Publications by authors named "Yoomi Lee"

18 Publications

  • Page 1 of 1

Clinical advantage of targeted sequencing for unbiased tumor mutational burden estimation in samples with low tumor purity.

J Immunother Cancer 2020 10;8(2)

Samsung Genome Institute, Samsung Medical Center, Seoul, Korea

Background: Tumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored.

Methods: We comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker's predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156).

Results: Low tumor purity was common (range 30%-45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (p<0.001). We found that wTMB was significantly underestimated in low purity samples with a large proportion of clonal variants undetected by whole-exome sequencing. Interestingly, pTMB more accurately predicted progression-free survival (PFS) after immunotherapy than wTMB owing to its superior performance in the low tumor purity subgroup (p=0.054 vs p=0.358). Multivariate analysis revealed pTMB (p=0.016), but not wTMB (p=0.32), as an independent predictor of PFS even in low-purity samples. The net reclassification index using pTMB was 21.7% in the low-purity subgroup (p=0.016).

Conclusions: Our data suggest that TMB characterization with targeted deep sequencing might have potential strength in predicting ICI responsiveness due to its enhanced sensitivity for hard-to-detect variants at low-allele fraction. Therefore, pTMB could act as an invaluable biomarker in the setting of both clinical trials and practice outside of trials based on its reliable performance in mitigating the purity-related bias.
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http://dx.doi.org/10.1136/jitc-2020-001199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574938PMC
October 2020

High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via Interleukin 8 and Alterations to the Gut Microbiome.

Gastroenterology 2019 08 15;157(2):492-506.e2. Epub 2019 Apr 15.

Irvine Cancer Research Center, Columbia University, New York, New York.

Background & Aims: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice.

Methods: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions.

Results: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development.

Conclusions: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
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http://dx.doi.org/10.1053/j.gastro.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662596PMC
August 2019

Detection of Premalignant Gastrointestinal Lesions Using Surface-Enhanced Resonance Raman Scattering-Nanoparticle Endoscopy.

ACS Nano 2019 02 4;13(2):1354-1364. Epub 2019 Feb 4.

Department of Radiology , Memorial Sloan Kettering Cancer Center , New York , New York 10065 , United States.

Cancers of the gastrointestinal (GI) tract are among the most frequent and most lethal cancers worldwide. An important reason for this high mortality is that early disease is typically asymptomatic, and patients often present with advanced, incurable disease. Even in high-risk patients who routinely undergo endoscopic screening, lesions can be missed due to their small size or subtle appearance. Thus, current imaging approaches lack the sensitivity and specificity to accurately detect incipient GI tract cancers. Here we report our finding that a single dose of a high-sensitivity surface-enhanced resonance Raman scattering nanoparticle (SERRS-NP) enables reliable detection of precancerous GI lesions in animal models that closely mimic disease development in humans. Some of these animal models have not been used previously to evaluate imaging probes for early cancer detection. The studies were performed using a commercial Raman imaging system, a newly developed mouse Raman endoscope, and finally a clinically applicable Raman endoscope for larger animal studies. We show that this SERRS-NP-based approach enables robust detection of small, premalignant lesions in animal models that faithfully recapitulate human esophageal, gastric, and colorectal tumorigenesis. This method holds promise for much earlier detection of GI cancers than currently possible and could lead therefore to marked reduction of morbidity and mortality of these tumor types.
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http://dx.doi.org/10.1021/acsnano.8b06808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428194PMC
February 2019

Association of the Vitamin D Level and Quality of School Life in Adolescents with Irritable Bowel Syndrome.

J Clin Med 2018 Dec 1;7(12). Epub 2018 Dec 1.

Department of Pediatrics, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Korea.

