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1. Segmentation of human functional tissue units in support of a Human Reference Atlas

Author

Yashvardhan Jain, Leah L. Godwin, Yingnan Ju, Naveksha Sood, Ellen M. Quardokus, Andreas Bueckle, Teri Longacre, Aaron Horning, Yiing Lin, Edward D. Esplin, John W. Hickey, Michael P. Snyder, Nathan Heath Patterson, Jeffrey M. Spraggins, and Katy Börner

Subjects
Biology (General), QH301-705.5
Abstract

Abstract The Human BioMolecular Atlas Program (HuBMAP) aims to compile a Human Reference Atlas (HRA) for the healthy adult body at the cellular level. Functional tissue units (FTUs), relevant for HRA construction, are of pathobiological significance. Manual segmentation of FTUs does not scale; highly accurate and performant, open-source machine-learning algorithms are needed. We designed and hosted a Kaggle competition that focused on development of such algorithms and 1200 teams from 60 countries participated. We present the competition outcomes and an expanded analysis of the winning algorithms on additional kidney and colon tissue data, and conduct a pilot study to understand spatial location and density of FTUs across the kidney. The top algorithm from the competition, Tom, outperforms other algorithms in the expanded study, while using fewer computational resources. Tom was added to the HuBMAP infrastructure to run kidney FTU segmentation at scale—showcasing the value of Kaggle competitions for advancing research.

Published
2023
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2. Uterine Leiomyosarcoma with FN1-Anaplastic Lymphoma Kinase Fusion Responsive to Alectinib and Lorlatinib

Author

Stefano Testa, Lynn Million, Teri Longacre, and Nam Bui

Subjects
leiomyosarcoma, fn1-alk fusion, alectinib, lorlatinib, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Uterine leiomyosarcoma (LMS) is a rare malignant neoplasm of the female genital tract poorly responsive to conventional chemotherapy and radiotherapy, with an overall poor prognosis. Pazopanib is at the moment the only FDA-approved targeted molecular therapy for uterine LMS, given the exceedingly rare occurrence of actionable genetic mutations in this type of cancer. Here, we describe the first reported case of metastatic uterine LMS with an FN1-anaplastic lymphoma kinase (ALK) fusion mutation occurring in a 63-year-old woman with a history of uterine leiomyomas. The patient progressed on several lines of therapy, including conventional chemotherapy, pazopanib, and the first-generation ALK inhibitor crizotinib. Interestingly, the patient showed a remarkable 16-month response to second generation ALK inhibitors alectinib and lorlatinib. This case demonstrates that ALK inhibitors can be an effective therapeutic strategy for patients with ALK fusion-positive uterine LMS that has progressed on conventional chemotherapy.

Published
2021
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3. Prevalence of Lynch syndrome in women with mismatch repair‐deficient ovarian cancer

Author

Rachel Hodan, Kerry Kingham, Kristina Cotter, Ann K. Folkins, Allison W. Kurian, James M. Ford, and Teri Longacre

Subjects
germline, Lynch syndrome, mismatch repair, ovarian cancer, universal tumor screening, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background There are limited data on the prevalence of Lynch syndrome (LS) in women with primary ovarian cancer with mismatch repair deficiency (MMR‐D) by immunohistochemistry (IHC). Materials and Methods Three hundred and eight cases of primary ovarian, fallopian, and peritoneal cancer between January 2012 and December 2019 were evaluated for MMR‐D by IHC. The incidence of LS in this cohort was evaluated. Results MMR‐D by IHC was identified in 16 of 308 (5.2%) (95% CI: 3.2%–8.3%) primary ovarian‐related cancers. Most cases with MMR‐D were endometrioid (n = 11, 68.7%); (95% CI: 44.2%–86.1%). MSH2/MSH6 protein loss was detected in eight cases (50.0%); (95% CI: 28.0%–72.0%) and MLH1/PMS2 protein loss was detected in four cases (25.0%); (95% CI: 9.7%–50.0%). MSH6 protein loss was detected in two cases (12.5%); (95% CI: 2.2%–37.3%) and PMS2 protein loss was detected in two cases (12.5%); (95% CI: 2.2%–37.3%). All four cases with MLH1/PMS2 protein loss had MLH1 promotor hypermethylation. All 12 women with ovarian cancer suggestive of LS underwent germline testing and 8 (66.6%); (95% CI: 38.8%–86.5%) were confirmed to have LS. Conclusions Most ovarian cancers with somatic MMR‐D were confirmed to have LS in this cohort. Germline testing for LS in addition to BRCA1/2 for all women with an epithelial ovarian cancer would be efficient and would approach 100% sensitivity for identifying Lynch syndrome. Utilization of a multigene panel should also be considered, given the additional non‐Lynch germline mutation identified in this cohort.

