Christine A Iacobuzio-Donahue

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (180)1399.07 Total impact

  • Christine A Iacobuzio-Donahue, Joseph M Herman
    New England Journal of Medicine 04/2014; 370(14):1352-3. · 51.66 Impact Factor
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    ABSTRACT: Deoxycytidine kinase (dCK) and human antigen R (HuR) have been associated with response to gemcitabine in small studies. The present study investigates the prognostic and predictive value of dCK and HuR expression levels for sensitivity to gemcitabine and 5-fluorouracil (5-FU) in a large phase III adjuvant trial with chemoradiation backbone in pancreatic ductal adenocarcinoma (PDA). The dCK and HuR expression levels were determined by immunohistochemistry on a tissue microarray of 165 resected PDAs from the Radiation Therapy Oncology Group (RTOG) 9704 trial. Association with overall survival (OS) and disease-free survival (DFS) status were analyzed using the log-rank test and the Cox proportional hazards model. Experiments with cultured PDA cells were performed to explore mechanisms linking dCK and HuR expression to drug sensitivity. dCK expression levels were associated with improved OS for all patients analyzed from RTOG 9704 (HR: 0.66, 95% CI [0.47-0.93], P = 0.015). In a subset analysis based on treatment arm, the effect was restricted to patients receiving 5-FU (HR: 0.53, 95% CI [0.33-0.85], P = 0.0078). Studies in cultured cells confirmed that dCK expression rendered cells more sensitive to 5-FU. HuR cytoplasmic expression was neither prognostic nor predictive of treatment response. Previous studies along with drug sensitivity and biochemical studies demonstrate that radiation interferes with HuR's regulatory effects on dCK, and could account for the negative findings herein based on the clinical study design (i.e., inclusion of radiation). Finally, we demonstrate that 5-FU can increase HuR function by enhancing HuR translocation from the nucleus to the cytoplasm, similar to the effect of gemcitabine in PDA cells. For the first time, in the pre-treatment tumor samples, dCK and HuR cytoplasmic expression were strongly correlated (chi-square P = 0.015). This dual-institutional follow up study, in a multi-institutional PDA randomized clinical trial, observed that dCK expression levels were prognostic and had predictive value for sensitivity to 5-FU.
    Cancer biology & therapy 03/2014; 15(6). · 3.29 Impact Factor
  • Kalpesh Patel, Christine A Iacobuzio-Donahue, Paul E Gormley, Scott E Kern, Steven C Cunningham
    Journal of Clinical Oncology 03/2014; · 18.04 Impact Factor
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    ABSTRACT: Cancers comprise a heterogeneous group of human diseases. Unifying characteristics include unchecked abilities of tumor cells to proliferate and spread anatomically, and the presence of clonal advantageous genetic changes. However, universal and highly specific tumor markers are unknown. Herein, we report widespread long interspersed element-1 (LINE-1) repeat expression in human cancers. We show that nearly half of all human cancers are immunoreactive for a LINE-1-encoded protein. LINE-1 protein expression is a common feature of many types of high-grade malignant cancers, is rarely detected in early stages of tumorigenesis, and is absent from normal somatic tissues. Studies have shown that LINE-1 contributes to genetic changes in cancers, with somatic LINE-1 insertions seen in selected types of human cancers, particularly colon cancer. We sought to correlate this observation with expression of the LINE-1-encoded protein, open reading frame 1 protein, and found that LINE-1 open reading frame 1 protein is a surprisingly broad, yet highly tumor-specific, antigen.
    American Journal Of Pathology 03/2014; · 4.52 Impact Factor
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    ABSTRACT: CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance.