There is no treatment of choice for irritable bowel syndrome, which affects up to 20% of school-aged children. This cross-sectional study evaluated the difference in the average vitamin D level between subtypes of irritable bowel syndrome, and the relationship between the vitamin D level as well as the severity of irritable bowel syndrome symptoms. We included 124 adolescents aged 10⁻17 years (68 boys, 56 girls; mean age 12.29 ± 1.92 years) from 2014 to 2016. Patients with irritable bowel syndrome were diagnosed by Rome III criteria and classified by clinical manifestation: irritable bowel syndrome with constipation ( = 29), irritable bowel syndrome with diarrhea ( = 63), and irritable bowel syndrome with constipation and diarrhea ( = 32). The severity of irritable bowel syndrome symptoms and school absence were evaluated. Vitamin D levels were measured by serum 25-hydroxyvitamin D. The chi-square test and analysis of variance were used. The patients' average vitamin D level was 16.25 ± 6.58 ng/mL. There was a significant negative association of the 25-hydroxyvitamin D level with symptom severity and school absence ( = 0.022 and < 0.001, respectively). Vitamin D supplementation could be considered as a choice of therapeutic method.
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http://dx.doi.org/10.3390/jcm7120500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306771PMC
December 2018

Gastrin stimulates a cholecystokinin-2-receptor-expressing cardia progenitor cell and promotes progression of Barrett's-like esophagus.

Oncotarget 2017 Jan;8(1):203-214

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.

Objective: The incidence of esophageal adenocarcinoma (EAC) is increasing, but factors contributing to malignant progression of its precursor lesion, Barrett's esophagus (BE), have not been defined. Hypergastrinemia caused by long-term use of proton pump inhibitors (PPIs), has been suggested as one possible risk factor. The gastrin receptor, CCK2R, is expressed in the cardia and upregulated in BE, suggesting the involvement of the gastrin-CCK2R pathway in progression. In the L2-IL-1β mouse model, Barrett's-like esophagus arises from the gastric cardia. Therefore, we aimed to analyze the effect of hypergastrinemia on CCK2R+ progenitor cells in L2-IL-1β mice.

Design: L2-IL-1β mice were mated with hypergastrinemic (INS-GAS) mice or treated with PPIs to examine the effect of hypergastrinemia in BE progression. CCK2R-CreERT crossed with L2-IL-1β mice were used to analyze the lineage progenitor potential of CCK2R+ cells. Cardia glands were cultured in vitro, and the effect of gastrin treatment analyzed. L2-IL-1β mice were treated with a CCK2R antagonist YF476 as a potential chemopreventive drug.

Results: Hypergastrinemia resulted in increased proliferation and expansion of Barrett's-like esophagus. Lineage tracing experiments revealed that CCK2R+ cells are long-lived progenitors that can give rise to such lesions under chronic inflammation. Gastrin stimulated organoid growth in cardia culture, while CCK2R inhibition prevented Barrett's-like esophagus and dysplasia.

Conclusions: Our data suggest a progression model for BE to EAC in which CCK2R+ progenitor cells, stimulated by hypergastrinemia, proliferate to give rise to metaplasia and dysplasia. Hypergastrinemia can result from PPI use, and the effects of hypergastrinemia in human BE should be studied further.
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http://dx.doi.org/10.18632/oncotarget.10667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352112PMC
January 2017

A Trial Activation Initiative to Accelerate Trial Opening in an Academic Medical Center.

Ther Innov Regul Sci 2015 Mar;49(2):234-238

1 Asan Medical Center, Clinical Trial Center, Seoul, Korea.

Delays in trial opening should be considered critical for the sake of not only the sponsor but the patients, as they may result in inequities of care. The Asan Medical Center, in Seoul, Korea, implemented a trial activation initiative in July 2012, in an aim to expedite the trial initiation timeline. Time intervals between trial initiation steps and the rate of institutional review board (IRB) and clinical trial agreement (CTA) parallel submission were assessed. A higher rate of parallel IRB and CTA submissions was observed after initiative implementation (25.5% vs 52.3%; P < .001). Initiative applications were shown to significantly accelerate the median trial opening time, from 114 to 81 days ( P < .001). Strategic processing of parallel submissions greatly shortened the median time required for trial initiation from 117 to 61 days compared with sequential submissions ( P < .001). A trial activation initiative including parallel IRB and CTA submissions is an effective tool for accelerating trial commencements.
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http://dx.doi.org/10.1177/2168479014554399DOI Listing
March 2015

CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis.

