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Development of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization. Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles, and NCI-MATCH arms. Compared with human tumors, PDXs typically have higher purity and fit to investigate dynamic driver events and molecular properties via multiple time points from same case PDXs. Here, we report on dynamic genomic landscapes and pharmacogenomic associations, including associations between activating oncogenic events and drugs, correlations between whole-genome duplications and subclone events, and the potential PDX models for NCI-MATCH trials. Lastly, we provide a web portal having comprehensive pan-cancer PDX genomic profiles and source code to facilitate identification of more druggable events and further insights into PDXs’ recapitulation of human tumors., Patient-derived xenograft models (PDX) have been extensively used to study the molecular and clinical features of cancers. Here the authors present a cohort of 536 PDX models from 25 cancers, as well as their genomic and evolutionary profiles and their suitability for clinical trials.

Summary Understanding the impact of elevated CO2 (eCO2) in global agriculture is important given climate change projections. Breeding climate‐resilient crops depends on genetic variation within naturally varying populations. The effect of genetic variation in response to eCO2 is poorly understood, especially in crop species. We describe the different ways in which Solanum lycopersicum and its wild relative S. pennellii respond to eCO2, from cell anatomy, to the transcriptome, and metabolome. We further validate the importance of translational regulation as a potential mechanism for plants to adaptively respond to rising levels of atmospheric CO2., Significance Statement In a domesticated and a wild Solanum species, translational and transcriptional regulation feedback onto each other and show interspecific differences in response to elevated CO2.

Gastric cancer (GC) disproportionally affects people of Latino ancestry and represent a leading cause of incidence and mortality disparities in this minority populations. When compared to Non-Latino Whites, Latinos are ~2-fold more likely to be diagnosed with and to die of GC. The goal of our research program is to contribute to GC research in patients of Latino ancestry and advance cancer health disparity research. One of the research projects aims at identifying germline variants associated with GC risk. To do so, we are identifying novel gastric cancer genes and detecting mutations in previously reported GC genes, using whole-exome sequencing, in 500 patients who have been diagnosed with early-onset GC and/or who had GC and family history of cancer. Whole exome sequence data collection was recently completed and is being analyzed with the primary goals of estimating the prevalence and penetrance in known cancer genes as well as the identification of new GC genes. Using in-house exome data and publicly available genetic data, we will identify variants with predicted impact in the phenotype to design a panel that will be used for their detection in gastric preneoplasia biopsies. These variants will be tested using duplex sequencing, a highly sensitive method that can detect very rare mutations with ultra-depth sequencing. We will then select the variants with likely functional consequences for tumor initiation and/or progression to generate isogenic gastric organoids to investigate their effect in proliferation, differentiation, and gene expression. We aim to generate a body of work that can be used for risk assessment, prevention, early diagnostic, and that will lead to better outcomes for GC in this important U.S. minority. Dr. Ana Estrada-Florez is the recipient of the AACR Cancer Health Disparities Fellowship. Citation Format: Ana Patricia Estrada-Florez, Paul Lott, Ted Toal, Nicole Halmai, Elizabeth Quino, Alma Poceros-Coba, Alix Guevara, Fabian Castro, Jhon Suarez, John Mcpherson, Rasika Venkatesh, Hongyong Zhang, Apri Vang, Guadalupe Polanco, Joana Guerra, Graciela Molina, Carol Parra, Adriana Della Valle, Esteban Castelao, Manuel Teixeira, Mabel Bohorquez, Javier Torres, Alejandro Carvajal Corvalan, Luis G. Carvajal-Carmona. Identification of predisposition and progression gastric cancer biomarkers in Latinos [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2274.

Arsenic contamination in drinking water is one of the major health issues worldwide. Over 140 million people from 50+ countries are exposed to drinking water containing arsenic at levels above “safe” levels of 10 μg/L. Several studies indicate that chronic arsenic exposure is associated with the development of carcinogenic changes in the lungs, bladder, liver, and skin and other potential health problems. In this project, we aim to characterize bladder cancer mutational signatures and somatic mutations in a cohort of bladder cancer patients known to have been highly exposed to arsenic in northern Chile by using whole-exome sequencing (WES). We analyzed WES data and identified somatic mutations and mutational signatures using Mutec2 and SigProfiler. Preliminary analyses from a small number of exposed patients identified two mutational signatures, previously described as having “unknown” etiology, that showed an association with arsenic exposure. We are currently validating these findings in additional samples and with functional studies. Alma Poceros-Coba Ph.D. Candidate is the recipient of the Conacyt-UC-MEXUS Doctoral Fellowship and is the recipient of the UCDCCC Travel Award. Citation Format: Alma A. Poceros-Coba, Ana Estrada-Florez, Ted Toal, Paul Lott, Macarena Garrido, Craig Steinmaus, Catterina Ferrecio R., Luis Carvajal-Carmona. Elucidating arsenic dependent carcinogenesis in humans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 229.

Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. While overall incidence and mortality rates have dropped in recent decades, GC remains a significant health disparity in Hispanic/Latino Americans (HLAs) and in Asian Americans, Native Hawaiians and Pacific Islanders (AANHPIs), who are twice as likely to be diagnosed with and die from GC compared to non-Hispanic whites. In the U.S, these two groups represent the largest and fastest growing minority populations, respectively. Despite such high minority cancer burden, currently there are few FDA-approved targeted therapies for GC, in contrast to dozens of approved targeted therapies for breast, lung, colon, and prostate cancers. The low numbers of GC targeted therapies can be partially explained by limited availability of race/ethnic appropriate cancer genome data and of minority patient-derived models, limiting target identification and drug efficacy studies. Filling these research gaps is crucially important to improve cancer health disparities. Our group has spearheaded the development of the University of California Minority Patient-Derived Xenograft Development and Trial Center (UCaMP) with the goal of addressing these critical issues for GC patient care. In our initial efforts, we have successfully established both patient-derived xenograft (PDX) and organoid (PDO) models for 10 minority GC patient samples. Our PDX and PDO models recapitulate the tumor heterogeneity observed in the patient samples, but also demonstrate varying levels of clonal evolution upon increased time in culture. Importantly, when we performed whole exome, RNA and DNA methylation sequencing on patient tumor and model sample sets, we observe high prevalence of cell cycle regulation/cyclin-dependent kinase (CDK) and PI3K/AKT/mTOR pathway alterations. This is significant, as the FDA has already approved several CDK inhibitors and PI3K/AKT/mTOR inhibitors for other cancer types and even more have shown promise in clinical trials. Indeed, when treat our patient-derived models with these inhibitors, we observe significant responses both in vitro and in vivo. Our findings highlight an important molecular distinction of GC development in racial/ethnic U.S. minorities that provides a rationale for alternative treatments to address GC health disparities that plague these groups and help bring the field closer to precision cancer medicine. Citation Format: Nicole B. Coggins, Hongyong Zhang, Paul Lott, Ana Estrada-Florez, Ted Toal, Alexa Morales Arana, Guadalupe Carvajal, Amanda Kirane, May Cho, Javier Torres, Elizabeth Quino, Sienna Rocha, Rasika Venkatesh, Luis Carvajal-Carmona. Identifying clinically relevant molecular distinctions in gastric cancer development among US minorities to address cancer health disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2972.

The goal of this study was to examine gastric (stomach) cancer mutational intratumoral heterogeneity (ITH) in Latinos using multiregion sequencing (MSEQ). Gastric cancer is the 2nd leading cause of cancer-related death worldwide. It is diagnosed in 25,000 Americans each year, with Latinos twice as likely to succumb as Whites. Treatment is currently limited to a few molecularly guided therapies, but TCGA data show that 70% of GC patients have a mutation in a gene targetable with existing drugs. Significant ITH has been identified in a variety of tumor types to date, although a GC study has yet to be published. ITH is an important consideration for personalized therapy. Driver gene mutations are frequently found to be nonclonal, a crucial factor when assessing effective druggability. In this study, two to five tumor biopsies and adjacent normal tissue were obtained from 33 Latino patients, totaling 120 tumor (T) biopsies and 33 normal (N) samples. DNA was extracted from the tissues and the coding regions of 762 cancer-related genes were sequenced using Agilent target enrichment and Illumina sequencing. For each biopsy, estimates were made of sample purity and ploidy, somatic mutations were called using joint analysis of all T and N sequence data for each patient, cancer cell fraction (CCF) was estimated for each mutation, and copy number variation (CNV) was called across the genome. Somatic mutations and copy number changes were analyzed for clonality in each patient. We found a high degree of heterogeneity, both intratumoral and interpatient, with the fraction of functional somatic mutations that are clonal ranging from 0 to 68%, the fraction private to one biopsy ranging from 32% to 100%, and the fraction shared between multiple but not all biopsies ranging from 0 to 42%. For 10 of the 33 samples there was at least one gene, containing a clonal functional mutation, for which there is an FDA-approved targeted therapy. In summary, our study is the first to assess ITH in GC. Our results are important to understand the genetic diversity and clonal architecture of these tumors and to improve molecular diagnostics. This abstract is also being presented as Poster D107. Citation Format: Ted Toal, Guadalupe P. Echeverry, Ruta Sahasrabudhe, Mabel Bohorquez, Javier Torres, Shiro Urayama, Amanda Kirane, Magdalena Echeverry, Luis G. Carvajal Carmona. Intratumoral heterogeneity in Latino gastric adenocarcinomas [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr PR15.