Published
2021
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4. Ensuring remote diagnostics for pathologists: an open letter to the US Congress

Author

Jochen K. Lennerz, Liron Pantanowitz, Mitual B. Amin, Isam-Eldin Eltoum, Meera R. Hameed, Alexana N. Kalof, Elham Khanafshar, Lakshmi P. Kunju, Audrey J. Lazenby, Kathleen T. Montone, Christopher N. Otis, Michelle D. Reid, Paul N. Staats, Christa L. Whitney-Miller, Catherine S. Abendroth, Manju Aron, George G. Birdsong, Ira J. Bleiweiss, Mary P. Bronner, Jennifer Chapman, Nicole A. Cipriani, Gustavo de la Roza, Michael J. Esposito, Oluwole Fadare, Karen Ferrer, Christopher D. Fletcher, David P. Frishberg, Fernando U. Garcia, Laurette Geldenhuys, Ryan M. Gill, Dorina Gui, Shams Halat, Omar Hameed, Jason L. Hornick, Aaron R. Huber, Dhanpat Jain, Nirag Jhala, Merce Jorda, Julie M. Jorns, Jeffrey Kaplan, Mahmoud A. Khalifa, Ashraf Khan, Grace E. Kim, Eun Y. Lee, Virginia A. LiVolsi, Teri Longacre, Cristina Magi-Galluzzi, Shannon J. McCall, Laron McPhaul, Vikas Mehta, Mihai Merzianu, Stacey B. Miller, Kyle H. Molberg, Andre L. Moreira, Bita V. Naini, Vania Nosé, Kathleen O’Toole, Maria Picken, Victor G. Prieto, James M. Pullman, Charles M. Quick, Jordan P. Reynolds, Andrew E. Rosenberg, Stuart J. Schnitt, Mary R. Schwartz, Marin Sekosan, Michael T. Smith, Aliyah Sohani, Anne Stowman, Vijay K. Vanguri, Beverly Wang, John C. Watts, Shi Wei, Kathleen Whitney, Mamoun Younes, Sui Zee, and Erika R. Bracamonte

Subjects
General Medicine, General Biochemistry, Genetics and Molecular Biology
Published
2022
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5. Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer

Author

Winston R. Becker, Stephanie A. Nevins, Derek C. Chen, Roxanne Chiu, Aaron M. Horning, Tuhin K. Guha, Rozelle Laquindanum, Meredith Mills, Hassan Chaib, Uri Ladabaum, Teri Longacre, Jeanne Shen, Edward D. Esplin, Anshul Kundaje, James M. Ford, Christina Curtis, Michael P. Snyder, and William J. Greenleaf

Subjects
Genetics
Abstract

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of pre-cancer-associated fibroblasts. In the cancerous state, we observe T cell exhaustion, RUNX1-regulated cancer-associated fibroblasts and increasing accessibility associated with HNF4A motifs in epithelia. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.

