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  • 1
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-08-24)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 2
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-01-07)
    Type of Medium: Online Resource
    ISSN: 2041-1723
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 2784-2784
    Abstract: Breast cancer (BC) is the most frequently diagnosed cancer among women with an estimated 1,676,633 new cases resulting in ∼521,817 deaths each year globally. Thus, it is no surprise BC research has become one of the hottest cancer research areas in the past three decades. Past studies examining and identifying BC risk loci have focused on three major populations (European, African, and Asian). Past research has led to greater understanding of the etiology (genetic and environmental) and treatment of BC; resulting in a ∼30% decrease in mortality rate in wealthy countries. However, when looking at BC incidence and mortality in low to middle income nations similar gains are not seen; in fact, in these countries mortality has increased in the past 20 years. This trend holds true for the Hispanic community. While Hispanic women have a ∼27% lower rate of BC than in non-Hispanic white women, Hispanic women are more likely to be diagnosed with larger tumors and later stage cancer, leading to ∼20% increase in mortality for Hispanic women compared to their non-Hispanic white counterpart with similar diagnosis stage and age. Differences in incidence and mortality have been attributed to environmental and genetic factors. This case-control association study aims to address a research disparity by examining the role of ethnicity and genetics on development of BC risk in central Colombian Hispanic populations. It provides one of the first assessments of known BC risk factors in the South American Hispanic community. The study was conducted in central Colombia using ∼600 breast cancer cases from COLUMBUS initiative & ∼700 matched cancer-free controls from the CHIBCHA consortium. Cases were genotyped using Affymetrix Axiom UK Biobank arrays and controls were genotyped using both Affymetrix Axiom LAT and Axiom Custom arrays followed by imputation using 1000 Genomes data. We analyzed previously discovered BC loci and under independent analysis found 6 significant loci: rs11780156 (P = 0.005, OR: 1.34), rs2981582 (P = 0.007, OR: 1.25), rs4784227 (P = 0.016, OR: 1.22), rs2981579 (P = 0.017, OR 1.21), rs1011970 (P = 0.0274, OR 1.20), rs1219648 (P = 0.042, OR 1.18) and several loci showing borderline significant associations involving the same risk allele. Interestingly, we identified additional novel BC risk loci that were genome-wide significant and are undergoing replication in populations from Central Mexico. In summary, we performed an assessment of BC risk loci in central Colombian Hispanic population and found significant overlap with BC risk loci previously identified in European and East Asian populations as well as potentially novel loci that are unique to Hispanic populations. These results are integral to the establishment of personalized medicine programs and will form the basis for future BC prevention and treatment program in Latin American and US Hispanics. Citation Format: Paul C. Lott, Angel Criollo, Anna Marie Tuazon, Carolina Ramirez Alfonso, Ruta Sahasrabudhe, Ana Estrada, Elisha Garcia, Rodrigo Prieto, John Williamson, Javier Torres, Mabel Bohorquez, Maria Magdalena Echeverry de Polanco, CHIBCHA Consortium, COLUBMUS Consortium, Luis G. Carvajal-Carmona. Genetic analysis of breast cancer in admixed populations of central Colombia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2784. doi:10.1158/1538-7445.AM2015-2784
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 4
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 12_Supplement ( 2020-12-01), p. IA13-IA13