Gastric cancer (GC) is the 2nd leading cause of cancer-related death worldwide, with a five-year survival rate lower than 30%. GC is diagnosed in 25,000 Americans each year, with Latinos twice as likely to succumb compared to non-Hispanic whites. Treatment is currently limited to only two molecularly guided therapies. The Cancer Genome Atlas (TCGA) data show that 70% of GC patients have a mutation in a gene targetable with existing drugs. Significant spatial mutational intratumoral heterogeneity (ITH) has been identified in a variety of tumor types to date, although a GC ITH study has yet to be investigated. ITH is an important consideration for personalized therapy. Driver gene mutations are frequently found to be nonclonal, a crucial factor when assessing effective druggability. The goal of the present study was to examine GC ITH in Latino GC patients using targeted multiregional sequencing (MSEQ). Two to five biopsies from different tumor regions and adjacent normal tissue were obtained from 34 GC patients; DNA was extracted from the tumor and the normal tissues and the coding regions of 783 cancer genes were sequenced using Agilent enrichment and Illumina sequencing. Somatic mutations were called in each tumor sample, using joint analysis of all samples for each patient. Tumor cell fractions were estimated for each mutation in each sample, and phylogenetic trees were made for visualize each patient's somatic mutational patterns. We found a high degree of ITH, both intratumoral and interpatient, with the fraction of functional somatic mutations that are clonal ranging from 0 to 52%, the fraction private to one tumor sample ranging from 48% to 94%, and the fraction shared between multiple but not all samples ranging from 0 to 21%. There was at least one known drug interaction with a gene containing a clonal functional mutation for 11 of the 16 samples, and in 6 samples there were two or more known drug interactions. Our study is the first one to assess ITH in GC, and our results are important to understand the clonal architecture of these GCs and to improve molecular diagnostics. Citation Format: Ted Toal, Guadalupe M. Polanco-Echevery, Ruta Sahasrabudhe, Ana Estrada, Mabel Bohorquez, Magdalena Echeverry, Javier Torres, Luis G. Carvajal-Carmona. Gastric tumors from Latino patients show extensive intratumor heterogeneity [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr C030.

Regulation of plant root angle is critical for obtaining nutrients and water and is an important trait for plant breeding. A plant’s final, long-term root angle is the net result of a complex series of decisions made by a root tip in response to changes in nutrient availability, impediments, the gravity vector and other stimuli. When a root tip is displaced from the gravity vector, the short-term process of gravitropism results in rapid reorientation of the root toward the vertical. Here, we explore both short- and long-term regulation of root growth angle, using natural variation in tomato to identify shared and separate genetic features of the two responses. Mapping of expression quantitative trait loci mapping and leveraging natural variation between and within species including Arabidopsis suggest a role for PURPLE ACID PHOSPHATASE 27 and CELL DIVISION CYCLE 73 in determining root angle.

In Arabidopsis, DNA damage-induced programmed cell death is limited to the meristematic stem cell niche and its early descendants. The significance of this cell-type-specific programmed cell death is unclear. Here, we demonstrate in roots that it is the programmed destruction of the mitotically compromised stem cell niche that triggers its regeneration, enabling growth recovery. In contrast to wild-type plants, sog1 plants, which are defective in damage-induced programmed cell death, maintain the cell identities and stereotypical structure of the stem cell niche after irradiation, but these cells fail to undergo cell division, terminating root growth. We propose DNA damage-induced programmed cell death is employed by plants as a developmental response, contrasting with its role as an anticarcinogenic response in animals. This role in plants may have evolved to restore the growth of embryos after the accumulation of DNA damage in seeds.