    Epigenetics: official journal of the DNA Methylation Society 02/2014; 9(5). · 4.58 Impact Factor
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    ABSTRACT: C-reactive protein (CRP), an inflammation marker, is associated with colorectal cancer (CRC) risk in some prospective studies. Whether increased CRP is indicative of colonic inflammation, a possible CRC cause, or of other sources of inflammation (e.g., adiposity), is unknown. Thus, we evaluated the association between CRP and colonic mucosal measures of inflammation. 151 adults undergoing colonoscopy provided a blood sample and random left- and right-side colonic mucosal biopsies. Height and weight were measured, and lifestyle information was collected. High-sensitivity C-reactive protein (hsCRP) was measured by immunoturbidometric assay. A gastrointestinal pathologist evaluated biopsies for seven colonic inflammation measures. Of 119 participants with complete information, 24 had an inflammatory bowel disease (IBD) history and were analyzed separately. We calculated the number of colonic inflammation measures present in both biopsies, and separately for right and left biopsies. Adjusted geometric mean hsCRP was calculated using linear regression, overall, by demographic and lifestyle factors, and inflammation measures. Most participants had ≥1 colonic inflammation measure (0: 21 %, 1: 39 %, ≥2: 40 %). Adjusted mean hsCRP did not increase with increasing number of inflammation measures (0: 1.67; 1: 1.33; ≥2: 1.01 mg/L; p trend = 0.21). Obese (2.03 mg/L) and overweight (1.61 mg/L) participants had higher adjusted mean hsCRP than normal-weight participants (0.62 mg/L; p trend <0.0001). Patterns were similar for participants with a history of IBD. hsCRP concentration was not associated with colonic inflammation, although hsCRP increased with adiposity. The hsCRP-CRC association may be explained by residual confounding by other risk factors, such as adiposity, rather than by CRP marking colonic inflammation.
    Cancer Causes and Control 01/2014; · 3.20 Impact Factor
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    ABSTRACT: Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5' truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context.
    Nature Communications 01/2014; 5:3644. · 10.02 Impact Factor
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    ABSTRACT: Cancers comprise a heterogeneous group of human diseases. Unifying characteristics include unchecked abilities of tumor cells to proliferate and spread anatomically, and the presence of clonal advantageous genetic changes. However, universal and highly specific tumor markers are unknown. Herein, we report widespread long interspersed element-1 (LINE-1) repeat expression in human cancers. We show that nearly half of all human cancers are immunoreactive for a LINE-1–encoded protein. LINE-1 protein expression is a common feature of many types of high-grade malignant cancers, is rarely detected in early stages of tumorigenesis, and is absent from normal somatic tissues. Studies have shown that LINE-1 contributes to genetic changes in cancers, with somatic LINE-1 insertions seen in selected types of human cancers, particularly colon cancer. We sought to correlate this observation with expression of the LINE-1–encoded protein, open reading frame 1 protein, and found that LINE-1 open reading frame 1 protein is a surprisingly broad, yet highly tumor-specific, antigen.
    The American Journal of Pathology. 01/2014;
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    ABSTRACT: Large-magnitude numerical distinctions (>10-fold) among drug responses of genetically contrasting cancers were crucial for guiding the development of some targeted therapies. Similar strategies brought epidemiological clues and prevention goals for genetic diseases. Such numerical guides, however, were incomplete or low magnitude for Fanconi anemia pathway (FANC) gene mutations relevant to cancer in FANC-mutation carriers (heterozygotes). We generated a four-gene FANC-null cancer panel, including the engineering of new PALB2/FANCN-null cancer cells by homologous recombination. A characteristic matching of FANCC-null, FANCG-null, BRCA2/FANCD1-null, and PALB2/FANCN-null phenotypes was confirmed by uniform tumor regression on single-dose cross-linker therapy in mice and by shared chemical hypersensitivities to various inter-strand cross-linking agents and γ-radiation in vitro. Some compounds, however, had contrasting magnitudes of sensitivity; a strikingly high (19- to 22-fold) hypersensitivity was seen among PALB2-null and BRCA2-null cells for the ethanol metabolite, acetaldehyde, associated with widespread chromosomal breakage at a concentration not producing breaks in parental cells. Because FANC-defective cancer cells can share or differ in their chemical sensitivities, patterns of selective hypersensitivity hold implications for the evolutionary understanding of this pathway. Clinical decisions for cancer-relevant prevention and management of FANC-mutation carriers could be modified by expanded studies of high-magnitude sensitivities.