Gut 2015 Apr 20;64(4):544-53. Epub 2014 Jun 20.

Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.

Objective: Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined.

Design: We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis.

Results: Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5(neg or low) cell population but was distinct from typical antral Lgr5(high) stem cells. Treatment with progastrin interconverts Lgr5(neg or low) CCK2R+ cells into Lgr5(high) cells, increases CCK2R+ cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansion and carcinogenesis.

Conclusions: CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy.
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http://dx.doi.org/10.1136/gutjnl-2014-307190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627594PMC
April 2015

Integrative and comparative genomic analysis of lung squamous cell carcinomas in East Asian patients.

J Clin Oncol 2014 Jan 9;32(2):121-8. Epub 2013 Dec 9.

Youngwook Kim, Ji-ae Yoon, Yoomi Lee, Yeong Kyung Yoo, and Keunchil Park, Samsung Medical Center, Samsung Biomedical Research Institute; Jong-Mu Sun, Hong Kwan Kim, Yong Soo Choi, Kwhanmien Kim, Young Mog Shim, Yoon-La Choi, Jhingook Kim, Jin Seok Ahn, Myung-Ju Ahn, and Keunchil Park, Samsung Medical Center, Sungkyunkwan University School of Medicine; Sukki Cho, Seoul National University Bundang Hospital, College of Medicine, Seoul National University, Seoul; In-Jae Oh, Kyu-Sik Kim, Sang-Yun Song, Kook-Ju Na, and Young-Chul Kim, Chonnam National University Hwasun Hospital, Jeonnam, Republic of Korea; Peter S. Hammerman, Jaegil Kim, Chandra Sekhar Pedamallu, Kristian Cibulskis, Michael S. Lawrence, Petar Stojanov, Scott L. Carter, Aaron McKenna, Chip Stewart, Andrey Y. Sivachenko, Gad Getz, and Matthew Meyerson, Broad Institute of Harvard and MIT, Cambridge; Matthew Meyerson, Harvard Medical School; Peter S. Hammerman and Chandra Sekhar Pedamallu, Dana-Farber Cancer Institute; Gad Getz, Massachusetts General Hospital Cancer Center, Boston, MA; and Matthew D. Wilkerson and D. Neil Hayes, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Purpose: Lung squamous cell carcinoma (SCC) is the second most prevalent type of lung cancer. Currently, no targeted therapeutics are approved for treatment of this cancer, largely because of a lack of systematic understanding of the molecular pathogenesis of the disease. To identify therapeutic targets and perform comparative analyses of lung SCC, we probed somatic genome alterations of lung SCC by using samples from Korean patients.

Patients And Methods: We performed whole-exome sequencing of DNA from 104 lung SCC samples from Korean patients and matched normal DNA. In addition, copy-number analysis and transcriptome analysis were conducted for a subset of these samples. Clinical association with cancer-specific somatic alterations was investigated.

Results: This cancer cohort is characterized by a high mutational burden with an average of 261 somatic exonic mutations per tumor and a mutational spectrum showing a signature of exposure to cigarette smoke. Seven genes demonstrated statistical enrichment for mutation: TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA). Comparative analysis between Korean and North American lung SCC samples demonstrated a similar spectrum of alterations in these two populations in contrast to the differences seen in lung adenocarcinoma. We also uncovered recurrent occurrence of therapeutically actionable FGFR3-TACC3 fusion in lung SCC.

Conclusion: These findings provide new steps toward the identification of genomic target candidates for precision medicine in lung SCC, a disease with significant unmet medical needs.
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http://dx.doi.org/10.1200/JCO.2013.50.8556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062710PMC
January 2014

Harnessing gemcitabine metabolism: a step towards personalized medicine for pancreatic cancer.