    Abstract: Gastric cancer is a leading cause of cancer mortality in Latinos, who are two times more likely to die of gastric cancer when compared to non-Latino Whites. Gastric cancer outcomes in this minority are poor as most tumors are detected in the metastatic setting, where five-year survival is less than 5%. Despite such a high mortality burden in Latinos and other minority populations, there are only three molecularly-guided therapies approved by the Food and Drug Administration to treat gastric cancer. To advance precision medicine in minority groups, the NCI Center to Reduce Cancer Health Disparities funded our University of California Minority Patient-Derived Xenograft (PDX) Development and Trial Center (UCaMP), which is currently creating and characterizing PDXs and patient-derived organoids from minority patients including those with gastric cancer. In this presentation, we will present an overview of recent advances in gastric cancer precision modeling using patient-derived organoids and xenografts from Latino patients. We will summarize the most promising druggable genes and pathways in gastric tumors and will present initial findings on the development of promising combinations using PIK3CA inhibitors. Citation Format: Hongyong Zhang, Nicole Coggins, Paul Lott, Ana Estrada, Guadalupe Polanco, Alexa Morales, Sienna Rocha, Amanda Kirane, Shiro Urayama, Javier Torres, Mabel Bohorquez, Magdalena Echeverry, UCaMP Consortium, Luis G. Carvajal-Carmona. Advancing gastric cancer precision medicine through minority patient derived modeling [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr IA13.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
    Online Resource
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    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 6_Supplement_1 ( 2020-06-01), p. C030-C030
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 6_Supplement_1 ( 2020-06-01), p. C030-C030
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 6
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 101, No. 3 ( 2016-03-01), p. 1098-1103
    Abstract: A recent study reported the nonsynonymous G534E (rs7080536, allele A) variant in the HABP2 gene as causal in familial nonmedullary thyroid cancer (NMTC). Objective: The objective of this study was to evaluate the causality of HABP2 G534E in the TCUKIN study, a multicenter population-based study of NMTC cases from the British Isles. Design and Setting: A case-control analysis of rs7080536 genotypes was performed using 2105 TCUKIN cases and 5172 UK controls. Participants: Cases comprised 2105 NMTC cases. Patient subgroups with papillary (n = 1056), follicular (n = 691), and Hürthle cell (n = 86) thyroid cancer cases were studied separately. Controls comprised 5172 individuals from the 1958 Birth Cohort and the National Blood Donor Service study. The controls had previously been genotyped using genome-wide single nucleotide polymorphism arrays by the Wellcome Trust Case Control Consortium study. Outcome Measures: Association between HABP2 G534E (rs7080536A) and NMTC risk was evaluated using logistic regression. Results: The frequency of the HABP2 G534E was 4.2% in cases and 4.6% in controls. We did not detect an association between this variant and NMTC risk (odds ratio [OR] = 0.896; 95% confidence interval, 0.746–1.071; P = .233). We also failed to detect an association between the HABP2 G534E and cases with papillary (1056 cases; G534E frequency = 3.5%; OR = 0.74; P = .017), follicular (691 cases; G534E frequency = 4.7%; OR = 1.00; P = 1.000), or Hürthle cell (86 cases; G534E frequency = 6.3%; OR = 1.40; P = .279) histology. Conclusions: We found that HABP2 G534E is a low-to-moderate frequency variant in the British Isles and failed to detect an association with NMTC risk, independent of histological type. Hence, our study does not implicate HABP2 G534E or a correlated polymorphism in familial NMTC, and additional data are required before using this variant in NMTC risk assessment.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
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    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2016
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  • 7
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 23, No. 11_Supplement ( 2014-11-01), p. B10-B10
    Abstract: Colorectal and breast cancers are leading causes of cancer morbidity and mortality in Hispanics. Most of the genes predisposing to these common malignancies are yet to be identified. Moreover, the prevalence of mutations in known cancer genes in Hispanic populations remains largely undetermined. Our present study aims to establish the prevalence of mutations that predispose to cancer susceptibility syndromes in Hispanics using a high throughput next-generation sequencing approach. We have developed an amplicon sequencing method that uses microfluidics PCR to simultaneously identify mutations in up to 480 amplicons. This amount of sequence data is enough to cover, at a high depth, the coding sequence of ∼20 different genes in a single reaction. To do so, the samples are barcoded individually using indexing adapters that allows pooling of