    American Journal Of Pathology 11/2013; · 4.52 Impact Factor
  • International journal of radiation oncology, biology, physics 11/2013; 87(3):458-9. · 4.59 Impact Factor
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    ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer deaths and there currently is no reliable modality for the early detection of this disease. Here we identify cancer-specific promoter DNA methylation of BNC1 and ADAMTS1 as a promising biomarker detection strategy meriting investigation in pancreatic cancer. We used a genome-wide pharmacologic transcriptome approach to identify novel cancer-specific DNA methylation alterations in pancreatic cancer cell lines. Of 8 promising genes, we focused our studies on BNC1 and ADAMTS1 for further downstream analysis including methylation and expression. We used a nanoparticle-enabled MOB (Methylation On Beads) technology to detect early stage pancreatic cancers by analyzing DNA methylation in patient serum. We identified 2 novel genes, BNC1 (92%) and ADAMTS1, (68%) that showed a high frequency of methylation in pancreas cancers (n=143), up to 100% in PanIN-3 and 97% in Stage I invasive cancers. Using the nanoparticle-enabled MOB technology, these alterations could be detected in serum samples (n=42) from pancreas cancer patients, with a sensitivity for BNC1 of 79% (95%CI:66-91%) and for ADAMTS1 of 48% (95%CI:33-63%), while specificity was 89% for BNC1 (95%CI:76-100%) and 92% for ADAMTS1 (95%CI:82-100%). Overall sensitivity using both markers is 81% (95%CI:69-93%) and specificity is 85% (95%CI:71-99%). Promoter DNA methylation of BNC1 and ADAMTS1 are potential biomarkers to detect early stage pancreatic cancers. Assaying the promoter methylation status of these genes in circulating DNA from serum is a promising strategy for early-detection of pancreatic cancer and has the potential to improve mortality from this disease.
    Clinical Cancer Research 10/2013; · 7.84 Impact Factor
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    ABSTRACT: Like the p16, SMAD4, and RB1 genes, FAM190A lies at a consensus site of homogeneous genomic deletions in human cancer. FAM190A transcripts in 40% of cancers also contain in-frame deletions of evolutionarily conserved exons. Its gene function was unknown. We found an internal deletion of the FAM190A gene in a pancreatic cancer having prominent focal multinuclearity. The experimental knockdown of FAM190A expression by shRNA caused focal cytokinesis defects, multipolar mitosis, and multinuclearity as observed in time-lapse microscopy. FAM190A was localized to the γ-tubulin ring complex of early mitosis and to the midbody in late cytokinesis by immunofluorescence assay and was present in the nuclear fraction of unsynchronized cells by immunoblot. FAM190A interacted with EXOC1 and Ndel1, which function in cytoskeletal organization and the cell division cycle. Levels of FAM190A protein peaked 12 hours after release from thymidine block, corresponding to M-phase. Slower-migrating phosphorylated forms accumulated toward M-phase and disappeared after release from a mitotic block and before cytokinesis. Studies of FAM190A alterations may provide mechanistic insights into mitotic dysregulation and multinuclearity in cancer. We propose that FAM190A is a regulator or structural component required for normal mitosis and that both the rare truncating mutations and common in-frame deletion alteration of FAM190A may contribute to the chromosomal instability of cancer.
    American Journal Of Pathology 05/2013; · 4.52 Impact Factor
  • Alvin Makohon-Moore, Jacqueline A Brosnan, Christine A Iacobuzio-Donahue
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    ABSTRACT: Pancreatic cancer is a highly lethal tumor type for which there are few viable therapeutic options. It is also caused by the accumulation of mutations in a variety of genes. These genetic alterations can be grouped into those that accumulate during pancreatic intraepithelial neoplasia (precursor lesions) and thus are present in all cells of the infiltrating carcinoma, and those that accumulate specifically within the infiltrating carcinoma during subclonal evolution, resulting in genetic heterogeneity. Despite this heterogeneity there are nonetheless commonly altered cellular functions, such as pathways controlling the cell cycle, DNA damage repair, intracellular signaling and development, which could provide for a variety of drug targets. This review aims to summarize current knowledge of the genetics and genomics of pancreatic cancer from its inception to metastatic colonization, and to provide examples of how this information can be translated into the clinical setting for therapeutic benefit and personalized medicine.