Ther Adv Med Oncol 2012 Nov;4(6):341-6

Director, GI Oncology Program, Tufts University School of Medicine, 800 Washington Street, Box 295, Boston, MA 02111, USA.

Pancreatic cancer is a lethal malignancy with a 5-year survival rate of only 6%. Surgical resection remains the only cure, yet even after resection the 5-year survival is only 20% due to a high recurrence rate. Thus, a high proportion of patients with this disease will ultimately require systemic chemotherapy for advanced pancreatic cancer (APC). While the advent of personalized medicine has resulted in significant advances in the management of many cancer types, the standard of care for pancreatic cancer remains gemcitabine based, with very few exceptions. This article first aims to provide an overview of the benefits and limitations of gemcitabine alone, gemcitabine combinations, and different modes of administration of gemcitabine in APC. It then discusses research, suggesting that pharmacogenomic differences in enzymes that affect gemcitabine transport and metabolism can predict benefit from this drug in pancreatic cancer. Finally, the article outlines novel therapies and combinations that exploit these interindividual variations in gemcitabine metabolism to improve the efficacy of this drug in the management of APC.
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http://dx.doi.org/10.1177/1758834012453755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3481558PMC
November 2012

Barrett esophagus: what a mouse model can teach us about human disease.

Cell Cycle 2012 Dec 24;11(23):4328-38. Epub 2012 Oct 24.

II. Medizinische Klinik, Klinikum rechts der Isar, München, Germany.

The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the western world and accounts for 2% of all cancer-related deaths. The precursor lesion for EAC is Barrett esophagus (BE), which is strongly associated with gastresophageal reflux disease. A major limitation to the study of EAC has been the absence of tractable and genetically modifiable preclinical models of BE. A mouse model of BE and EAC that resembles human disease could provide novel insights into the origins and molecular pathogenesis of BE. In addition, validated animal models could help stratify BE patients given the limited predictive power of current standard endoscopic measures and clinical assessment. Here, we review the findings from recently developed mouse models of BE and EAC and their impact on clinical decision making, surveillance programs and therapeutic options. The data, taken together, suggest potential origins of BE from the gastric cardia, a role of bile acid and hypergatrinemia for carcinogenesis, a growing importance for columnar-like epithelium and a critical role for Notch signaling.
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http://dx.doi.org/10.4161/cc.22485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552915PMC
December 2012

Secondary tumors of the pancreas: a case series.

Anticancer Res 2012 Apr;32(4):1449-52

Columbia University College of Physicians and Surgeons, New York, NY, USA.

Metastatic carcinoma of the pancreas from another primary site is uncommon and it accounts for 2-5% of all pancreatic cancer cases. We reported the case of one patient with pancreatic metastasis from colon carcinoma in the past and would like to add another six cases of pancreatic metastases from different types of cancer. The diagnosis of cancer metastatic to the pancreas should be suspected when patients have a history of malignancy, especially of kidney, skin, lung, colon and breast cancer. Besides imaging studies, such as computed tomography (CT) scan, bone scan and positron emission tomography (PET)/CT scan, endoscopic ultrasound (EUS)-guided biopsy has most value in ruling out second primary pancreatic cancer. The prognosis of pancreatic metastases is essentially determined by the underlying primary cancer and the potential treatment options.
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April 2012

Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.

Cancer Cell 2012 Jan;21(1):36-51

Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA.

Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5(+) gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling.
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http://dx.doi.org/10.1016/j.ccr.2011.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266546PMC
January 2012

Temozolomide (Temodar®) and capecitabine (Xeloda®) treatment of an aggressive corticotroph pituitary tumor.