multiple amplicon libraries for up to 384 samples in a single MiSeq run. The sequence data is analyzed with a locally developed bioinformatics pipeline that uses BWA, VarScan V2.0 and custom shell and Perl scripts. Our preliminary data, in several hundred familial and early-onset colon and breast cancer patients from South America, have identified many individuals with mutations in known cancer genes, such as APC, MSH2, MLH1, BRCA1 and BRCA2, and that have been previously reported in Southern European populations. We have also identified several mutations that have not been reported previously and that appear to have an Amerindian origin. Interestingly, a large fraction of these mutations are shared by multiple patients and suggest that founder effects are common in some of these populations. We have also found that more than over 50% of the patients screened so far are mutation negative. We plan to use this latter set of samples for novel gene discovery by whole exome or genome sequencing in the next phase of our study. In conclusion, we have developed a rapid, cost effective, and efficient method for screening mutations in known cancer genes in the Hispanic population. Hispanics are the youngest, largest and the fastest growing US minority and the largest population group living in the Americas. However, to a large extent, this population remains under-studied and under-screened, contributing to health care disparities. Prevalence of mutations in known cancer genes as well as novel mutations identified in our study can be used during initial steps of genetic testing programs that can improve the detection of early cancers among Hispanic communities. Citation Format: Ruta Sahasrabudhe, Anna-Marie Tuazon, Paul Lott, Ana Estrada, Mabel Bohorquez, Rodrigo Prieto, Angel Criollo, Carolina Ramirez, Magdalena Echeverry, Luis G. Carvajal-Carmona. Development of high-throughput screening methods for detecting germline cancer causing mutations in the Hispanic population. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B10. doi:10.1158/1538-7755.DISP13-B10
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1786-1786
    Abstract: Breast cancer is the leading cause of cancer incidence and mortality among Hispanic women, who are often diagnosed with late stage tumors and are more likely to die after diagnosis when compared to non-Hispanic whites. While strides have been made in understanding Hispanic breast cancer genetics, most studies have been limited to investigating cases from high-risk clinics. In this study, we aimed to assess the prevalence of pathogenic mutations in three most important breast cancer genes (BRCA1, BRCA2 and PALB2) in an unselected Hispanic breast cancer cohort. Initially, six hundred and forty-six unselected Colombian breast cancer cases were screened for four known Hispanic BRCA1/2 mutations by genotyping. Subsequently, cases that remained mutation negative, as well as 186 cancer-free controls, were screened for BRCA1, BRCA2 and PALB2 mutations using targeted next generation sequencing. We identified 67 cases with pathogenic mutations, one case with a likely-pathogenic variant, and 16 carriers of variants of unknown significance. Among the pathogenic mutation carriers, 88.1% harbored a founder mutation (n = 59), which includes the known BRCA1 3450del4 mutation, strikingly found in 32 unrelated cases. Remarkably, we found that 1 in 4 of the cases diagnosed with breast cancer by age 40 years, regardless of family history of cancer, carried a pathogenic mutation. The high frequency of pathogenic mutations in this unselected cohort (10.4%), in particular those with an early age of onset (25.3%), suggests that population-based genetic testing among Hispanic communities can identify most carriers who would otherwise ineligible for testing. Identifying mutation carriers of these genes has implications in clinical management and surveillance for Hispanic women, a population that is vulnerable to breast cancer disparities in the U.S. and Latin America. Citation Format: Anna Marie Tuazon, Mabel Bohorquez, Carolina Ramirez, Paul Lott, Ana Estrada, Angel Criollo, Cathy Wang, Magdalena Echeverry, John Suarez, COLUMBUS Consortium, LaFamilia Consortium, Luis G. Carvajal Carmona. One in four Hispanic women with early onset breast cancer carry BRCA1, BRCA2, or PALB2 mutations: Results from a population-based study in South America. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1786.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 23_Supplement ( 2014-12-01), p. 42-42