Published
2022
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6. Gastrointestinal stromal tumors (GISTs) arising in uncommon locations: clinicopathologic features and risk assessment of esophageal, colonic, and appendiceal GISTs

Author

Shaomin Hu, Lindsay Alpert, Justin M.M. Cates, Raul S. Gonzalez, Rondell Graham, John R. Goldblum, Ahmed Bakhshwin, Sindhu Shetty, Hanlin L. Wang, Trang Lollie, Changqing Ma, Ayesha Siddique, Dipti M. Karamchandani, Fengming Chen, Rhonda K. Yantiss, Erika Hissong, Deyali Chatterjee, Shefali Chopra, Wei Chen, Jennifer Vazzano, Wei-Lien Wang, Di Ai, Jingmei Lin, Lan Zheng, Jessica L. Davis, Brian Brinkerhoff, Amanda Breitbarth, Michelle Yang, Sepideh Madahian, Nicole Panarelli, Kevin Kuan, Jonathan Pomper, Teri Longacre, Shyam Raghavan, Joseph Misdraji, Min Cui, Zhaohai Yang, Deepika Savant, Noam Harpaz, Xiuxu Chen, Murray Resnick, Elizabeth Yiru Wu, David Klimstra, Jinru Shia, Monika Vyas, Sanjay Kakar, Won-Tak Choi, Marie E. Robert, Hongjie Li, Michael Lee, Ian Clark, Yongchao Li, Wenqing Cao, Qing Chang, Mary P. Bronner, Zachary Dong, Wei Zhang, Darya Buehler, Paul E. Swanson, Jose G. Mantilla, Andrew M. Bellizzi, Michael Feely, Harry S. Cooper, Rajeswari Nagarathinam, Rish Pai, Suntrea Hammer, Mojgan Hosseini, JingJing Hu, Maria Westerhoff, Jerome Cheng, Diana Agostini-Vulaj, Gregory Lauwers, Masoumeh Ghayouri, Maryam K. Pezhouh, Jianying Zeng, Rong Xia, Feng Yin, Tao Zhang, Zu-hua Gao, Nadine Demko, Hannah H. Chen, Sanhong Yu, and John Hart

Subjects
Pathology, medicine.medical_specialty, Abdominal pain, GiST, business.industry, Stomach, Rectum, Cell morphology, medicine.disease, digestive system diseases, Appendix, Pathology and Forensic Medicine, medicine.anatomical_structure, medicine, Gastrointestinal stromal tumors (GISTs), Esophagus, medicine.symptom, business, neoplasms
Abstract

Risk stratification of gastrointestinal stromal tumors (GISTs) is based on experience with tumors of the stomach, small bowel, and rectum, which are far more common than GISTs of other sites. In this study from 47 institutions, we analyzed GISTs of the esophagus (n = 102), colon (n = 136), and appendix (n = 27) for their size, mitotic rate, morphology, and outcome to determine which criteria predict their behavior. Esophageal GISTs were small (median: 2.5 cm) with spindle cell morphology and a low mitotic rate (mean: 3.6/5 mm2). Twelve (12%) tumors progressed, including 11 with a mitotic rate >5/5 mm2 and one large (6.8 cm) GIST with a mitotic rate of 2/5 mm2. Colonic GISTs were smaller (median: 1.4 cm) and presented with abdominal pain or bleeding in 29% of cases. Most (92%) were composed of spindle cells with a mean mitotic rate of 4.6/5 mm2. Sixteen (12%) tumors progressed: 14 had mitotic rates >5/5 mm2, and two were >5.0 cm with a mitotic rate 5/5 mm2) and size >5.0 cm. These findings support the use of size and mitotic rate for prognostication of GISTs in these locations, similar to tumors of the stomach, small bowel, and rectum.