Pituitary 2011 Dec;14(4):418-24

Department of Medicine, Division of Medical Oncology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

Only rarely do corticotroph pituitary tumors become invasive leading to symptoms caused by compression of cranial nerves and other local structures. When aggressive pituitary neuroendocrine tumors do develop, conventional treatment options are of limited success. A 50-year-old man developed a giant invasive corticotroph pituitary tumor 2 years after initial presentation. His tumor and symptoms failed to respond to maximal surgical, radio-surgical, radiation and medical therapy and a bilateral adrenalectomy was done. He subsequently developed rapid growth of his tumor leading to multiple cranial nerve deficits. He was administered salvage chemotherapy with capecitabine and temozolomide (CAPTEM), a novel oral chemotherapy regimen developed at our institution for treatment of neuroendocrine tumors. After two cycles of CAPTEM, his tumor markedly decreased in size and ACTH levels fell by almost 90%. Despite further decreases in ACTH levels, his tumor recurred after 5 months with increased avidity on PET scan suggesting a transformation to a more aggressive phenotype. Temozolomide had been reported to be effective against other pituitary tumors and this case adds to this literature demonstrating its use along with capecitabine (CAPTEM) against a corticotroph tumor. Further evaluation of the CAPTEM regimen in patients with pituitary neuroendocrine tumors which fail to respond to classic treatments is warranted.
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http://dx.doi.org/10.1007/s11102-009-0211-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891584PMC
December 2011

Selective POTE paralogs on chromosome 2 are expressed in human embryonic stem cells.

Stem Cells Dev 2008 Apr;17(2):325-32

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

POTE is a primate-specific gene family that encodes cancer testis antigens that contain three domains, although the proteins vary greatly in size. The amino-terminal domain is novel and has three cysteine-rich domains of 37 amino acids. The second and third domains are rich in ankyrin repeats and spectrin-like helices respectively. In humans, 13 highly homologous paralogs are dispersed among eight chromosomes. Some members of the POTE gene family have an actin insertion at the carboxyl end of the protein. The expression of the POTE gene in normal adult tissues is restricted, but several POTE paralogs are frequently expressed in many cancers including breast, prostate, and lung cancers. We show here that POTE is expressed in several human embryonic stem (ES) cell lines. We found that UC06, WA01 and ES03 cell lines express mainly a POTE-2gamma transcript but ES02 and ES04 cell lines predominantly express POTE-2alpha. The WA09 cell line expressed both POTE-2gamma and POTE-2alpha. There is no detectable POTE gene expression in fetal tissues (ages 16-36 weeks). The POTE paralogs that are expressed in ES cells may have a specific function during lineage-specific differentiation of ES cells.
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http://dx.doi.org/10.1089/scd.2007.0079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233169PMC
April 2008

Expression of POTE protein in human testis detected by novel monoclonal antibodies.

Biochem Biophys Res Commun 2008 Jan 9;365(4):603-8. Epub 2007 Nov 9.

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.

The POTE gene family is composed of 13 highly homologous paralogs preferentially expressed in prostate, ovary, testis, and placenta. We produced 10 monoclonal antibodies (MAbs) against three representative POTE paralogs: POTE-21, POTE-2gammaC, and POTE-22. One reacted with all three paralogs, six MAbs reacted with POTE-2gammaC and POTE-22, and three MAbs were specific to POTE-21. Epitopes of all 10 MAbs were located in the cysteine-rich repeats (CRRs) motifs located at the N-terminus of each POTE paralog. Testing the reactivity of each MAb with 12 different CRRs revealed slight differences among the antigenic determinants, which accounts for differences in cross-reactivity. Using MAbs HP8 and PG5 we were able to detect a POTE-actin fusion protein in human testis by immunoprecipitation followed by Western blotting. By immunohistochemistry we demonstrated that the POTE protein is expressed in primary spermatocytes, implying a role in spermatogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2007.10.195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189737PMC
January 2008

Evolution and expression of chimeric POTE-actin genes in the human genome.

Proc Natl Acad Sci U S A 2006 Nov 13;103(47):17885-90. Epub 2006 Nov 13.

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.