    Abstract: Cancer is a leading cause of non-communicable morbidity and mortality worldwide. While many genes that predispose individuals for different cancers have been discovered, the population prevalence of mutations in these genes remains largely undetermined in many populations. Developing customized screening panels and screening for novel variants for a large population samples can be expensive and time consuming. We have developed a low-cost high-throughput pipeline and method to screen 480 customizable amplicons (∼20 genes, ∼144Kbp) for up to 384 samples per run. By combining a bioinformatics pipeline for design and analysis with Fluidigm microfluidics PCR and Illumina MiSeq, we can quickly screen the full coding sequence of multiple cancer panels at a high depth of coverage at a low cost per sample (∼$20-40/sample). The amplicon design pipeline provides ability to develop amplicon primer sets and pooling strategies. Libraries of 384 barcoded samples are run in a single MiSeq lane. Sequencing data is analyzed by an automated pipeline, which aligns using BWA-MEM, calls variants using VarScan 2, and annotates variants using multiple datasets using Annovar. We have applied these pipelines and methods to identify mutation in known cancer genes, such as APC, MSH2, MLH1, BRCA1, and BRCA2, in several hundred Hispanic individuals with familial and early-onset colon and breast cancer. While many of these mutations have been previously reported, we have identified several novel pathogenic changes that appear to have Amerindian origin. Of which, a few are shared among many individuals in isolated geographic locations, suggesting founder effects are common in some of these populations. In conclusion, we have developed a low-cost high-throughput method for screening customizable panels for known and novel mutations. These panels typically consist of 20 cancer genes and our group has already developed panels that are specific for breast cancer, colon cancer and thyroid cancer. Our study is an initial step to assess prevalence of known cancer causing genes and identify novel genes/mutations that contribute to different cancers in the Hispanic community. These discoveries provide a foundation for early detection, prevention, and treatment of familial cancers. Citation Format: Ruta Sahasrabudhe,, Paul Lott, Anna Marie Tuazon, John Williamson, Natalia Belter, Ana Estrada, Mabel Bohorquez, Rodrigo Prieto, Angel Criollo, Alejandro Velez, Jorge Castro, Gilbert Mateus, Magdalena Echhevery, Luis G. Carvajal-Carmona. Development of low-cost high-throughput screening methods for detecting germline mutations in multiple cancer genes. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 20 14;74(23 Suppl):Abstract nr 42. doi:10.1158/1538-7445.CANSUSC14-42
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 10
    In: Endocrine-Related Cancer, Bioscientifica, Vol. 22, No. 5 ( 2015-10), p. 841-849
    Abstract: The G allele of the rs6983267 single-nucleotide polymorphism, located on chromosome 8q24, has been associated with increased risk of several cancer types. The association between rs6983267G and thyroid cancer (TC) has been tested in different populations, mostly of European ancestry, and has led to inconclusive results. While significant associations have been reported in the British and Polish populations, no association has been detected in populations from Spain, Italy and the USA. To further investigate the role of rs6983267G in TC susceptibility, we evaluated rs6983267 genotypes in three populations of different continental ancestry (British Isles, Colombia and Japan), providing a total of 3067 cases and 8575 controls. We detected significant associations between rs6983267G and TC in the British Isles (odds ratio (OR)=1.19, 95% CI: 1.11–1.27, P =4.03×10 −7 ), Japan (OR=1.20, 95% CI: 1.03–1.41, P =0.022) and a borderline significant association of similar effect direction and size in Colombia (OR=1.19, 95% CI: 0.99–1.44, P =0.069). A meta-analysis of our multi-ethnic study and previously published non-overlapping datasets, which included a total of 5484 cases and 12 594 controls, confirmed the association between rs6983267G and TC ( P =1.23×10 −7 , OR=1.13, 95% CI: 1.08–1.18). Our results therefore support the notion that rs6983267G is a bona fide TC risk variant that increases the risk of disease by ∼13%.
    Type of Medium: Online Resource
    ISSN: 1351-0088 , 1479-6821
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2015
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