Published
2022
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7. Percent Agreement Between Immunohistochemistry and Next-Generation Sequencing in Testing Patients for Mismatch Repair Deficiency

Author

Lauren, Lawrence, Teri, Longacre, Atif, Saleem, and Christian, Kunder

Subjects
Histology, Brain Neoplasms, High-Throughput Nucleotide Sequencing, DNA Mismatch Repair, Immunohistochemistry, Pathology and Forensic Medicine, Medical Laboratory Technology, MutS Homolog 2 Protein, Neoplastic Syndromes, Hereditary, Humans, Female, Colorectal Neoplasms, MutL Protein Homolog 1, Mismatch Repair Endonuclease PMS2, Retrospective Studies
Abstract

The presence of mismatch repair deficiency is frequently assessed in gastrointestinal and gynecologic neoplasms by surgical pathologists using immunohistochemical methods. Targeted next-generation sequencing (NGS) covering some genes in the mismatch repair complex is used with increasing frequency, however, the percent positive and negative agreement of immunohistochemical methods and NGS of mismatch repair genes is not well-described in the literature. We sought to compare performance of immunohistochemistry (IHC) and NGS of mismatch repair genes on our institutional targeted panel. We evaluated the concordance of immunohistochemical and panel-based gene sequencing methods in a retrospective cohort study of patients evaluated at our center with both immunohistochemical and panel-based sequencing. Our NGS panel covers only MLH1 and MSH2, whereas our immunohistochemical panel assesses for expression of MLH1, PMS2, MSH2, and MSH6. We identified 68 unique patients with both immunohistochemical evaluation of mismatch repair protein expression and NGS panel sequencing, of which 67 were suitable for analysis given the patterns of immunohistochemical loss of expression observed. The percent positive agreement for NGS with IHC was 50%, albeit with very rare positive cases (n=2/4). Percent negative agreement was also high at 100% (n=63/63). One case with loss of MLH1, PMS2, and MSH6 expression by IHC and no pathogenic variants by NGS exhibited MLH1 promoter hypermethylation. Percent negative agreement between immunohistochemical and NGS gene sequencing is high, although firm conclusions regarding percent positive agreement between NGS and IHC are limited by low numbers of positive cases in our cohort. In general, we consider the findings to support continued use of immunohistochemical methods to screen for the presence of mismatch repair deficiency and consider additional testing by NGS likely to add little diagnostic value in the context of intact immunohistochemical expression of mismatch repair proteins.

Published
2022
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8. Global loss of fine-scale chromatin architecture and rebalancing of gene expression during early colorectal cancer development

Author

Yizhou Zhu, Hayan Lee, Annika K. Weimer, Aaron Horning, Stephanie A. Nevins, Edward D. Esplin, Kristina Paul, Gat Krieger, Zohar Shipony, Meredith Mills, Rozelle Laquindanum, Uri Ladabaum, Roxanne Chiu, Teri Longacre, Jeanne Shen, Ariel Jaimovich, Doron Lipson, Anshul Kundaje, William J. Greenleaf, Christina Curtis, James M. Ford, and Michael P. Snyder

Abstract

Although 3D genome architecture is essential for long-range gene regulation, the significance of distal regulatory chromatin contacts is challenged by recent findings of low correlation between contact propensity and gene expression. To better understand the role of long-range interactions between distal regulatory elements during the early transformation from healthy colon to colorectal cancer, here we performed high resolution chromatin conformation capture for 33 samples including non-neoplastic mucosa, adenomatous polyps and adenocarcinomas, mostly from Familial Adenomatous Polyposis (FAP) patients. We identified hundreds of thousands of chromatin micro-structures, such as architectural stripes and loops, which originated from active cis-regulatory elements. Surprisingly, these structures progressively decayed throughout cancer progression, particularly at promoters. Meta-analyses revealed that this decay was independent of alterations in DNA methylation and chromatin accessibility. Interestingly, the degree of interaction loss was poorly correlated with gene expression changes. Instead, genes whose expression were disproportionately lower and higher than their relative promoter interaction in mucosa shifted their expression in polyps and adenocarcinomas to yield a more direct relationship between strength of interaction and gene expression. Our work provides the first high resolution 3D conformation maps during early cancer formation and progression, and provides novel insights into transcriptional readouts associated with fine-scale chromatin conformation alterations.