While the Arabidopsis (Arabidopsis thaliana) root has been elegantly characterized with respect to specification of cell identity, its development is missing a number of cellular features present in other species. We have characterized the root development of a wild and a domesticated tomato species, Solanum pennellii and Solanum lycopersicum ‘M82.’ We found extensive differences between these species for root morphology and cellular development including root length, a novel gravity set point angle, differences in cortical cell layer patterning, stem cell niche structure, and radial cell division. Using an introgression line population between these two species, we identified numerous loci that regulate these distinct aspects of development. Specifically we comprehensively identified loci that regulate (1) root length by distinct mechanisms including regulation of cell production within the meristem and the balance between cell division and expansion, (2) the gravity set point angle, and (3) radial cell division or expansion either in specific cell types or generally across multiple cell types. Our findings provide a novel perspective on the regulation of root growth and development between species. These loci have exciting implications with respect to regulation of drought resistance or salinity tolerance and regulation of root development in a family that has undergone domestication.

© 2016 American Society of Plant Biologists. All Rights Reserved. Genetic markers are essential when developing or working with genetically variable populations. Indel Group in Genomes (IGG) markers are primer pairs that amplify single-locus sequences that differ in size for two or more alleles. They are attractive for their ease of use for rapid genotyping and their codominant nature. Here, we describe a heuristic algorithm that uses a k-merbased approach to search two or more genome sequences to locate polymorphic regions suitable for designing candidate IGG marker primers. As input to the IGG pipeline software, the user provides genome sequences and the desired amplicon sizes and size differences. Primer sequences flanking polymorphic insertions/deletions are produced as output. IGG marker files for three sets of genomes, Solanum lycopersicum/Solanum pennellii, Arabidopsis (Arabidopsis thaliana) Columbia-0/Landsberg erecta-0 accessions, and S. lycopersicum/S. pennellii/Solanum tuberosum (three-way polymorphic) are included.

Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer. Fil: Sahasrabudhe, Ruta. University of California at Davis; Estados Unidos Fil: Lott, Paul. University of California at Davis; Estados Unidos Fil: Bohorquez, Mabel. Universidad del Tolima; Colombia Fil: Toal, Ted. University of California at Davis; Estados Unidos Fil: Estrada, Ana P.. Universidad del Tolima; Colombia Fil: Suarez, John J.. Universidad del Tolima; Colombia Fil: Brea Fernández, Alejandro. Ciber Enfermedades Raras; España Fil: Cameselle Teijeiro, José. Complejo Hospitalario Universitario de Santiago; España Fil: Pinto, Carla. Instituto Portugues de Oncologia de Francisco Gentil Porto; Portugal Fil: Ramos, Irma. Instituto Mexicano del Seguro Social; México Fil: Mantilla, Alejandra. Departamento de Patologia la Unidad Medica Alta Especialidad Oncologia; México Fil: Prieto, Rodrigo. Universidad del Tolima; Colombia Fil: Corvalan, Alejandro. Pontificia Universidad Católica de Chile; Chile Fil: Norero, Enrique. Pontificia Universidad Católica de Chile; Chile Fil: Alvarez, Carolina. Universidad Católica de Chile; Chile Fil: Tapia, Teresa. Pontificia Universidad Católica de Chile; Chile Fil: Carvallo, Pilar. Pontificia Universidad Católica de Chile; Chile Fil: Gonzalez, Luz M.. Instituto de Cancerologia, Las Americas; Colombia Fil: Cock-Rada, Alicia. Instituto de Cancerologia, Las Americas; Colombia Fil: Solano, Angela Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Centro de Educaciones Médicas e Investigación Clínica ; Argentina. Universidad de Buenos Aires; Argentina Fil: Neffa, Florencia. Laboratorio Genia; Uruguay Fil: Della Valle, Adriana. Laboratorio Genia; Uruguay Fil: Yau, Chris. University of Oxford; Reino Unido Fil: Soares, Gabriela. Centro Hospitalar Do Porto; Portugal Fil: Borowsky, Alexander. University of California at Davis; Estados Unidos Fil: Hu, Nan. National Cancer Institute; Estados Unidos Fil: He, Li-Ji. Yangcheng Cancer Hospital; China Fil: Han, Xiao-You. Shanxi Cancer Hospital; China Fil: Taylor, Philip R.. National Institutes of Health; Estados Unidos Fil: Goldstein, Alisa M.. National Institutes of Health; Estados Unidos Fil: Torres, Javier. Instituto Mexicano del Seguro Social; México Fil: Echeverry, Magdalena. Universidad del Tolima; Colombia Fil: Ruiz-Ponte, Clara. Centro de Investigación Biomédica en Red de Enfermedades Raras; España Fil: Teixeira, Manuel R.. Universidad de Porto; Portugal Fil: Carvajal Carmona, Luis G.. University of California at Davis; Estados Unidos