We previously described a primate-specific gene family, POTE, that is expressed in many cancers but in a limited number of normal organs. The 13 POTE genes are dispersed among eight different chromosomes and evolved by duplications and remodeling of the human genome from an ancestral gene, ANKRD26. Based on sequence similarity, the POTE gene family members can be divided into three groups. By genome database searches, we identified an actin retroposon insertion at the carboxyl terminus of one of the ancestral POTE paralogs. By Northern blot analysis, we identified the expected 7.5-kb POTE-actin chimeric transcript in a breast cancer cell line. The protein encoded by the POTE-actin transcript is predicted to be 120 kDa in size. Using anti-POTE mAbs that recognize the amino-terminal portion of the POTE protein, we detected the 120-kDa POTE-actin fusion protein in breast cancer cell lines known to express the fusion transcript. These data demonstrate that insertion of a retroposon produced an altered functional POTE gene. This example indicates that new functional human genes can evolve by insertion of retroposons.
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http://dx.doi.org/10.1073/pnas.0608344103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1693842PMC
November 2006

POTE paralogs are induced and differentially expressed in many cancers.

Cancer Res 2006 Jan;66(1):52-6

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892-4264, USA.

To identify new antigens that are targets for the immunotherapy of prostate and breast cancer, we used expressed sequence tag and genomic databases and discovered POTE, a new primate-specific gene family. Each POTE gene encodes a protein that contains three domains, although the proteins vary greatly in size. The NH2-terminal domain is novel and has properties of an extracellular domain but does not contain a signal sequence. The second and third domains are rich in ankyrin repeats and spectrin-like helices, respectively. The protein encoded by POTE-21, the first family member discovered, is localized on the plasma membrane of the cell. In humans, 13 highly homologous paralogs are dispersed among eight chromosomes. The expression of POTE genes in normal tissues is restricted to prostate, ovary, testis, and placenta. A survey of several cancer samples showed that POTE was expressed in 6 of 6 prostate, 12 of 13 breast, 5 of 5 colon, 5 of 6 lung, and 4 of 5 ovarian cancers. To determine the relative expression of each POTE paralog in cancer and normal samples, we employed a PCR-based cloning and analysis method. We found that POTE-2alpha, POTE-2beta, POTE-2gamma, and POTE-22 are predominantly expressed in cancers whereas POTE expression in normal tissues is somewhat more diverse. Because POTE is primate specific and is expressed in testis and many cancers but only in a few normal tissues, we conclude POTE is a new primate-specific member of the cancer-testis antigen family. It is likely that POTE has a unique role in primate biology.
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http://dx.doi.org/10.1158/0008-5472.CAN-05-3014DOI Listing
January 2006

N-linked glycosylation is required for optimal function of Kaposi's sarcoma herpesvirus-encoded, but not cellular, interleukin 6.

J Exp Med 2004 Feb;199(4):503-14

Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520, USA.

Kaposi's sarcoma-associated herpesvirus interleukin-6 (vIL-6) is a structural and functional homologue of the human cytokine IL-6 (hIL-6). hIL-6 and vIL-6 exhibit similar biological functions and both act via the gp130 receptor subunit to activate the Janus tyrosine kinase (JAK)1 and signal transducer and activator of transcription (STAT)1/3 pathway. Here we show that vIL-6 is N-linked glycosylated at N78 and N89 and demonstrate that N-linked glycosylation at site N89 of vIL-6 markedly enhances binding to gp130, signaling through the JAK1-STAT1/3 pathway and functions in a cytokine-dependent cell proliferation bioassay. Although hIL-6 is also N-glycosylated at N73 and multiply O-glycosylated, neither N-linked nor O-linked glycosylation is necessary for IL-6 receptor alpha-dependent binding to gp130 or signaling through JAK1-STAT1/3. As distinct from vIL-6, unglycosylated hIL-6 is as potent as glycosylated hIL-6 in stimulating B cell proliferation. These findings highlight distinct functional roles of N-linked glycosylation in viral and cellular IL-6.
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http://dx.doi.org/10.1084/jem.20031205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211829PMC
February 2004
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