Published
2022
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9. The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution

Author

Orit Rozenblatt-Rosen, Aviv Regev, Philipp Oberdoerffer, Tal Nawy, Anna Hupalowska, Jennifer E. Rood, Orr Ashenberg, Ethan Cerami, Robert J. Coffey, Emek Demir, Li Ding, Edward D. Esplin, James M. Ford, Jeremy Goecks, Sharmistha Ghosh, Joe W. Gray, Justin Guinney, Sean E. Hanlon, Shannon K. Hughes, E. Shelley Hwang, Christine A. Iacobuzio-Donahue, Judit Jané-Valbuena, Bruce E. Johnson, Ken S. Lau, Tracy Lively, Sarah A. Mazzilli, Dana Pe’er, Sandro Santagata, Alex K. Shalek, Denis Schapiro, Michael P. Snyder, Peter K. Sorger, Avrum E. Spira, Sudhir Srivastava, Kai Tan, Robert B. West, Elizabeth H. Williams, Denise Aberle, Samuel I. Achilefu, Foluso O. Ademuyiwa, Andrew C. Adey, Rebecca L. Aft, Rachana Agarwal, Ruben A. Aguilar, Fatemeh Alikarami, Viola Allaj, Christopher Amos, Robert A. Anders, Michael R. Angelo, Kristen Anton, Jon C. Aster, Ozgun Babur, Amir Bahmani, Akshay Balsubramani, David Barrett, Jennifer Beane, Diane E. Bender, Kathrin Bernt, Lynne Berry, Courtney B. Betts, Julie Bletz, Katie Blise, Adrienne Boire, Genevieve Boland, Alexander Borowsky, Kristopher Bosse, Matthew Bott, Ed Boyden, James Brooks, Raphael Bueno, Erik A. Burlingame, Qiuyin Cai, Joshua Campbell, Wagma Caravan, Hassan Chaib, Joseph M. Chan, Young Hwan Chang, Deyali Chatterjee, Ojasvi Chaudhary, Alyce A. Chen, Bob Chen, Changya Chen, Chia-hui Chen, Feng Chen, Yu-An Chen, Milan G. Chheda, Koei Chin, Roxanne Chiu, Shih-Kai Chu, Rodrigo Chuaqui, Jaeyoung Chun, Luis Cisneros, Graham A. Colditz, Kristina Cole, Natalie Collins, Kevin Contrepois, Lisa M. Coussens, Allison L. Creason, Daniel Crichton, Christina Curtis, Tanja Davidsen, Sherri R. Davies, Ino de Bruijn, Laura Dellostritto, Angelo De Marzo, David G. DeNardo, Dinh Diep, Sharon Diskin, Xengie Doan, Julia Drewes, Stephen Dubinett, Michael Dyer, Jacklynn Egger, Jennifer Eng, Barbara Engelhardt, Graham Erwin, Laura Esserman, Alex Felmeister, Heidi S. Feiler, Ryan C. Fields, Stephen Fisher, Keith Flaherty, Jennifer Flournoy, Angelo Fortunato, Allison Frangieh, Jennifer L. Frye, Robert S. Fulton, Danielle Galipeau, Siting Gan, Jianjiong Gao, Long Gao, Peng Gao, Vianne R. Gao, Tim Geiger, Ajit George, Gad Getz, Marios Giannakis, David L. Gibbs, William E. Gillanders, Simon P. Goedegebuure, Alanna Gould, Kate Gowers, William Greenleaf, Jeremy Gresham, Jennifer L. Guerriero, Tuhin K. Guha, Alexander R. Guimaraes, David Gutman, Nir Hacohen, Sean Hanlon, Casey R. Hansen, Olivier Harismendy, Kathleen A. Harris, Aaron Hata, Akimasa Hayashi, Cody Heiser, Karla Helvie, John M. Herndon, Gilliam Hirst, Frank Hodi, Travis Hollmann, Aaron Horning, James J. Hsieh, Shannon Hughes, Won Jae Huh, Stephen Hunger, Shelley E. Hwang, Heba Ijaz, Benjamin Izar, Connor A. Jacobson, Samuel Janes, Reyka G. Jayasinghe, Lihua Jiang, Brett E. Johnson, Bruce Johnson, Tao