    Genome Medicine 03/2013; 5(3):26. · 3.40 Impact Factor
  • S Yachida, C A Iacobuzio-Donahue
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    ABSTRACT: Efficient metastasis is believed as the result of multiple genetic, epigenetic and/or post-translational events in the lifetime of a carcinoma. At the genetic level, these events may be categorized into those that occur during carcinogenesis, and those that occur during subclonal evolution. This review summarizes current knowledge of the genetics of pancreatic cancer from its initiation within a normal cell until the time that is has disseminated to distant organs, many features of which can be extrapolated to other solid tumor types. The implications of these findings to personalize genome analyses of an individual patient's tumor are also discussed.Oncogene advance online publication, 18 February 2013; doi:10.1038/onc.2013.29.
    Oncogene 02/2013; · 7.36 Impact Factor
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    ABSTRACT: Cathepsin K is consistently and diffusely expressed in alveolar soft part sarcoma (ASPS) and a subset of translocation renal cell carcinomas (RCCs). However, cathepsin K expression in human neoplasms has not been systematically analyzed. We constructed tissue microarrays (TMA) from a wide variety of human neoplasms, and performed cathepsin K immunohistochemistry (IHC). Only 2.7% of 1,140 carcinomas from various sites exhibited cathepsin K labeling, thus suggesting that among carcinomas, cathepsin K labeling is highly specific for translocation RCC. In contrast to carcinomas, cathepsin K labeling was relatively common (54.6%) in the 414 mesenchymal lesions studied, including granular cell tumor, melanoma, and histiocytic lesions, but not paraganglioma, all of which are in the morphologic differential diagnosis of ASPS. Cathepsin K IHC can be helpful in distinguishing ASPS and translocation RCC from some but not all of the lesions in their differential diagnosis.
    American Journal of Clinical Pathology 02/2013; 139(2):151-9. · 2.88 Impact Factor
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  • Alvin Makohon-Moore, Christine A Iacobuzio-Donahue
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    ABSTRACT: Sequencing analyses have been invaluable in identifying the genes associated with pancreatic -carcinogenesis. However, whereas gene discovery related to carcinogenesis can be fairly straightforward, there are several additional aspects of experimental design that need to be considered when performing genetic analyses of metastatic disease. This chapter aims to review these issues and provide examples of the types of data generated.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 980:121-9.
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    ABSTRACT: Human pancreatic ductal adenocarcinoma (PDAC) is characterized by early systemic dissemination. Although RhoC has been implicated in cancer cell migration, the relevant underlying molecular mechanisms remain unknown. RhoC has been implicated in the enhancement of cancer cell migration and invasion, with actions which are distinct from RhoA (84% homology), and are possibly attributed to the divergent C-terminus domain. Here, we confirm that RhoC significantly enhances the migratory and invasive properties of pancreatic carcinoma cells. In addition, we show that RhoC over-expression decreases cancer cell adhesion and, in turn, accelerates cellular body movement and focal adhesion turnover, especially, on fibronectin-coated surfaces. Whilst RhoC over-expression did not alter integrin expression patterns, we show that it enhanced integrin α5β1 internalization and re-cycling (trafficking), an effect that was dependent specifically on the C-terminus (180-193 amino acids) of RhoC protein. We also report that RhoC and integrin α5β1 co-localize within the peri-nuclear region of pancreatic tumor cells, and by masking the CAAX motif at the C-terminal of RhoC protein, we were able to abolish this interaction in vitro and in vivo. Co-localization of integrin α5β1 and RhoC was demonstrable in invading cancer cells in 3D-organotypic cultures, and further mimicked in vivo analyses of, spontaneous human, (two distinct sources: operated patients and rapid autopsy programme) and transgenic murine (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre), pancreatic cancers. In both cases, co-localization of integrin α5β1 and RhoC correlated with poor differentiation status and metastatic potential. We propose that RhoC facilitates tumor cell invasion and promotes subsequent metastasis, in part, by enhancing integrin α5β1 trafficking. Thus, RhoC may serve as a biomarker and a therapeutic target.
