Watt, Stephen, Teague, Jon, Edkins, Sara, Birney, Ewan, Easton, Douglas F., Wooster, Richard, Futreal, P. Andrew, Stratton, Michael R., and Vogelstein, Bert

Published
2005

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