Ju, Humam Kadara, Klaus Kaestner, Jacob Kagan, Lukas Kalinke, Robert Keith, Aziz Khan, Warren Kibbe, Albert H. Kim, Erika Kim, Junhyong Kim, Annette Kolodzie, Mateusz Kopytra, Eran Kotler, Robert Krueger, Kostyantyn Krysan, Anshul Kundaje, Uri Ladabaum, Blue B. Lake, Huy Lam, Rozelle Laquindanum, Ashley M. Laughney, Hayan Lee, Marc Lenburg, Carina Leonard, Ignaty Leshchiner, Rochelle Levy, Jerry Li, Christine G. Lian, Kian-Huat Lim, Jia-Ren Lin, Yiyun Lin, Qi Liu, Ruiyang Liu, William J.R. Longabaugh, Teri Longacre, Cynthia X. Ma, Mary Catherine Macedonia, Tyler Madison, Christopher A. Maher, Anirban Maitra, Netta Makinen, Danika Makowski, Carlo Maley, Zoltan Maliga, Diego Mallo, John Maris, Nick Markham, Jeffrey Marks, Daniel Martinez, Robert J. Mashl, Ignas Masilionais, Jennifer Mason, Joan Massagué, Pierre Massion, Marissa Mattar, Richard Mazurchuk, Linas Mazutis, Eliot T. McKinley, Joshua F. McMichael, Daniel Merrick, Matthew Meyerson, Julia R. Miessner, Gordon B. Mills, Meredith Mills, Suman B. Mondal, Motomi Mori, Yuriko Mori, Elizabeth Moses, Yael Mosse, Jeremy L. Muhlich, George F. Murphy, Nicholas E. Navin, Michel Nederlof, Reid Ness, Stephanie Nevins, Milen Nikolov, Ajit Johnson Nirmal, Garry Nolan, Edward Novikov, Brendan O’Connell, Michael Offin, Stephen T. Oh, Anastasiya Olson, Alex Ooms, Miguel Ossandon, Kouros Owzar, Swapnil Parmar, Tasleema Patel, Gary J. Patti, Itsik Pe'er, Tao Peng, Daniel Persson, Marvin Petty, Hanspeter Pfister, Kornelia Polyak, Kamyar Pourfarhangi, Sidharth V. Puram, Qi Qiu, Álvaro Quintanal-Villalonga, Arjun Raj, Marisol Ramirez-Solano, Rumana Rashid, Ashley N. Reeb, Mary Reid, Adam Resnick, Sheila M. Reynolds, Jessica L. Riesterer, Scott Rodig, Joseph T. Roland, Sonia Rosenfield, Asaf Rotem, Sudipta Roy, Charles M. Rudin, Marc D. Ryser, Maria Santi-Vicini, Kazuhito Sato, Deborah Schrag, Nikolaus Schultz, Cynthia L. Sears, Rosalie C. Sears, Subrata Sen, Triparna Sen, Alex Shalek, Jeff Sheng, Quanhu Sheng, Kooresh I. Shoghi, Martha J. Shrubsole, Yu Shyr, Alexander B. Sibley, Kiara Siex, Alan J. Simmons, Dinah S. Singer, Shamilene Sivagnanam, Michal Slyper, Artem Sokolov, Sheng-Kwei Song, Austin Southard-Smith, Avrum Spira, Janet Stein, Phillip Storm, Elizabeth Stover, Siri H. Strand, Timothy Su, Damir Sudar, Ryan Sullivan, Lea Surrey, Mario Suvà, Nadezhda V. Terekhanova, Luke Ternes, Lisa Thammavong, Guillaume Thibault, George V. Thomas, Vésteinn Thorsson, Ellen Todres, Linh Tran, Madison Tyler, Yasin Uzun, Anil Vachani, Eliezer Van Allen, Simon Vandekar, Deborah J. Veis, Sébastien Vigneau, Arastoo Vossough, Angela Waanders, Nikhil Wagle, Liang-Bo Wang, Michael C. Wendl, Robert West, Chi-yun Wu, Hao Wu, Hung-Yi Wu, Matthew A. Wyczalkowski, Yubin Xie, Xiaolu Yang, Clarence Yapp, Wenbao Yu, Yinyin Yuan, Dadong Zhang, Kun Zhang, Mianlei Zhang, Nancy Zhang, Yantian Zhang, Yanyan Zhao, Daniel Cui Zhou, Zilu Zhou, Houxiang Zhu, Qin Zhu, Xiangzhu Zhu, Yuankun Zhu, and Xiaowei Zhuang