    PLoS ONE 01/2013; 8(12):e81575. · 3.73 Impact Factor
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    ABSTRACT: BACKGROUND: The median age of pancreatic ductal adenocarcinoma (PDAC) patients is 71 years. PDAC rarely affects individuals under the age of 45. We investigated features of PDAC occurring in young patients (≤45 years) who underwent surgical resection in order to determine if any difference exists in comparison to elderly patients (≥70 years). METHODS: A retrospective analysis of patients with PDAC who were ≤ 45 years on the date of surgery between 1975 and 2009 was performed. This cohort was compared with PDAC patients whose ages were over 70 years on the date of surgery over the same time interval. Information reviewed included demographics, Charlson Age-Comorbidity Index (CACI), pathological staging, surgical management, and death or last follow-up. RESULTS: Seventy five patients with PDAC of age ≤ 45 years at surgery were identified. The reference group consisted of 870 patients with a median age of 75. The most common symptoms of young patients were jaundice (45 %), abdominal pain (32 %), or weight loss (33 %). This did not differ significantly from older patients. Among the younger patients, 7 (9 %) underwent total pancreatectomy, 60 (80 %) underwent pancreaticoduodenectomy, and 8 (11 %) had distal pancreatectomy. The distribution of type of surgery was similar between two groups. Fifty-two of the young patients (69 %) had an R0 resection and this did not differ from the older age group (n = 616; 71 %). The rate of lymph node positivity was 68 % for younger patients and 74 % for older patients (p = 0.27). Of the younger patients, 11, 13, 49, and 2 were classified as stage I, IIA, IIB, and III, respectively, and did not differ from the older age group. The median overall survival for the young patients cohort was 19 months (95 % CI 15-22 months) which is longer than 16 months (95 % CI 14-17 months) of the older group (p = 0.007). The actual 5- and 10- year survival in young age group (24 and 17 %) was longer than that in old age group (11 and 3 %) (p < 0.05). The median CACI of the younger patients was 0.5 and was lower than 4.1 of the older patients (p < 0.0001). CONCLUSIONS: The demographic, pathologic, and treatment characteristics of PDAC patients younger than 45 years were similar to those older than 70 years. Younger patients had fewer complications after curative resections. The better survival among younger patients is likely related to fewer comorbidities in this group. These findings will be useful in counseling young patients with resectable pancreatic cancer.
    Journal of Gastrointestinal Surgery 11/2012; · 2.36 Impact Factor
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    ABSTRACT: 10.1038/nature11547
    Nature 10/2012; advance online publication. · 38.60 Impact Factor

Publication Stats

9k Citations
1k Downloads
1,399.07 Total Impact Points

Institutions

  • 2003–2014
    • Johns Hopkins University
      • • Department of Pathology
      • • Department of Radiation Oncology and Molecular Radiation Sciences
      • • Department of Surgery
      Baltimore, Maryland, United States
  • 2000–2014
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, Maryland, United States
  • 2012
    • Dongnam Inst. of Radiological & Medical Sciences
      Ryōzan, South Gyeongsang, South Korea
    • Third Military Medical University
      Ch’ung-ch’ing-shih, Chongqing Shi, China
  • 2009–2012
    • Cambridge Institute for Medical Research
      Cambridge, England, United Kingdom
    • Northwestern University
      • Department of Radiology
      Evanston, IL, United States
  • 2011
    • Cancer Research UK Cambridge Institute
      Cambridge, England, United Kingdom
  • 2007
    • Johns Hopkins Bloomberg School of Public Health
      • Department of Biostatistics
      Baltimore, MD, United States
  • 2005–2006
    • Sapienza University of Rome
      Roma, Latium, Italy
    • University of Michigan
      • Department of Pathology
      Ann Arbor, MI, United States