The plant vascular system serves as a conduit for delivery of both nutrients and signaling molecules to various distantly located organs. The anucleate sieve tube system of the angiosperm phloem delivers sugars and amino acids to developing organs, and has recently been shown to contain a unique population of RNA and proteins. Grafting studies have established that a number of these macromolecules are capable of moving long distances between tissues, thus providing support for operation of a phloem-mediated inter-organ communication network. Currently, our knowledge of the roles played by such phloem-borne macromolecules is in its infancy. Here, we show that, in tomato, translocation of a phloem-mobile cyclophilin, SlCyp1, from a wild-type scion into a mutant rootstock results in restoration of vascular development and lateral root initiation. This process occurs through reactivation of auxin response pathways and reprogramming of the root transcriptome. Moreover, we show that long-distance trafficking of SlCyp1 is associated with regulation of the shoot-to-root ratio in response to changing light intensities, by modulating root growth. We conclude that long-distance trafficking of SlCyp1 acts as a rheostat to control the shoot-to-root ratio, by mediating root development to integrate photosynthesis and light intensity with requirements for access to water and mineral nutrients.

The plant cell wall is an important factor for determining cell shape, function and response to the environment. Secondary cell walls, such as those found in xylem, are composed of cellulose, hemicelluloses and lignin and account for the bulk of plant biomass. The coordination between transcriptional regulation of synthesis for each polymer is complex and vital to cell function. A regulatory hierarchy of developmental switches has been proposed, although the full complement of regulators remains unknown. Here we present a protein-DNA network between Arabidopsis thaliana transcription factors and secondary cell wall metabolic genes with gene expression regulated by a series of feed-forward loops. This model allowed us to develop and validate new hypotheses about secondary wall gene regulation under abiotic stress. Distinct stresses are able to perturb targeted genes to potentially promote functional adaptation. These interactions will serve as a foundation for understanding the regulation of a complex, integral plant component.

Gastric cancer (GC) is the third common cause of cancer related deaths worldwide and its risk is partially mediated by inherited factors. However, the majority of GC heritability remains to be discovered. The goal of this study was to identify novel GC genes. To identify novel GC genes, we undertook a multi-staged approach of whole exome sequencing (WES), followed by targeted sequencing and genotyping in germline DNA samples from hereditary diffuse GC (HDGC) and isolated GC cases recruited in Europe and Latin America. We also performed WES in 4 available tumor samples to analyze loss of heterozygosity and somatic mutation signature. Our study identified eleven cases with mutations in homologous recombination repair (HR) genes, including seven with PALB2 mutations, three with BRCA1 mutations and one with a RAD51C mutation. Out of 361 total unrelated GC cases analyzed, 6.45% of the HDGC cases (2 out of 31) and 2.7% (9 out of 330) of isolated/non-HDGC cases had mutations in PALB2, BRCA1 or RAD51C. Most of these mutations are known as pathogenic in other cancer types and three were shared by multiple Hispanic and European cases. None of these mutations were present in 1,170 population-matched controls (P=5.75x10-7). Tumor samples from four mutation carriers exhibited mutational signature indicative of defects in HR pathway. Our results suggest that mutations in HR genes are likely involved in GC susceptibility. Our findings have potential clinical implications as these cases and their families could benefit from risk reducing surveillance and possibly benefit from platinum or PARP inhibitor based therapies. Citation Format: Ruta Sahasrabudhe, Paul Lott, Mabel Bohorquez, Ted Toal, Ana Estrada, John Suarez, Alejandro Brea-Fernández, Jose Cameselle-Teijeiro, Carla Pinto, Irma Ramos, Alejandra Mantilla, Rodrigo Prieto, Alejandro Corvalan, Enrique Norero, Carolina Alvarez, Teresa Tapia, Pilar Carvallo, Luz Gonzalez, Alicia Cock-Rada, Angela Solano, Florencia Neffa, Adriana Della Valle, Chris Yau, Gabriela Soares, Alexander Borowsky, Xiao-You Han, Li-JI He, Phillip Taylor, Alisa Goldstein, Nan Hu, Javier Torres, Magdalena Echeverry, Clara Ruiz-Ponte, Manuel Teixeira, Luis G. Carvajal-Carmona. Germline mutations in PALB2, BRCA1 and RAD51C observed in gastric cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-158. doi:10.1158/1538-7445.AM2017-LB-158