Subjects
Cell, Genomics, Computational biology, Tumor initiation, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Metastasis, 03 medical and health sciences, Atlases as Topic, 0302 clinical medicine, Neoplasms, Tumor Microenvironment, medicine, Humans, Precision Medicine, 030304 developmental biology, 0303 health sciences, Atlas (topology), Cancer, medicine.disease, 3. Good health, Human tumor, Cell Transformation, Neoplastic, medicine.anatomical_structure, Single-Cell Analysis, Single point, 030217 neurology & neurosurgery
Abstract

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous large-scale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.

Published
2020
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10. Robust and generalizable segmentation of human functional tissue units

Author

Leah L. Godwin, Yingnan Ju, Naveksha Sood, Yashvardhan Jain, Ellen M. Quardokus, Andreas Bueckle, Teri Longacre, Aaron Horning, Yiing Lin, Edward D. Esplin, John W. Hickey, Michael P. Snyder, N. Heath Patterson, Jeffrey M. Spraggins, and Katy Börner

Abstract

The Human BioMolecular Atlas Program aims to compile a reference atlas for the healthy human adult body at the cellular level. Functional tissue units (FTU, e.g., renal glomeruli and colonic crypts) are of pathobiological significance and relevant for modeling and understanding disease progression. Yet, annotation of FTUs is time consuming and expensive when done manually and existing algorithms achieve low accuracy and do not generalize well. This paper compares the five winning algorithms from the “Hacking the Kidney” Kaggle competition to which more than a thousand teams from sixty countries contributed. We compare the accuracy and performance of the algorithms on a large-scale renal glomerulus Periodic acid-Schiff stain dataset and their generalizability to a colonic crypts hematoxylin and eosin stain dataset. Results help to characterize how the number of FTUs per unit area differs in relationship to their position in kidney and colon with respect to age, sex, body mass index (BMI), and other clinical data and are relevant for advancing pathology, anatomy, and surgery.

Published
2021
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11. Single-cell analyses define a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer

Author

Winston R, Becker, Stephanie A, Nevins, Derek C, Chen, Roxanne, Chiu, Aaron M, Horning, Tuhin K, Guha, Rozelle, Laquindanum, Meredith, Mills, Hassan, Chaib, Uri, Ladabaum, Teri, Longacre, Jeanne, Shen, Edward D, Esplin, Anshul, Kundaje, James M, Ford, Christina, Curtis, Michael P, Snyder, and William J, Greenleaf

Subjects
Adenoma, Cell Transformation, Neoplastic, Humans, DNA Methylation, Single-Cell Analysis, Colorectal Neoplasms
Abstract

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of pre-cancer-associated fibroblasts. In the cancerous state, we observe T cell exhaustion, RUNX1-regulated cancer-associated fibroblasts and increasing accessibility associated with HNF4A motifs in epithelia. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.

Published
2021

12. Pathology of Uterine Sarcomas

Author

Michael Hendrickson, Teri Longacre, and Richard Kempson

Subjects
Steroid hormone, medicine.medical_specialty, Endocrinology, business.industry, Endometrial cancer, medicine.medical_treatment, Internal medicine, Medicine, Normal endometrium, business, medicine.disease, Receptor
Published
2004
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